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Classifications

Harrison's Part

Mechanistic Nosology

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Inheritance

1

Autosomal dominant HP:0000006

Heterozygous pathogenic variants (or whole-locus duplication) in APP, PSEN1, or PSEN2 are transmitted in an autosomal dominant pattern with essentially complete penetrance by the family-typical age at onset; each child of an affected carrier has a 50% risk. Non-penetrance before age 61 is uncommon for PSEN1 and APP variants, although PSEN2 variants have later and more variable onset.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:10441572 SUPPORT Human Clinical

"nonpenetrance at age <61 years is probably infrequent for PSEN1 or APP mutations"

Supports essentially complete penetrance of PSEN1 and APP variants by the expected age at onset, the defining feature of the dominant form.

PMID:22784036 SUPPORT Human Clinical

"As expected with an autosomal dominant inheritance pattern, approximately 50% of the asymptomatic participants were mutation carriers."

DIAN cohort composition directly reflects autosomal dominant transmission within at-risk pedigrees.

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Subtypes

4

PSEN1-associated ADAD MONDO:0011913

The most common and, on average, earliest-onset genetic form of ADAD. Missense variants in PSEN1 (chromosome 14, the AD3 locus) alter the catalytic subunit of gamma-secretase. PSEN1 variants account for the majority of mutation-positive ADAD families and are the source of the large Colombian (PSEN1 E280A) kindred. Atypical features - spastic paraparesis, myoclonus, seizures, cerebellar signs - are over-represented relative to APP and PSEN2 forms.

Show evidence (4 references)

PMID:7596406 SUPPORT Human Clinical

"Five different missense mutations have been found that cosegregate with early-onset familial Alzheimer's disease."

Original identification of PSEN1 (S182) missense variants cosegregating with early-onset familial Alzheimer disease, establishing this subtype.

PMID:10441572 SUPPORT Human Clinical

"In 19 (56%) of these families, we identified 16 distinct PSEN1 missense mutations"

Population-based French series quantifying PSEN1 as the largest genetic subgroup of autosomal dominant early-onset Alzheimer disease.

PMID:27777022 SUPPORT Human Clinical

"Age at onset differed by mutation, with a younger onset for individuals with PSEN1 mutations than for those with APP mutations"

Establishes the earlier mean age at onset of the PSEN1 subtype relative to APP, one of the defining features that justifies splitting these subtypes.

+ 1 more reference

APP-associated ADAD (point mutation) MONDO:0007088

Missense variants in APP, typically clustered around the secretase cleavage sites flanking the amyloid-beta peptide (e.g. the original V717I "London" variant), that shift APP processing toward Abeta42 or alter the aggregation properties of the peptide itself. Mean onset is somewhat later than PSEN1.

Show evidence (1 reference)

PMID:1671712 SUPPORT Human Clinical

"Here we demonstrate that in this kindred, which shows linkage to chromosome 21 markers, there is a point mutation in the APP gene. This mutation causes an amino-acid substitution (Val----Ile) close to the carboxy terminus of the beta-amyloid peptide."

The founding demonstration that an APP point mutation adjacent to the amyloid-beta peptide cosegregates with familial Alzheimer disease.

APP locus duplication (gene-dosage ADAD) MONDO:1060190

Copy-number gain of the whole APP locus on chromosome 21, causing ADAD purely by gene dosage rather than by altered peptide chemistry. It is the human genetic counterpart of the trisomy-21 Alzheimer phenotype and is characteristically accompanied by severe cerebral amyloid angiopathy with lobar haemorrhage. Note that the bound `subtype_term` is the closest available MONDO class: MONDO has no distinct term for APP locus duplication, so this subtype is anchored on the APP-related brain and vascular amyloidosis grouping, which captures the parenchymal-plus-vascular amyloid phenotype that distinguishes it. The `preferred_term` records the intended narrower concept.

Show evidence (1 reference)

PMID:16369530 SUPPORT Human Clinical

"We report duplication of the APP locus on chromosome 21 in five families with autosomal dominant early-onset Alzheimer disease (ADEOAD) and cerebral amyloid angiopathy (CAA)."

Defines the gene-dosage subtype and its cerebral amyloid angiopathy phenotype.

PSEN2-associated ADAD MONDO:0011743

The rarest of the three genetic forms, exemplified by the PSEN2 N141I founder variant of the Volga German kindreds. PSEN2 variants have significantly later and more variable age at onset than PSEN1 or APP variants, with onset sometimes extending into the seventh decade, so PSEN2 disease can be missed if dominant AD is assumed always to be early in onset.

Show evidence (1 reference)

PMID:7638622 SUPPORT Human Clinical

"A point mutation in STM2, resulting in the substitution of an isoleucine for an asparagine (N141l), was identified in affected people from Volga German AD kindreds."

Original identification of the PSEN2 (STM2) N141I founder variant in the Volga German ADAD kindreds.

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Mechanistic Hypotheses

2

Deterministic amyloid cascade: mutation-driven Abeta42 overproduction is the sufficient upstream cause of the entire ADAD pathophysiology

deterministic_amyloid_cascade CANONICAL

Evidence balance 2 support

In ADAD the amyloid cascade is not merely correlative. All three causal genes sit on the amyloid-beta biosynthetic axis; APP locus duplication shows a pure gene-dosage effect; and the DIAN cross-sectional cascade recovers exactly the predicted temporal order (CSF Abeta42 change, then fibrillar amyloid, then tau, then atrophy and hypometabolism, then cognition). This entry's pathophysiology chain is modelled on that ordering. Downstream causal edges that belong to this model opt in via hypothesis_groups: [deterministic_amyloid_cascade].

Retained as CANONICAL, but the cascade being sufficient to CAUSE the disease is not the same as amyloid removal being sufficient to TREAT it: the DIAN-TU double-blind period showed target engagement and biomarker change without cognitive benefit. See the qualitative-Abeta-profile alternative below and the open discussions.

Pathograph links

Pathogenic APP, PSEN1, or PSEN2 Germline Variant -> Altered Gamma-Secretase Processing of APP and Increased Abeta42 Fraction

Pathogenic APP, PSEN1, or PSEN2 Germline Variant -> Increased APP Substrate Dosage

Altered Gamma-Secretase Processing of APP and Increased Abeta42 Fraction -> Amyloid-beta Misfolding and Soluble Oligomer Formation

Increased APP Substrate Dosage -> Amyloid-beta Misfolding and Soluble Oligomer Formation

Amyloid-beta Misfolding and Soluble Oligomer Formation -> Fibrillar Amyloid-beta Plaque Formation and Deposition

Fibrillar Amyloid-beta Plaque Formation and Deposition -> Progressive Cortical Amyloid Accumulation

Progressive Cortical Amyloid Accumulation -> Site-Specific Soluble Tau Hyperphosphorylation

Site-Specific Soluble Tau Hyperphosphorylation -> Neurofibrillary Tangle Formation

Neurofibrillary Tangle Formation -> Neuronal Loss and Cortical Atrophy

Neuronal Loss and Cortical Atrophy -> Cerebral Glucose Hypometabolism

Neuronal Loss and Cortical Atrophy -> Progressive Dementia

Cerebral Glucose Hypometabolism -> Progressive Dementia

Show evidence (2 references)

PMID:22784036 SUPPORT Human Clinical

"the order and magnitude of changes indicate that genetic mutations cause increased Aβ42, which is followed by brain amyloidosis, tauopathy, brain atrophy, and decreased glucose metabolism"

Reports the observed sequence of pathophysiological change in ADAD carriers, the empirical backbone of this hypothesis.

PMID:16369530 SUPPORT Human Clinical

"Duplication of the APP locus, resulting in accumulation of amyloid-beta peptides, causes ADEOAD with CAA."

A pure gene-dosage cause is the strongest available human argument that increased amyloid-beta production alone is sufficient to cause the disease.

Qualitative Abeta profile, not simply the Abeta42:Abeta40 ratio, determines familial Alzheimer pathogenicity

qualitative_abeta_profile ALTERNATIVE

Evidence balance 2 support

An alternative reading of the proximal step. Kinetic dissection of gamma-secretase shows that familial Alzheimer disease mutations act through at least three distinct mechanisms and change the qualitative spectrum of Abeta products, not only the Abeta42 fraction - and that many PSEN variants paradoxically IMPAIR gamma-secretase rather than simply activating an Abeta42-generating gain of function. This matters therapeutically because it predicts that indiscriminate gamma-secretase inhibition (which failed clinically) is the wrong intervention, while modulation of the carboxypeptidase-like activity is the right one.

Show evidence (2 references)

PMID:22505025 SUPPORT In Vitro

"Here, we use kinetic studies to demonstrate that FAD mutations affect Aβ generation via three different mechanisms, resulting in qualitative changes in the Aβ profiles, which are not limited to Aβ42."

Directly states the qualitative-profile alternative to a simple Abeta42-quantity model.

PMID:22505025 SUPPORT In Vitro

"However, many PSEN mutations paradoxically impair γ-secretase and 'loss-of-function' mechanisms have also been postulated."

Notes the loss-of-function observation that a pure gain-of-toxic-function model does not accommodate. Marked PARTIAL because the sentence frames a postulate rather than establishing it.

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Discussions and Knowledge Gaps

3

Does complete, sustained removal of cerebral amyloid before symptom onset prevent or delay dementia in autosomal dominant Alzheimer disease carriers, or is the amyloid cascade causally sufficient to initiate the disease but no longer the rate-limiting step once tau pathology and neurodegeneration are established?

KNOWLEDGE GAP OPEN gap_adad_amyloid_removal_clinical_benefit

Attached to

pathophysiology#Progressive Cortical Amyloid Accumulation pathophysiology#Site-Specific Soluble Tau Hyperphosphorylation pathophysiology#Neurofibrillary Tangle Formation

ADAD is the cleanest available test of the amyloid hypothesis: causation is monogenic and deterministic, onset is predictable, and asymptomatic carriers can be treated years before symptoms. Yet the DIAN-TU-001 double-blind period showed unambiguous target engagement and downstream biomarker movement (plaques, total tau, phospho-tau181, neurofilament light chain) with NO cognitive benefit. The open-label extension hints at a benefit from long-term complete removal (hazard ratio 0.53 in the longest-treated group), but it is open-label with external controls, was terminated early by the sponsor, and the authors explicitly caution against over-reading it. The gap is therefore not whether amyloid causes ADAD - the genetics settle that - but whether amyloid removal is a sufficient intervention, and at what point in the cascade it stops being one. This is a genuine absence of evidence rather than a model-system translation problem, hence KNOWLEDGE_GAP.

Proposed experiments

Randomised, controlled primary-prevention trial of sustained complete amyloid removal in far-presymptomatic ADAD carriers

exp_adad_primary_prevention_full_removal

Enrol mutation carriers substantially earlier than DIAN-TU-001 did - before amyloid PET positivity, i.e. more than 15 years before expected symptom onset - and treat to and maintain amyloid-negative status with an internal randomised control arm rather than external controls. Primary endpoint: time to first CDR progression; key secondary: whether tau PET and CSF pT217 trajectories are prevented from ever diverging from non-carriers. A negative result under these conditions would constrain the amyloid hypothesis far more sharply than any trial to date.

Show evidence (1 reference)

PMID:40120616 SUPPORT Human Clinical

"Conclusions are limited due to the OLE design and use of external controls and need to be confirmed in long term trials."

The trialists themselves state that the question of clinical benefit from long-term amyloid removal in ADAD remains open.

By what mechanism does homozygous APOE3 Christchurch (R136S) uncouple very high cerebral amyloid burden from tau pathology, neurodegeneration, and cognitive onset in a PSEN1 E280A carrier, and can that mechanism be pharmacologically reproduced?

KNOWLEDGE GAP OPEN gap_adad_apoe_christchurch_resilience

Attached to

pathophysiology#Site-Specific Soluble Tau Hyperphosphorylation pathophysiology#Neurofibrillary Tangle Formation

A single PSEN1 E280A carrier homozygous for APOE3 Christchurch remained free of mild cognitive impairment until her seventies - three decades past the expected onset for that variant - despite unusually high brain amyloid. This is a human experiment showing that the amyloid-to-tau edge in this entry's pathograph is not obligate and can be broken downstream of amyloid. What is not known is which APOE function (lipidation, heparan sulfate proteoglycan binding, astrocytic or microglial signalling) is responsible, whether the effect generalises beyond a single individual and genotype, and whether an APOE-directed drug could reproduce it. Resolving this would identify a tau-arm target that acts even when amyloid removal has failed.

Show evidence (1 reference)

PMID:31686034 SUPPORT Human Clinical

"We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset."

Documents the resilience observation that defines this gap.

Given that familial Alzheimer disease variants alter the qualitative spectrum of amyloid-beta products through at least three distinct mechanisms - with many PSEN variants paradoxically IMPAIRING gamma-secretase rather than activating an Abeta42-generating gain of function - does a single Abeta42:Abeta40-ratio model adequately describe the proximal lesion across all ADAD genotypes?

KNOWLEDGE GAP OPEN gap_adad_gamma_secretase_mechanism_heterogeneity

Attached to

pathophysiology#Altered Gamma-Secretase Processing of APP and Increased Abeta42 Fraction

This entry's second pathophysiology node is written around an increased Abeta42 fraction, which is the standard formulation and is what the DIAN biomarker data are consistent with at the level of the whole cohort. But the kinetic dissection of gamma-secretase shows the proximal step is mechanistically heterogeneous across variants, so a per-genotype description may be required - which matters directly for drug design, since it is the reason indiscriminate gamma-secretase inhibitors failed while modulators remain of interest. Whether the mechanistic subclasses map onto differences in age at onset, biomarker trajectory, or treatment response in living carriers is untested.

Show evidence (1 reference)

PMID:22505025 SUPPORT In Vitro

"Overall, we provide a coherent explanation for the effect of different FAD mutations, demonstrating the importance of qualitative rather than quantitative changes in the Aβ products, and suggest fundamental improvements for current drug development efforts."

States the qualitative-versus-quantitative mechanistic question that this gap records as unresolved in vivo.

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Pathophysiology

15

Pathogenic APP, PSEN1, or PSEN2 Germline Variant

The proximal cause is a heterozygous germline pathogenic variant in one of three genes on the amyloid-beta biosynthetic axis: APP (the substrate, by missense variant near a secretase cleavage site or by whole-locus duplication), PSEN1, or PSEN2 (the catalytic subunit of the gamma-secretase that performs the final cleavage). More than 230 such variants are catalogued. Because the lesion is present from conception and acts constitutively, the entire downstream cascade is deterministic rather than probabilistic, and its timing is set largely by which variant is carried.

Deterministic amyloid cascade: mutation-driven Abeta42 overproduction is the sufficient upstream cause of the entire ADAD pathophysiology

APP hgnc:620 PSEN1 hgnc:9508 PSEN2 hgnc:9509

Downstream

Altered Gamma-Secretase Processing of APP and Increased Abeta42 Fraction

Increased APP Substrate Dosage

Show evidence (2 references)

PMID:24928124 SUPPORT Human Clinical

"Researchers have identified more than 230 different autosomal dominant Alzheimer disease (ADAD) mutations located in the genes for amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2)"

Establishes the three-gene allelic architecture that constitutes the trigger of this chain.

PMID:22784036 SUPPORT Human Clinical

"Mutations in one of three genes (APP, PSEN1, and PSEN2) have been identified that cause alterations in Aβ processing"

Links the germline variant directly to altered amyloid-beta processing, the next node.

Altered Gamma-Secretase Processing of APP and Increased Abeta42 Fraction

The qualitative arm of the proximal lesion, and the mechanism of the point-mutation subtypes (PSEN1, PSEN2, and APP missense). Pathogenic variants shift the sequential, carboxypeptidase-like gamma-secretase cleavage of the APP C-terminal fragment so that longer, more aggregation-prone amyloid-beta species are released, raising the Abeta42:Abeta40 ratio. This node is the ADAD-specific substitution for the amyloidogenesis module's generic "amyloidogenic precursor protein" trigger: the precursor is amyloid-beta, and what destabilises it is not aging or somatic mutation but a constitutive germline change in how it is generated. A mechanistic caveat is carried by the qualitative_abeta_profile hypothesis: kinetic work shows familial Alzheimer variants change the qualitative spectrum of Abeta products through several distinct mechanisms, not only the Abeta42 quantity, and many PSEN variants paradoxically impair the enzyme. The parallel quantitative (gene-dosage) arm is modelled as the sibling node "Increased APP Substrate Dosage" rather than folded in here, because copy-number gain of APP does not alter gamma-secretase processing and does not by itself raise the Abeta42:Abeta40 ratio - it raises total substrate.

Deterministic amyloid cascade: mutation-driven Abeta42 overproduction is the sufficient upstream cause of the entire ADAD pathophysiology

amyloid precursor protein catabolic process GO:0042987 ⚠ ABNORMAL amyloid-beta metabolic process GO:0050435 ↑ INCREASED

gamma-secretase endopeptidase activity GO:0004175 ⚠ ABNORMAL

Downstream

Amyloid-beta Misfolding and Soluble Oligomer Formation

Show evidence (2 references)

PMID:22505025 SUPPORT In Vitro

"FAD mutations increase the release of amyloid β (Aβ)42 relative to Aβ40 by an unknown, possibly gain-of-toxic-function, mechanism."

Directly states the shift in the Abeta42:Abeta40 ratio produced by familial Alzheimer disease mutations.

PMID:40120616 SUPPORT Human Clinical

"Dominantly inherited Alzheimer’s disease (DIAD) is caused by autosomal dominant mutations in presenilin-1 (PSEN1), presenilin-2 (PSEN2), or the amyloid-beta precursor protein (APP) genes that alter APP processing, resulting in overproduction of aggregation prone amyloid β"

States the causal step from variant to altered APP processing to overproduction of aggregation-prone amyloid-beta.

Increased APP Substrate Dosage

The quantitative (gene-dosage) arm of the proximal lesion, and the sibling of the gamma-secretase-processing node. Copy-number gain of the whole APP locus on chromosome 21 increases the amount of APP substrate presented to the normal secretase machinery, so more amyloid-beta is produced without any change in the enzyme or in the Abeta42:Abeta40 ratio. It is modelled as a distinct node precisely because it is the cleanest human dose-response argument for the amyloid hypothesis: no altered peptide chemistry is required, only more of the normal precursor. This node is arguably the more literal instance of the amyloidogenesis module's "amyloidogenic precursor protein" trigger, whose description names overproduction alongside mutation as a route to a metastable precursor. It converges with the qualitative arm on the shared downstream misfolding node, and its vascular emphasis is carried onward by the cerebral amyloid angiopathy node.

Deterministic amyloid cascade: mutation-driven Abeta42 overproduction is the sufficient upstream cause of the entire ADAD pathophysiology

APP hgnc:620

amyloid-beta metabolic process GO:0050435 ↑ INCREASED

Downstream

Amyloid-beta Misfolding and Soluble Oligomer Formation

Show evidence (1 reference)

PMID:16369530 SUPPORT Human Clinical

"Duplication of the APP locus, resulting in accumulation of amyloid-beta peptides, causes ADEOAD with CAA."

States the gene-dosage mechanism explicitly: duplication of the locus, not an altered peptide or enzyme, produces amyloid-beta accumulation and disease.

Amyloid-beta Misfolding and Soluble Oligomer Formation

The excess longer amyloid-beta species depart their soluble monomeric conformation and self-associate into beta-sheet-rich, proteotoxic soluble oligomers that both seed further aggregation and directly impair synaptic function. In ADAD this step is read out in vivo as the earliest detectable biomarker change: CSF Abeta42 concentration begins to fall about 25 years before expected symptom onset as the peptide is sequestered out of the soluble pool.

Deterministic amyloid cascade: mutation-driven Abeta42 overproduction is the sufficient upstream cause of the entire ADAD pathophysiology

protein folding GO:0006457 ⚠ ABNORMAL

cerebral cortex UBERON:0000956

Downstream

Fibrillar Amyloid-beta Plaque Formation and Deposition

Show evidence (1 reference)

PMID:22784036 SUPPORT Human Clinical

"Beginning 25 years before expected symptom onset, Aβ42 concentrations in the CSF in mutation carriers appeared to decline, as compared with those in noncarriers."

The falling soluble CSF Abeta42 pool is the in vivo signature of amyloid-beta leaving solution, and is the earliest measurable event in the ADAD cascade.

Fibrillar Amyloid-beta Plaque Formation and Deposition

Oligomers nucleate and elongate into insoluble cross-beta amyloid fibrils that deposit as extracellular parenchymal plaques. This is the ADAD instance of the amyloidogenesis module's central effector. It is directly imaged in living carriers with Pittsburgh compound B PET, which becomes abnormal about 15 years before expected symptom onset, and characteristically shows early and prominent neostriatal signal - a feature more typical of ADAD than of sporadic disease. No non-carrier in the DIAN cohort had a positive scan, so the genotype-to-deposition link is essentially deterministic.

Deterministic amyloid cascade: mutation-driven Abeta42 overproduction is the sufficient upstream cause of the entire ADAD pathophysiology

amyloid fibril formation GO:1990000 ↑ INCREASED

cerebral cortex UBERON:0000956

Downstream

Progressive Cortical Amyloid Accumulation

Cerebral Amyloid Angiopathy

Show evidence (2 references)

PMID:22784036 SUPPORT Human Clinical

"As compared with noncarriers, mutation carriers had significant amyloid deposition in the precuneus 15 years before expected symptom onset"

Times fibrillar amyloid deposition in living ADAD carriers and anchors it in the cascade.

PMID:22784036 SUPPORT Human Clinical

"There was no detectable amyloid deposition in noncarriers."

The absence of any deposition in non-carriers of the same pedigrees supports a deterministic genotype-to-fibril relationship.

Progressive Cortical Amyloid Accumulation

Fibril deposition continues to accumulate as a growing cortical amyloid burden, expanding monotonically as the carrier approaches expected symptom onset. This is the ADAD instance of the amyloidogenesis module's tissue-accumulation effector: it converts the molecular fibril-formation event into an organ-level structural lesion and is the quantity that anti-amyloid antibody therapy is designed to reverse.

Deterministic amyloid cascade: mutation-driven Abeta42 overproduction is the sufficient upstream cause of the entire ADAD pathophysiology

cerebral cortex UBERON:0000956

Downstream

Site-Specific Soluble Tau Hyperphosphorylation

Microglial Activation and Neuroinflammation

Show evidence (1 reference)

PMID:22784036 SUPPORT Human Clinical

"The amount of amyloid deposition in mutation carriers increased as a function of estimated years from expected symptom onset at least until clinical symptom onset."

Documents progressive, time-dependent accumulation of the tissue amyloid burden.

Cerebral Amyloid Angiopathy

A parallel vascular arm of the same deposition process: amyloid-beta, especially the shorter Abeta40 species, deposits in the walls of leptomeningeal and cortical arterioles. This is present to some degree in most ADAD but is a defining and severe feature of APP locus duplication, where it produces lobar intracerebral haemorrhage. Its clinical importance has grown because cerebral amyloid angiopathy is the substrate for amyloid-related imaging abnormalities during anti-amyloid antibody therapy.

cerebral cortex UBERON:0000956

Downstream

Vessel Wall Fragility and Intracerebral Haemorrhage

Show evidence (1 reference)

PMID:16369530 SUPPORT Human Clinical

"Brains from individuals with APP duplication showed abundant parenchymal and vascular deposits of amyloid-beta peptides."

Documents the vascular deposition arm alongside the parenchymal plaque arm in the gene-dosage subtype.

Vessel Wall Fragility and Intracerebral Haemorrhage

Amyloid infiltration of the arteriolar media and adventitia weakens the vessel wall, so cerebral amyloid angiopathy terminates in haemorrhagic events: lobar intracerebral haemorrhage and cortical microhaemorrhage. This is the clinical endpoint of the vascular arm, and it is also the substrate that makes anti-amyloid antibody therapy hazardous in this disease - amyloid-related imaging abnormalities (microhaemorrhage and vasogenic oedema) occurred in 53% of participants in the high-dose DIAN-TU gantenerumab extension. The evidence cited here is the trial's ARIA safety readout, which documents the haemorrhagic events themselves rather than the untreated natural history; the untreated-CAA haemorrhage claim in this node's description is not separately cited and should be treated as a described clinical association pending a properly quotable source.

cerebral cortex UBERON:0000956

Show evidence (1 reference)

PMID:40120616 SUPPORT Human Clinical

"Amyloid-related imaging abnormalities occurred in 53% (39/73) of participants: 47% (34/73) with microhaemorrhages, 30% (22/73) with oedema, and 6% (5/73) were associated with symptoms."

Documents haemorrhagic events (microhaemorrhage) and vasogenic oedema in ADAD carriers. Marked PARTIAL because these were observed under high-dose anti-amyloid antibody treatment, so the quote supports the vessel-wall vulnerability of this node but not the untreated haemorrhage rate.

Site-Specific Soluble Tau Hyperphosphorylation

The first tau event, roughly two decades before symptoms and separated from tangle formation by about 20 years. Cortical amyloid pathology triggers a stereotyped, ordered, site-specific rise in soluble tau phosphorylation occupancy measurable in CSF: threonine 217 first (about 21 years before expected onset, essentially in lockstep with rising amyloid PET signal), then threonine 181, then total tau, then threonine 205. This is the mechanistic bridge from the amyloid arm into the tau arm, and is why p-tau217 is now the leading amyloid-proximal fluid biomarker. It is modelled separately from tangle formation because the two events are ~20 years apart and, critically, move in OPPOSITE directions once tangles appear (see the downstream node).

Deterministic amyloid cascade: mutation-driven Abeta42 overproduction is the sufficient upstream cause of the entire ADAD pathophysiology

cortical pyramidal neuron CL:0000598

peptidyl-threonine phosphorylation GO:0018107 ↑ INCREASED

Downstream

Neurofibrillary Tangle Formation

Show evidence (2 references)

PMID:32161412 SUPPORT Human Clinical

"phosphorylation of tau at threonine 217 (pT217/T217) (which occurred at around −21 EYO) was followed by that of threonine 181 (pT181/T181) (−19 EYO), then t-tau increase (−17 EYO), then phosphorylation of tau at threonine 205 (pT205/T205) (−13 EYO)"

Establishes the ordered sequence of site-specific soluble tau hyperphosphorylation in ADAD and times it two decades before symptoms.

PMID:32161412 SUPPORT Human Clinical

"These results suggest that the events initially leading to increased tau phosphorylation in AD are probably related to aggregated Aβ pathology"

Supports the causal edge from cortical amyloid accumulation to soluble tau hyperphosphorylation.

Neurofibrillary Tangle Formation

Aggregation of hyperphosphorylated tau into intraneuronal paired helical filaments and neurofibrillary tangles. In ADAD this is a LATE event: tau-PET signal in mutation carriers rises only near the time of symptom onset, roughly two decades after soluble p-tau hyperphosphorylation begins. At that point soluble pT217 and pT181 occupancy paradoxically FALL - plausibly through sequestration into the aggregates - while total tau keeps rising, so the soluble and aggregated tau species diverge. That opposite direction of change is the reason this is a separate node from the upstream hyperphosphorylation event, and it is what makes stage-blind interpretation of a p-tau result unsafe.

Deterministic amyloid cascade: mutation-driven Abeta42 overproduction is the sufficient upstream cause of the entire ADAD pathophysiology

cortical pyramidal neuron CL:0000598

neurofibrillary tangle assembly GO:1902988 ↑ INCREASED

cerebral cortex UBERON:0000956

Downstream

Neuronal Loss and Cortical Atrophy

Show evidence (2 references)

PMID:32161412 SUPPORT Human Clinical

"First, we confirmed that tau-PET SUVR in mutation carriers only increased near the time of symptom onset"

Times aggregated tangle pathology to near symptom onset, ~20 years after the upstream soluble hyperphosphorylation node.

PMID:32161412 SUPPORT Human Clinical

"Second, pT217/T217 and pT181/T181 began to decline significantly near the time of symptom onset, while phosphorylation at pT205/T205 slowed and t-tau levels continued to increase."

Documents the opposite direction of change (falling soluble p-tau as tangles form) that requires this to be a node distinct from the upstream hyperphosphorylation event.

Microglial Activation and Neuroinflammation

Plaque-associated microglia and reactive astrocytes mount a chronic innate immune response around amyloid deposits. In ADAD this arm is directly measurable and pharmacologically reversible: CSF markers of microglial activity, other inflammatory markers, and astrocyte activation all improved under gantenerumab treatment in DIAN-TU, showing this is a process downstream of amyloid rather than an independent one. It is modelled separately from synaptic loss, which is its consequence rather than the same event.

microglial cell CL:0000129 astrocyte CL:0000127

neuroinflammatory response GO:0150076 ↑ INCREASED

Downstream

Synaptic Loss

Show evidence (1 reference)

PMID:40120616 SUPPORT Human Clinical

"gantenerumab treatment significantly improved multiple CSF measures of synaptic degeneration, microglial activity, other inflammatory markers, and astrocyte activation markers"

Shows that the microglial, astrocytic, and inflammatory markers are downstream of amyloid in ADAD and move when amyloid is removed.

Synaptic Loss

Loss of synapses in the neuropil surrounding plaques, driven both by proteotoxic soluble amyloid-beta oligomers and by microglial synaptic pruning. Synaptic loss is the structural correlate that best tracks cognitive impairment in Alzheimer disease, and it sits downstream of - not alongside - the microglial/inflammatory response. Like that response, CSF measures of synaptic degeneration improved under gantenerumab in DIAN-TU.

neuron CL:0000540

synapse organization GO:0050808 ⚠ ABNORMAL synapse pruning GO:0098883 ↑ INCREASED

Downstream

Neuronal Loss and Cortical Atrophy

Show evidence (1 reference)

PMID:40120616 SUPPORT Human Clinical

"gantenerumab treatment significantly improved multiple CSF measures of synaptic degeneration"

Documents synaptic degeneration as a measurable, amyloid-downstream, treatment-responsive process in ADAD.

Neuronal Loss and Cortical Atrophy

Neuronal death producing measurable structural loss. Increased atrophy of the bilateral hippocampi is detectable on volumetric MRI about 15 years before expected symptom onset, with the precuneus and medial temporal structures affected earliest - matching the topography of early amyloid deposition. This is modelled separately from cerebral hypometabolism, which the same DIAN analysis times five years later.

Deterministic amyloid cascade: mutation-driven Abeta42 overproduction is the sufficient upstream cause of the entire ADAD pathophysiology

neuron CL:0000540

neuron apoptotic process GO:0051402 ↑ INCREASED

hippocampal formation UBERON:0002421 cerebral cortex UBERON:0000956

Downstream

Cerebral Glucose Hypometabolism

Progressive Dementia

Show evidence (1 reference)

PMID:22784036 SUPPORT Human Clinical

"Increased atrophy of bilateral hippocampi was detected in mutation carriers 15 years before expected symptom onset"

Times the structural neurodegeneration node at about 15 years before expected symptom onset.

Cerebral Glucose Hypometabolism

Regional failure of cerebral glucose utilisation, measured by FDG-PET, in territories losing synapses and neurons. In DIAN carriers a significant decrease in precuneus metabolism appears about 10 years before expected symptom onset - five years after hippocampal atrophy becomes detectable, which is why it is a distinct node rather than being bundled with atrophy.

Deterministic amyloid cascade: mutation-driven Abeta42 overproduction is the sufficient upstream cause of the entire ADAD pathophysiology

cerebral cortex UBERON:0000956

Downstream

Progressive Dementia

Show evidence (1 reference)

PMID:22784036 SUPPORT Human Clinical

"A significant decrease in cerebral metabolism in the precuneus was detected in mutation carriers 10 years before expected symptom onset"

Times cerebral hypometabolism at about 10 years before expected symptom onset, distinct from the 15-year atrophy timing of the upstream node.

Progressive Dementia

The clinical end state, and the ADAD instance of the amyloidogenesis module's organ-dysfunction consequence, with the brain as the affected organ. Impaired episodic memory appears about 10 years before expected symptom onset, global cognitive impairment about 5 years before, and criteria for mild dementia are met about 3 years after expected onset, with progression to death over roughly a decade. Non-amnestic and neurological features (myoclonus, seizures, spastic paraparesis) are more common than in late-onset disease.

Show evidence (1 reference)

PMID:22784036 SUPPORT Human Clinical

"Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset."

Times the clinical consequence node relative to the rest of the cascade.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

12

Nervous System 8

Progressive Dementia OBLIGATE HP:0000726

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:22784036 SUPPORT Human Clinical

"patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset"

Documents progression to dementia in mutation carriers at a predictable time relative to expected onset. Frequency is OBLIGATE because ADAD variants are essentially fully penetrant for dementia by the family-expected age (see the inheritance block and PMID:10441572).

Episodic Memory Impairment VERY_FREQUENT HP:0002354

Course: PROGRESSIVE

Show evidence (3 references)

PMID:22784036 SUPPORT Human Clinical

"Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset."

Directly establishes impaired episodic memory in ADAD mutation carriers and times it at about 10 years before expected symptom onset.

PMID:27777022 SUPPORT Human Clinical

"71 (84%) individuals with PSEN1 mutations and 35 (97%) with APP mutations presented with amnestic symptoms"

Supports the VERY_FREQUENT band directly: 84% of PSEN1 and 97% of APP carriers presented with amnestic symptoms, both within the 80-100% range, so the frequency is evidenced by quoted counts rather than inferred.

PMID:22784036 SUPPORT Human Clinical

"The typical clinical presentation is progressive loss of memory and cognitive function, ultimately leading to a loss of independence"

Establishes progressive memory loss as the typical presenting deficit of Alzheimer disease, the clinical form the ADAD deficit takes.

Cerebral Atrophy HP:0002059

Course: PROGRESSIVE

`frequency:` deliberately omitted. The cited evidence establishes that hippocampal atrophy is detectable at the group level in carriers 15 years before onset, which is a timing claim rather than a proportion, and docs/frequency-evidence-guidelines.md prefers omission over a band inferred from reasoning.

Show evidence (1 reference)

PMID:22784036 SUPPORT Human Clinical

"Increased atrophy of bilateral hippocampi was detected in mutation carriers 15 years before expected symptom onset"

Documents structural atrophy and its preclinical timing. Frequency VERY_FREQUENT because atrophy was detectable at the group level in carriers well before symptoms and is universal by the dementia stage.

Neurofibrillary Tangles HP:0002185

`frequency:` deliberately omitted. Neurofibrillary tangles are a required neuropathological criterion for Alzheimer disease, which would make OBLIGATE correct by definition, but the cited snippet reports the timing of tau-PET signal rather than a proportion of carriers, so the band would be inferred rather than evidenced.

Show evidence (1 reference)

PMID:32161412 SUPPORT Human Clinical

"First, we confirmed that tau-PET SUVR in mutation carriers only increased near the time of symptom onset"

Documents aggregated tangle pathology in ADAD carriers and its late timing relative to the soluble p-tau changes. Frequency is OBLIGATE because neurofibrillary tangles are a required neuropathological criterion for Alzheimer disease, which all ADAD carriers develop.

Myoclonus HP:0001336

`frequency:` is deliberately omitted even though the source reports 47% (PSEN1) and 33% (APP), which would map to FREQUENT. The reference validator strips square-bracketed content from snippets, so the bracketed percentages in the source sentence cannot be quoted verbatim, and per docs/frequency-evidence-guidelines.md a band should be omitted rather than asserted on a snippet that does not carry the number. The figures are recorded here and in the description, both attributable to PMID:27777022.

Show evidence (1 reference)

PMID:27777022 SUPPORT Human Clinical

"Myoclonus and seizures were the most common additional neurological features"

Establishes myoclonus as the most common additional neurological feature of ADAD in the largest single-centre series.

Seizures OCCASIONAL HP:0001250

Show evidence (1 reference)

PMID:27777022 SUPPORT Human Clinical

"which affected around a quarter of the patients in each group"

Quantifies seizures at around a quarter of symptomatic ADAD carriers in both the PSEN1 and APP groups, which falls in the OCCASIONAL band (5-29%), so the frequency is directly evidenced rather than inferred.

Cerebellar Signs Ataxia HP:0001251

`frequency:` omitted - the reported 4% appears only inside square brackets in the source sentence, which the reference validator strips from snippets.

Show evidence (1 reference)

PMID:27777022 SUPPORT Human Clinical

"A number of patients with PSEN1 mutations had ... cerebellar ... signs."

Documents cerebellar signs in PSEN1 mutation carriers.

Atypical Non-Amnestic Cognitive Presentation OCCASIONAL Atypical behavior HP:0000708

Show evidence (1 reference)

PMID:27777022 SUPPORT Human Clinical

"71 (84%) individuals with PSEN1 mutations and 35 (97%) with APP mutations presented with amnestic symptoms, making atypical cognitive presentations significantly more common in PSEN1 mutation carriers"

The complement of the quoted amnestic proportions gives 16% non-amnestic presentation in PSEN1 and 3% in APP; the PSEN1 figure falls in the OCCASIONAL band (5-29%), so the frequency is derived from the quoted counts rather than inferred. The bound HP term is broader than the intended concept - HPO has no single term for "non-amnestic cognitive presentation" - so the preferred_term carries the intended meaning.

Other 4

Amyloid-beta Plaque Deposition OBLIGATE Deposits immunoreactive to beta-amyloid protein HP:0003791

Show evidence (2 references)

PMID:16369530 SUPPORT Human Clinical

"Brains from individuals with APP duplication showed abundant parenchymal and vascular deposits of amyloid-beta peptides."

Neuropathological confirmation of abundant amyloid-beta deposits in ADAD brain.

PMID:22784036 SUPPORT Human Clinical

"our data suggest that amyloid deposition will develop and be detectable in all persons with a mutation while still asymptomatic, whereas no noncarriers had positive scans for amyloid deposition"

Directly supports the OBLIGATE frequency: amyloid deposition is expected in all mutation carriers and in no non-carriers.

Cerebral Amyloid Angiopathy HP:0011970

Show evidence (1 reference)

PMID:16369530 SUPPORT Human Clinical

"We report duplication of the APP locus on chromosome 21 in five families with autosomal dominant early-onset Alzheimer disease (ADEOAD) and cerebral amyloid angiopathy (CAA)."

Documents cerebral amyloid angiopathy as a defining feature of the APP duplication subtype. No `frequency` is asserted because the source reports a five-family series rather than a frequency band.

Pyramidal Signs Abnormal pyramidal sign HP:0007256

`frequency:` omitted for the same reason as myoclonus - the source reports 25% but only inside square brackets, which the reference validator strips, so the band cannot be carried by a verbatim snippet.

Show evidence (1 reference)

PMID:27777022 SUPPORT Human Clinical

"A number of patients with PSEN1 mutations had ... pyramidal ... signs."

Documents pyramidal signs specifically in PSEN1 mutation carriers, supporting both the phenotype and its PSEN1 subtype restriction.

Extrapyramidal Signs Abnormality of extrapyramidal motor function HP:0002071

`frequency:` omitted - the reported 14% appears only inside square brackets in the source sentence, which the reference validator strips from snippets.

Show evidence (1 reference)

PMID:27777022 SUPPORT Human Clinical

"A number of patients with PSEN1 mutations had ... extrapyramidal ... signs."

Documents extrapyramidal signs in PSEN1 mutation carriers.

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Genetic Associations

4

PSEN1 (Pathogenic missense variants (autosomal dominant, deterministic))

Gene: PSEN1 hgnc:9508

Show evidence (1 reference)

PMID:7596406 SUPPORT Human Clinical

"Genetic linkage studies have mapped a locus (AD3) associated with susceptibility to a very aggressive form of Alzheimer's disease to chromosome 14q24.3."

Maps and identifies the PSEN1 (AD3) locus underlying aggressive early-onset familial Alzheimer disease.

APP (Pathogenic missense variants near the secretase cleavage sites, and whole-locus duplication (autosomal dominant, deterministic))

Gene: APP hgnc:620

Show evidence (2 references)

PMID:1671712 SUPPORT Human Clinical

"This suggests that some cases of AD could be caused by mutations in the APP gene."

Original demonstration of APP as a causal gene for familial Alzheimer disease.

PMID:16369530 SUPPORT Human Clinical

"Duplication of the APP locus, resulting in accumulation of amyloid-beta peptides, causes ADEOAD with CAA."

Establishes gene dosage of APP as sufficient to cause the disease, a dose-response argument for the amyloid mechanism.

PSEN2 (Pathogenic missense variants (autosomal dominant, deterministic))

Gene: PSEN2 hgnc:9509

Show evidence (1 reference)

PMID:7638622 SUPPORT Human Clinical

"The presence of missense mutations in AD subjects in two highly similar genes strongly supports the hypothesis that mutations in both are pathogenic."

Establishes PSEN2 (STM2) as a second presenilin gene causal for familial Alzheimer disease.

APOE (Onset-modifying locus; the R136S "Christchurch" variant is protective)

Gene: APOE hgnc:613 relationship_type: MODIFIER

Show evidence (1 reference)

PMID:31686034 SUPPORT Human Clinical

"The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements."

Documents a protective APOE genotype uncoupling amyloid burden from tau, neurodegeneration, and clinical onset in an ADAD carrier.

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Medical Actions

5

Gantenerumab

Action: Pharmacotherapy NCIT:C15986

Agent: gantenerumab NCIT:C88580

A fully human IgG1 monoclonal antibody that binds aggregated amyloid-beta and promotes microglial plaque clearance. Gantenerumab is the anti-amyloid therapy with the most ADAD-specific evidence: in the DIAN-TU-001 double-blind period it engaged its target and significantly lowered amyloid plaques, CSF total tau and phospho-tau181, and attenuated the rise in neurofilament light chain, but did not slow cognitive decline. In the subsequent 3-year open-label extension at substantially higher doses, PiB-PET SUVR fell by 0.71 and the longest-treated participants showed a hazard ratio for CDR-SB progression of 0.53, suggesting - but not establishing - that long-term complete amyloid removal may delay symptom onset. Amyloid-related imaging abnormalities were common (53% overall in the extension). Development was discontinued for lack of a regulatory path, so this agent is not clinically available; its value here is as the definitive test of the amyloid hypothesis in the deterministic form of the disease.

Mechanism Target:

INHIBITS Progressive Cortical Amyloid Accumulation — Binds and opsonises aggregated amyloid-beta, driving microglial removal of established plaques and thereby reducing the accumulated cortical amyloid burden.

Show evidence (4 references)

PMID:34155411 SUPPORT Human Clinical

"Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain."

Demonstrates target engagement and downstream biomarker effect in ADAD mutation carriers.

PMID:34155411 REFUTE Human Clinical

"Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD."

Refutes a clinical (cognitive) benefit of gantenerumab in symptomatic ADAD in the double-blind period, despite biomarker engagement.

PMID:40120616 SUPPORT Human Clinical

"Partial or short-term amyloid removal did not show significant clinical effects. However, long-term full amyloid removal potentially delayed symptom onset and dementia progression."

Supports a possible clinical benefit of sustained complete amyloid removal in ADAD. Marked PARTIAL because the finding comes from an open-label extension with external controls, which the authors themselves flag as limiting.

+ 1 more reference

Solanezumab

Action: Pharmacotherapy NCIT:C15986

Agent: solanezumab NCIT:C88585

A humanised monoclonal antibody directed at the mid-domain of SOLUBLE monomeric amyloid-beta rather than aggregated plaque. Tested head-to-head with gantenerumab in DIAN-TU-001. It engaged its soluble target but produced no downstream biomarker benefit and was associated with greater cognitive decline on some measures - an informative negative result arguing that clearing soluble monomer is not therapeutically equivalent to clearing aggregated amyloid. Included here for that mechanistic contrast, not as a therapy.

Show evidence (1 reference)

PMID:34155411 REFUTE Human Clinical

"The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers."

Refutes clinical or biomarker benefit of solanezumab in ADAD and supports the aggregate-versus-monomer distinction.

Lecanemab

Action: Pharmacotherapy NCIT:C15986

Agent: lecanemab NCIT:C175105

A humanised IgG1 monoclonal antibody with high affinity for amyloid-beta protofibrils, approved for early symptomatic sporadic Alzheimer disease on the basis of the Clarity AD trial, where it lowered amyloid burden and modestly slowed decline. IMPORTANT SCOPE CAVEAT: the pivotal evidence is in sporadic early Alzheimer disease, NOT in autosomal dominant disease; efficacy specifically in ADAD carriers has not been established, and the failure of gantenerumab and solanezumab to move cognition in DIAN-TU-001 means extrapolation should not be assumed. It is listed here because protofibril-directed removal of aggregated amyloid is the same mechanistic strategy as gantenerumab and is the class currently available to clinicians caring for ADAD carriers.

Mechanism Target:

INHIBITS Progressive Cortical Amyloid Accumulation — Binds amyloid-beta protofibrils and promotes clearance of aggregated amyloid, reducing cortical amyloid burden.

Show evidence (1 reference)

PMID:36449413 SUPPORT Human Clinical

"Lecanemab reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events."

Establishes amyloid lowering and modest clinical benefit in EARLY SPORADIC Alzheimer disease. Marked PARTIAL because the trial population was not autosomal dominant carriers, so it supports the mechanism class but not ADAD-specific efficacy.

Donanemab

Action: Pharmacotherapy NCIT:C15986

Agent: donanemab NCIT:C166484

A monoclonal antibody targeting the N-terminal pyroglutamate-modified amyloid-beta epitope found only in established plaque, approved for early symptomatic sporadic Alzheimer disease after the TRAILBLAZER-ALZ 2 trial. The same scope caveat as lecanemab applies: the pivotal evidence is in sporadic disease and ADAD-specific efficacy is unestablished.

Mechanism Target:

INHIBITS Progressive Cortical Amyloid Accumulation — Binds pyroglutamate-modified amyloid-beta present only in deposited plaque, driving microglial plaque removal.

Show evidence (1 reference)

PMID:37459141 SUPPORT Human Clinical

"Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population."

Establishes clinical benefit in EARLY SPORADIC Alzheimer disease. Marked PARTIAL because the trial did not enrol autosomal dominant carriers.

Predictive Genetic Testing and Genetic Counselling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Because ADAD is deterministic and 50% of a carrier's children are at risk, formal genetic counselling with the option of presymptomatic predictive testing is a core, non-pharmacological part of care. It also enables reproductive options and, practically, is a prerequisite for participation in secondary-prevention trials such as the DIAN-TU open-label extension, which required participants to know their mutation status.

Show evidence (1 reference)

PMID:40120616 SUPPORT Human Clinical

"For inclusion in the OLE, participants at risk for DIAD had participated in the double-blind period of DIAN-TU-001 and were required to know their mutation status."

Documents genotype disclosure - and therefore predictive genetic testing with counselling - as an operational requirement of ADAD trial participation.

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Biochemical Markers

7

CSF Amyloid-beta 42 (Decreased)

Context: Cerebrospinal fluid. The earliest measurable biomarker change in ADAD: CSF Abeta42 concentration begins to decline about 25 years before expected symptom onset as the peptide is sequestered into plaques, reaching clearly abnormal levels about 10 years before onset. The magnitude of the decrease is similar to that seen in sporadic late-onset disease.

Show evidence (1 reference)

PMID:22784036 SUPPORT Human Clinical

"Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset."

Establishes the direction and preclinical timing of the CSF Abeta42 change in ADAD.

CSF Amyloid-beta 42/40 Ratio (Decreased)

Context: Cerebrospinal fluid. The ratio is preferred over Abeta42 alone because it normalises for individual differences in total amyloid-beta production, which matters especially in APP duplication carriers. It is used in DIAN as the dichotomising amyloid-status variable.

Reference Ranges

0.0776– 1 (DIAN autosomal dominant Alzheimer disease cohort; mass-spectrometry CSF assay. Values at or above the bound are amyloid-negative; values below are amyloid-positive.)

Amyloid positive (–0.0776 1) → Decreased amyloid beta 42 peptide CSF concentration Amyloid negative (0.0776– 1)

Amyloid positive: CSF amyloid-beta 42/40 ratio below the cutoff indicates cerebral amyloid pathology.

Amyloid negative: CSF amyloid-beta 42/40 ratio at or above the cutoff indicates no significant cerebral amyloid pathology.

Dimensionless ratio, so the UCUM unit is "1" and there is no upper bound. No `loinc_term` is asserted: this curator could not verify a LOINC code for the CSF Abeta42/Abeta40 ratio against an authoritative source, and LOINC is not in the dismech OAK validation config (conf/oak_config.yaml), so an unverified code would be an undetectable error. Adding the verified LOINC code later is a welcome improvement.

Show evidence (1 reference)

PMID:32161412 SUPPORT Human Clinical

"classifying participants as amyloid positive (Aβ 42/40 ≥ 0.0776) or amyloid negative (Aβ 42/40 < 0.0776)"

Source of the 0.0776 amyloid-positivity cutoff used to define these bands.

Show evidence (1 reference)

PMID:32161412 SUPPORT Human Clinical

"When using CSF-soluble Aβ in DIAD to determine abnormal amyloid levels, we found the same order for the soluble tau measures in classifying participants as amyloid positive (Aβ 42/40 ≥ 0.0776) or amyloid negative (Aβ 42/40 < 0.0776)"

Documents the use of the CSF Abeta42/40 ratio with an explicit cutoff to define amyloid status in the DIAN ADAD cohort.

CSF Phospho-tau 217 (pT217/T217 occupancy) (Increased)

Context: Cerebrospinal fluid, measured as phosphorylation occupancy by mass spectrometry. The most amyloid-proximal tau marker: occupancy begins to rise about 21 years before expected symptom onset, essentially in lockstep with the first rise in amyloid PET signal, and near-perfectly discriminates amyloid-positive from amyloid-negative carriers. It then falls again around symptom onset as tangle pathology accumulates, so its trajectory is non-monotonic and must be interpreted with disease stage.

Show evidence (2 references)

PMID:32161412 SUPPORT Human Clinical

"There is a near-perfect association with Aβ pathology for pT217/T217 (purple; AUC = 0.97)."

Quantifies the discriminative performance of CSF pT217 occupancy for amyloid pathology in ADAD.

PMID:32161412 SUPPORT Human Clinical

"Second, pT217/T217 and pT181/T181 began to decline significantly near the time of symptom onset, while phosphorylation at pT205/T205 slowed and t-tau levels continued to increase."

Documents the non-monotonic trajectory that complicates stage-blind interpretation of pT217 and pT181.

CSF Phospho-tau 181 (Increased)

Context: Cerebrospinal fluid. Rises about 19 years before expected symptom onset, shortly after pT217. It is the tau marker with the longest clinical assay history and was one of the biomarkers significantly lowered by gantenerumab in the DIAN-TU trial, making it a usable pharmacodynamic readout in ADAD.

Show evidence (1 reference)

PMID:34155411 SUPPORT Human Clinical

"Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain."

Demonstrates CSF phospho-tau181 as an amyloid-downstream, treatment-responsive biomarker in ADAD.

CSF Total Tau (Increased)

Context: Cerebrospinal fluid. Rises about 15-17 years before expected symptom onset and continues to increase monotonically as cognition declines, making it the tau measure that tracks neurodegeneration most directly.

Show evidence (1 reference)

PMID:22784036 SUPPORT Human Clinical

"In mutation carriers, levels of tau in the CSF were increased 15 years before expected symptom onset"

Times the rise in CSF total tau within the ADAD biomarker cascade.

Fibrillar Amyloid PET (PiB) Standardised Uptake Value Ratio (Increased)

Context: Imaging biomarker (11C-Pittsburgh compound B PET), reported as a cortical composite standardised uptake value ratio. Becomes abnormal about 15 years before expected symptom onset; no DIAN non-carrier had a positive scan. It is the primary pharmacodynamic endpoint for anti-amyloid antibody therapy in ADAD.

Reference Ranges

–1.25 1 (DIAN cohort; cortical PiB-PET composite. The normal cutoff was derived from the 95th percentile of asymptomatic non-carriers.)

Amyloid negative (–1.25 1) Amyloid positive (1.25– 1) → Deposits immunoreactive to beta-amyloid protein

Amyloid negative: Cortical PiB-PET SUVR below the DIAN cutoff indicates no significant fibrillar amyloid burden.

Amyloid positive: Cortical PiB-PET SUVR at or above the DIAN cutoff indicates significant fibrillar cerebral amyloid pathology.

Dimensionless uptake ratio, so the UCUM unit is "1" and there is no meaningful lower bound. No `loinc_term` is asserted because amyloid PET SUVR is an imaging-derived quantity rather than a LOINC-coded clinical laboratory analyte.

Show evidence (1 reference)

PMID:40120616 SUPPORT Human Clinical

"The DIAN normal cutoff was 1.25 PiB-PET SUVR"

Source of the 1.25 SUVR amyloid-positivity threshold used to define these bands.

Show evidence (1 reference)

PMID:22784036 SUPPORT Human Clinical

"Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset."

Times the amyloid PET biomarker within the preclinical cascade.

CSF Neurofilament Light Chain (Increased)

Context: Cerebrospinal fluid (and plasma). A non-specific marker of axonal neurodegeneration whose rate of increase tracks disease progression in ADAD and was attenuated by gantenerumab, providing evidence that anti-amyloid treatment slows the neurodegenerative arm even where cognitive endpoints did not move.

Show evidence (1 reference)

PMID:34155411 SUPPORT Human Clinical

"attenuated increases of neurofilament light chain"

Documents neurofilament light chain as a treatment-responsive neurodegeneration marker in ADAD.

🔬

Diagnosis

4

Molecular Genetic Testing of APP, PSEN1, and PSEN2 (Definitive)

The definitive diagnostic test. Because the disease is monogenic and deterministic, identifying a pathogenic variant in one of the three genes establishes the diagnosis in a symptomatic proband and, in an asymptomatic at-risk relative, is predictive rather than merely probabilistic. More than 230 pathogenic variants are catalogued across the three genes, and the specific variant is the strongest single predictor of age at onset, so genotype has direct prognostic value. Testing should be offered with formal genetic counselling (see the Predictive Genetic Testing and Genetic Counselling treatment entry) and is a practical prerequisite for entry into secondary-prevention trials. A negative result does not exclude the disease: in a stringently ascertained population series no PSEN1, PSEN2, or APP variant was identified in 10 of 34 ADEOAD families, so roughly 29% of clinically dominant early-onset pedigrees remain genetically unexplained.

Show evidence (3 references)

PMID:24928124 SUPPORT Human Clinical

"Researchers have identified more than 230 different autosomal dominant Alzheimer disease (ADAD) mutations located in the genes for amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2)"

Defines the three-gene testing panel that constitutes the definitive molecular diagnosis.

PMID:10441572 SUPPORT Human Clinical

"In the 10 remaining ADEOAD families and in 9 additional autosomal dominant Alzheimer disease families that did not fulfill the strict criteria for ADEOAD, no PSEN1, PSEN2, or APP mutation was identified."

Documents the diagnostic limitation of the three-gene panel: a substantial minority of clinically dominant early-onset pedigrees are variant-negative. Marked PARTIAL because it qualifies rather than supports the test's sensitivity.

PMID:27777022 SUPPORT Human Clinical

"This highlights the importance of considering genetic testing in young patients with dementia and additional neurological features in order to appropriately diagnose and treat their symptoms"

States the clinical indication for genetic testing: young-onset dementia with additional neurological features (myoclonus, seizures, pyramidal signs).

Pedigree Criterion for Autosomal Dominant Early-Onset Alzheimer Disease

The clinical/pedigree definition used to ascertain ADEOAD before or without molecular confirmation: at least three early-onset (age <61 years) Alzheimer disease cases across three generations. This is the stringent epidemiological criterion behind this entry's prevalence record. It is deliberately conservative and will miss de novo variants, small pedigrees, non-paternity, and the later-onset PSEN2 families; it is an ascertainment criterion, not a substitute for molecular testing.

Show evidence (1 reference)

PMID:10441572 SUPPORT Human Clinical

"EOAD was defined as onset of disease at age <61 years, and ADEOAD was defined as the occurrence of at least three EOAD cases in three generations."

States the pedigree criterion verbatim, including the age threshold and the three-generation requirement.

CSF Amyloid and Tau Biomarker Profile

Markers: CSF Amyloid-beta 42/40 Ratio; CSF Phospho-tau 217 (pT217/T217 occupancy); CSF Phospho-tau 181; CSF Total Tau

Cerebrospinal fluid Abeta42/Abeta40 ratio plus phosphorylated and total tau. In ADAD these establish that the Alzheimer pathological process is under way and stage it, rather than establishing the genetic diagnosis: the Abeta42/40 ratio dichotomises amyloid status at 0.0776 in the DIAN cohort, and site-specific p-tau (pT217, pT181) rises in a stereotyped order two decades before symptoms. See the corresponding `biochemical` entries for the reference ranges and interpretation bands. Note that p-tau trajectories are non-monotonic - pT217 and pT181 fall again around symptom onset - so a result must be read together with disease stage.

Show evidence (2 references)

PMID:32161412 SUPPORT Human Clinical

"classifying participants as amyloid positive (Aβ 42/40 ≥ 0.0776) or amyloid negative (Aβ 42/40 < 0.0776)"

Documents the CSF Abeta42/40 cutoff used to dichotomise amyloid status in the DIAN ADAD cohort.

PMID:32161412 SUPPORT Human Clinical

"There is a near-perfect association with Aβ pathology for pT217/T217 (purple; AUC = 0.97)."

Quantifies the diagnostic performance of CSF pT217 occupancy against amyloid pathology in ADAD.

Amyloid PET Imaging

Markers: Fibrillar Amyloid PET (PiB) Standardised Uptake Value Ratio

11C-Pittsburgh compound B (or an 18F equivalent) PET, reported as a cortical composite standardised uptake value ratio with the DIAN normal cutoff at 1.25. In ADAD its diagnostic value is unusually high because carrier status and scan status are almost perfectly concordant: amyloid deposition becomes detectable about 15 years before expected symptom onset in carriers and no non-carrier in the DIAN cohort had a positive scan. It is also the primary pharmacodynamic endpoint for anti-amyloid therapy.

Show evidence (1 reference)

PMID:22784036 SUPPORT Human Clinical

"our data suggest that amyloid deposition will develop and be detectable in all persons with a mutation while still asymptomatic, whereas no noncarriers had positive scans for amyloid deposition"

Establishes the near-perfect concordance between mutation carrier status and amyloid PET positivity that underpins the test's diagnostic value in ADAD pedigrees.

📈

Progression

3

Symptom onset

Age: mean 46.2 years

Mean age at first progressive cognitive symptoms across 1,307 affected individuals from 387 ADAD pedigrees was 46.2 years, roughly two decades earlier than sporadic late-onset disease. Onset is strongly predicted by mutation type and by parental/family age at onset, which is the basis for the "estimated years to symptom onset" (EYO) staging variable used throughout DIAN and DIAN-TU. PSEN1 variants have the earliest onset and PSEN2 the latest.

Show evidence (2 references)

PMID:24928124 SUPPORT Human Clinical

"Mean onset was 46.2 years for all affected patients in the combined dataset, clearly younger than the mean symptom onset of 68 years reported in late-onset AD."

Largest meta-analysis of ADAD age at onset, quantifying the shift relative to late-onset disease.

PMID:24928124 SUPPORT Human Clinical

"Significant proportions of the observed variance in age at symptom onset in ADAD can be explained by family history and mutation type, providing empirical support for use of these data to estimate onset in clinical research."

Establishes the predictability of onset that makes EYO-based staging and secondary-prevention trial design possible.

Symptomatic course to death

Duration: mean 9.7 years from symptom onset

Mean survival from symptom onset to death was 9.7 years, only modestly shorter than the ~11.3 years reported for sporadic Alzheimer disease - so the common belief that ADAD is uniformly more rapidly progressive is not supported. Disease course is non-linear in age at onset, with the very young and the very old at onset having the shortest survival.

Show evidence (2 references)

PMID:24928124 SUPPORT Human Clinical

"The average course from symptom onset to death in our dataset (9.7 years ± 5.06 SD) was only modestly shorter than the average course of 11.3 years from symptom onset to death reported in a large population with sporadic AD."

Quantifies disease duration and refutes an assumed uniformly accelerated course.

PMID:24928124 SUPPORT Human Clinical

"Patients with early (younger than 35 years) or late (older than 65 years) onset each had a shorter disease course than patients with onset in midlife (35–65 years)."

Documents the inverted-U relationship between age at onset and survival.

Preclinical biomarker cascade

Pathophysiological change begins more than two decades before symptoms. Relative to expected symptom onset, CSF Abeta42 declines at about -25 years, fibrillar amyloid PET signal and CSF tau become abnormal at about -15 years together with hippocampal atrophy, cerebral hypometabolism and impaired episodic memory appear at about -10 years, global cognitive impairment at about -5 years, and dementia criteria are met about 3 years after expected onset.

Show evidence (2 references)

PMID:22784036 SUPPORT Human Clinical

"Changes begin in the brain at least two decades before the estimated onset of clinical symptoms."

Summarises the DIAN finding that measurable pathophysiology long precedes symptoms in ADAD.

PMID:22784036 SUPPORT Human Clinical

"the order and magnitude of changes indicate that genetic mutations cause increased Aβ42, which is followed by brain amyloidosis, tauopathy, brain atrophy, and decreased glucose metabolism"

States the observed temporal ordering of the ADAD biomarker cascade, which this entry's pathophysiology chain reproduces.

📊

Prevalence

2

Rouen, France (city population 426,710)

Point Prevalence 5.3 per 100,000 1–9 per 100,000

Population-based ascertainment. ADEOAD was defined stringently as at least three early-onset (age <61 years) Alzheimer cases in three generations; the denominator is persons at risk. The same study measured early-onset Alzheimer disease overall at 41.2 per 100,000, so the deterministic dominant form is roughly one-eighth of all early-onset Alzheimer disease.

Show evidence (1 reference)

PMID:10441572 SUPPORT Human Clinical

"we calculated that the EOAD and ADEOAD prevalences per 100,000 persons at risk were 41.2 and 5.3, respectively"

Direct population-based point-prevalence estimate for autosomal dominant early-onset Alzheimer disease.

Worldwide, expressed as a fraction of all Alzheimer disease

Unknown Rare

Not a population rate. Recorded because the clinically salient number for ADAD is its share of the Alzheimer disease total: approximately 1% of all cases. Measure type is UNKNOWN because the source reports a case fraction rather than an occurrence measure with a defined population denominator; the population-rate figure is the Rouen record above.

Show evidence (1 reference)

PMID:22784036 SUPPORT Human Clinical

"autosomal dominant Alzheimer’s disease accounts for a relatively small proportion (approximately 1%) of cases of Alzheimer’s disease"

Quantifies ADAD as roughly 1% of all Alzheimer disease.

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Clinical Trials

2

NCT01760005 PHASE_III COMPLETED

DIAN-TU-001, the first secondary-prevention platform trial in autosomal dominant Alzheimer disease. Randomised, double-blind, placebo-controlled, multi-arm, enrolling mutation carriers from 15 years before to 10 years after their estimated years to symptom onset. Registered as a phase 2/3 trial; the gantenerumab and solanezumab arms ran from 2012 to 2019, and the gantenerumab open-label extension (2020-2023, NCT06424236) escalated to substantially higher doses.

Target Phenotypes: Dementia HP:0000726 Impaired episodic memory HP:0002354

Show evidence (2 references)

clinicaltrials:NCT01760005 SUPPORT Other

"The purpose of this study is to assess the safety, tolerability, biomarker, cognitive and clinical efficacy of investigational products in participants with an Alzheimer's disease-causing mutation"

ClinicalTrials.gov record confirming that this platform trial enrols carriers of Alzheimer disease-causing mutations, i.e. the ADAD population.

PMID:34155411 SUPPORT Human Clinical

"Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo."

Reports the randomised allocation of the DIAN-TU-001 double-blind period.

NCT00869817 NOT_APPLICABLE RECRUITING

The Dominantly Inherited Alzheimer Network (DIAN) observational study: a longitudinal, multi-site natural-history and biomarker cohort of members of ADAD pedigrees, both carriers and non-carriers. It produced the canonical preclinical biomarker cascade that this entry's pathophysiology chain is built on, and supplies the participants and the estimated-years-to-onset staging used by DIAN-TU. Observational, so no trial phase applies.

Show evidence (2 references)

clinicaltrials:NCT00869817 SUPPORT Other

"The purpose of this study is to identify potential biomarkers that may predict the development of Alzheimer's disease in people who carry an Alzheimer's mutation."

ClinicalTrials.gov record confirming the observational biomarker aim and the mutation-carrier population of the DIAN cohort.

PMID:22784036 SUPPORT Human Clinical

"Participants at risk for carrying a mutation for autosomal dominant Alzheimer’s disease were enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study at 1 of 10 sites."

Describes the DIAN observational cohort whose baseline data produced the biomarker cascade.

{ }

Source YAML

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name: Early-Onset Autosomal Dominant Alzheimer Disease
creation_date: "2026-07-31T00:00:00Z"
description: >-
  Early-onset autosomal dominant Alzheimer disease (EOAD/ADAD, also "dominantly
  inherited Alzheimer disease", DIAD, or ADEOAD) is the deterministic, fully
  penetrant Mendelian form of Alzheimer disease caused by pathogenic variants in
  one of three genes of the amyloid-beta biosynthetic axis - APP (the amyloid
  precursor protein itself, including whole-locus duplication), PSEN1, and PSEN2
  (the catalytic subunits of gamma-secretase). Nearly all such variants shift APP
  proteolysis toward longer, more aggregation-prone amyloid-beta species,
  increasing the Abeta42:Abeta40 ratio and committing carriers to cerebral
  amyloid deposition beginning in early-to-mid adulthood. Mean symptom onset is
  in the fifth decade (~46 years, and as early as the third decade for some
  PSEN1 variants), decades earlier than sporadic late-onset Alzheimer disease.
  Because age at onset is strongly predicted by mutation type and family history,
  ADAD provides the field's principal natural experiment for reading out the
  temporal order of Alzheimer pathophysiology in living humans: the Dominantly
  Inherited Alzheimer Network (DIAN) showed that CSF Abeta42 falls ~25 years,
  fibrillar amyloid PET signal and CSF tau rise ~15 years, hypometabolism and
  episodic memory decline ~10 years, and global cognitive impairment ~5 years
  before expected symptom onset. The clinical and neuropathological phenotype is
  otherwise that of typical Alzheimer disease, with an excess of non-amnestic and
  "atypical" features (myoclonus, seizures, spastic paraparesis, cerebellar
  signs, prominent cerebral amyloid angiopathy) relative to late-onset disease.
disease_term:
  preferred_term: early-onset autosomal dominant Alzheimer disease
  term:
    id: MONDO:0015140
    label: early-onset autosomal dominant Alzheimer disease
synonyms:
- EOFAD
- ADAD
- DIAD
- ADEOAD
- autosomal dominant Alzheimer disease
- dominantly inherited Alzheimer disease
- early-onset familial autosomal dominant Alzheimer disease
category: Neurodegenerative Disorder
parents:
- Alzheimer Disease
- Dementia
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      Progressive neurodegenerative dementia; the primary clinical home is the
      Harrison's neurology Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      Fully penetrant Mendelian (autosomal dominant) disorder of three defined
      genes, with predictive genetic testing and genetic counselling as a core
      management axis.
  mechanistic_category:
  - classification_value: amyloidopathy
    notes: >-
      The proximal and defining lesion is deterministic overproduction of
      aggregation-prone amyloid-beta with cerebral amyloid fibril deposition.
    evidence:
    - reference: PMID:40120616
      reference_title: >-
        Safety and efficacy of long-term gantenerumab treatment in dominantly
        inherited Alzheimer's disease: an open-label extension of the phase 2/3
        multicentre, randomised, double-blind, placebo-controlled platform
        DIAN-TU trial.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        resulting in overproduction of aggregation prone amyloid β and
        accumulation of amyloid β-plaque pathology in early to mid-adulthood
      explanation: >-
        Supports the amyloidopathy classification: the disease-defining lesion is
        amyloid-beta overproduction and plaque accumulation.
  - classification_value: tauopathy
    notes: >-
      Downstream neurofibrillary tau pathology is obligate and is what tracks
      neurodegeneration and clinical decline.
    evidence:
    - reference: PMID:32161412
      reference_title: >-
        A soluble phosphorylated tau signature links tau, amyloid and the
        evolution of stages of dominantly inherited Alzheimer's disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Intracellular NFTs in the cerebral cortex are a defining pathological
        feature of Alzheimer’s disease (AD)
      explanation: >-
        Supports the tauopathy classification: neurofibrillary tangles of
        hyperphosphorylated tau are a defining pathological feature.
  - classification_value: proteotoxic disease
    notes: >-
      Both arms (soluble Abeta oligomers, hyperphosphorylated tau) act through
      protein misfolding and proteotoxicity.
notes: >-
  LUMP-VS-SPLIT DECISION. dismech already carries `Alzheimer_Disease`
  (MONDO:0004975), which models Alzheimer disease as a whole and is dominated by
  the common late-onset, multifactorial/polygenic form. This entry is kept
  SEPARATE rather than folded into that one because ADAD is a mechanistically and
  epistemically distinct entity, not merely an early slice of the same disease:
  (i) causation is deterministic and monogenic with essentially complete
  penetrance, so the gene-to-amyloid step is a causal claim rather than a risk
  association; (ii) the proximal lesion is a defined shift in gamma-secretase
  processing of APP raising the Abeta42:Abeta40 ratio, whereas late-onset disease
  is driven mainly by impaired clearance and polygenic/APOE risk; (iii) age at
  onset is predictable from mutation type and family history, which makes ADAD
  the substrate for a completely different research and trial design (DIAN,
  DIAN-TU secondary prevention) than sporadic AD; and (iv) it carries its own
  MONDO term (MONDO:0015140, is_a MONDO:0100087 familial Alzheimer disease). This
  entry deliberately does NOT duplicate the general Alzheimer content in
  `Alzheimer_Disease` (broad amyloid-cascade discussion, late-onset risk factors,
  general symptomatic care, sporadic-AD epidemiology); it curates only what is
  specific to the deterministic autosomal dominant entity. `Alzheimer_Disease`
  retains an "Early-Onset Alzheimer's Disease" subtype covering the clinical
  category of onset before 65 years, which is BROADER than this entry - most
  early-onset AD is not autosomal dominant (Campion et al. report early-onset AD
  prevalence of 41.2 vs 5.3 per 100,000 for the autosomal dominant form,
  PMID:10441572). Read the two entries together: `Alzheimer_Disease` for the
  disease in general, this entry for the Mendelian deterministic form.
has_subtypes:
- name: PSEN1
  display_name: PSEN1-associated ADAD
  subtype_term:
    preferred_term: Alzheimer disease 3 (PSEN1)
    term:
      id: MONDO:0011913
      label: Alzheimer disease 3
  description: >-
    The most common and, on average, earliest-onset genetic form of ADAD.
    Missense variants in PSEN1 (chromosome 14, the AD3 locus) alter the catalytic
    subunit of gamma-secretase. PSEN1 variants account for the majority of
    mutation-positive ADAD families and are the source of the large Colombian
    (PSEN1 E280A) kindred. Atypical features - spastic paraparesis, myoclonus,
    seizures, cerebellar signs - are over-represented relative to APP and PSEN2
    forms.
  evidence:
  - reference: PMID:7596406
    reference_title: >-
      Cloning of a gene bearing missense mutations in early-onset familial
      Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five different missense mutations have been found that cosegregate with
      early-onset familial Alzheimer's disease.
    explanation: >-
      Original identification of PSEN1 (S182) missense variants cosegregating
      with early-onset familial Alzheimer disease, establishing this subtype.
  - reference: PMID:10441572
    reference_title: >-
      Early-onset autosomal dominant Alzheimer disease: prevalence, genetic
      heterogeneity, and mutation spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 19 (56%) of these families, we identified 16 distinct PSEN1 missense
      mutations
    explanation: >-
      Population-based French series quantifying PSEN1 as the largest genetic
      subgroup of autosomal dominant early-onset Alzheimer disease.
  - reference: PMID:27777022
    reference_title: >-
      Clinical phenotype and genetic associations in autosomal dominant familial
      Alzheimer's disease: a case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Age at onset differed by mutation, with a younger onset for individuals
      with PSEN1 mutations than for those with APP mutations
    explanation: >-
      Establishes the earlier mean age at onset of the PSEN1 subtype relative to
      APP, one of the defining features that justifies splitting these subtypes.
  - reference: PMID:27777022
    reference_title: >-
      Clinical phenotype and genetic associations in autosomal dominant familial
      Alzheimer's disease: a case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      within the PSEN1 group, 72% of age at onset variance was explained by the
      specific mutation
    explanation: >-
      Quantifies how strongly the specific PSEN1 variant determines age at onset,
      supporting variant-level rather than merely gene-level prognostication.
- name: APP
  display_name: APP-associated ADAD (point mutation)
  subtype_term:
    preferred_term: Alzheimer disease type 1 (APP)
    term:
      id: MONDO:0007088
      label: Alzheimer disease type 1
  description: >-
    Missense variants in APP, typically clustered around the secretase cleavage
    sites flanking the amyloid-beta peptide (e.g. the original V717I "London"
    variant), that shift APP processing toward Abeta42 or alter the aggregation
    properties of the peptide itself. Mean onset is somewhat later than PSEN1.
  evidence:
  - reference: PMID:1671712
    reference_title: >-
      Segregation of a missense mutation in the amyloid precursor protein gene
      with familial Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we demonstrate that in this kindred, which shows linkage to chromosome
      21 markers, there is a point mutation in the APP gene. This mutation causes
      an amino-acid substitution (Val----Ile) close to the carboxy terminus of
      the beta-amyloid peptide.
    explanation: >-
      The founding demonstration that an APP point mutation adjacent to the
      amyloid-beta peptide cosegregates with familial Alzheimer disease.
- name: APP Duplication
  display_name: APP locus duplication (gene-dosage ADAD)
  subtype_term:
    preferred_term: APP locus duplication
    term:
      id: MONDO:1060190
      label: APP-related brain and vascular amyloidosis
  description: >-
    Copy-number gain of the whole APP locus on chromosome 21, causing ADAD purely
    by gene dosage rather than by altered peptide chemistry. It is the human
    genetic counterpart of the trisomy-21 Alzheimer phenotype and is
    characteristically accompanied by severe cerebral amyloid angiopathy with
    lobar haemorrhage. Note that the bound `subtype_term` is the closest
    available MONDO class: MONDO has no distinct term for APP locus duplication,
    so this subtype is anchored on the APP-related brain and vascular amyloidosis
    grouping, which captures the parenchymal-plus-vascular amyloid phenotype that
    distinguishes it. The `preferred_term` records the intended narrower concept.
  evidence:
  - reference: PMID:16369530
    reference_title: >-
      APP locus duplication causes autosomal dominant early-onset Alzheimer
      disease with cerebral amyloid angiopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report duplication of the APP locus on chromosome 21 in five families
      with autosomal dominant early-onset Alzheimer disease (ADEOAD) and cerebral
      amyloid angiopathy (CAA).
    explanation: >-
      Defines the gene-dosage subtype and its cerebral amyloid angiopathy
      phenotype.
- name: PSEN2
  display_name: PSEN2-associated ADAD
  subtype_term:
    preferred_term: Alzheimer disease 4 (PSEN2)
    term:
      id: MONDO:0011743
      label: Alzheimer disease 4
  description: >-
    The rarest of the three genetic forms, exemplified by the PSEN2 N141I founder
    variant of the Volga German kindreds. PSEN2 variants have significantly later
    and more variable age at onset than PSEN1 or APP variants, with onset
    sometimes extending into the seventh decade, so PSEN2 disease can be missed
    if dominant AD is assumed always to be early in onset.
  evidence:
  - reference: PMID:7638622
    reference_title: Candidate gene for the chromosome 1 familial Alzheimer's disease locus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A point mutation in STM2, resulting in the substitution of an isoleucine
      for an asparagine (N141l), was identified in affected people from Volga
      German AD kindreds.
    explanation: >-
      Original identification of the PSEN2 (STM2) N141I founder variant in the
      Volga German ADAD kindreds.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous pathogenic variants (or whole-locus duplication) in APP, PSEN1,
    or PSEN2 are transmitted in an autosomal dominant pattern with essentially
    complete penetrance by the family-typical age at onset; each child of an
    affected carrier has a 50% risk. Non-penetrance before age 61 is uncommon for
    PSEN1 and APP variants, although PSEN2 variants have later and more variable
    onset.
  evidence:
  - reference: PMID:10441572
    reference_title: >-
      Early-onset autosomal dominant Alzheimer disease: prevalence, genetic
      heterogeneity, and mutation spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      nonpenetrance at age <61 years is probably infrequent for PSEN1 or APP
      mutations
    explanation: >-
      Supports essentially complete penetrance of PSEN1 and APP variants by the
      expected age at onset, the defining feature of the dominant form.
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As expected with an autosomal dominant inheritance pattern, approximately
      50% of the asymptomatic participants were mutation carriers.
    explanation: >-
      DIAN cohort composition directly reflects autosomal dominant transmission
      within at-risk pedigrees.
prevalence:
- population: Rouen, France (city population 426,710)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 5.3
  notes: >-
    Population-based ascertainment. ADEOAD was defined stringently as at least
    three early-onset (age <61 years) Alzheimer cases in three generations; the
    denominator is persons at risk. The same study measured early-onset Alzheimer
    disease overall at 41.2 per 100,000, so the deterministic dominant form is
    roughly one-eighth of all early-onset Alzheimer disease.
  evidence:
  - reference: PMID:10441572
    reference_title: >-
      Early-onset autosomal dominant Alzheimer disease: prevalence, genetic
      heterogeneity, and mutation spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we calculated that the EOAD and ADEOAD prevalences per 100,000 persons at
      risk were 41.2 and 5.3, respectively
    explanation: >-
      Direct population-based point-prevalence estimate for autosomal dominant
      early-onset Alzheimer disease.
- population: Worldwide, expressed as a fraction of all Alzheimer disease
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    Not a population rate. Recorded because the clinically salient number for
    ADAD is its share of the Alzheimer disease total: approximately 1% of all
    cases. Measure type is UNKNOWN because the source reports a case fraction
    rather than an occurrence measure with a defined population denominator; the
    population-rate figure is the Rouen record above.
  evidence:
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      autosomal dominant Alzheimer’s disease accounts for a relatively small
      proportion (approximately 1%) of cases of Alzheimer’s disease
    explanation: Quantifies ADAD as roughly 1% of all Alzheimer disease.
progression:
- phase: Symptom onset
  age_range: mean 46.2 years
  notes: >-
    Mean age at first progressive cognitive symptoms across 1,307 affected
    individuals from 387 ADAD pedigrees was 46.2 years, roughly two decades
    earlier than sporadic late-onset disease. Onset is strongly predicted by
    mutation type and by parental/family age at onset, which is the basis for the
    "estimated years to symptom onset" (EYO) staging variable used throughout
    DIAN and DIAN-TU. PSEN1 variants have the earliest onset and PSEN2 the
    latest.
  evidence:
  - reference: PMID:24928124
    reference_title: >-
      Symptom onset in autosomal dominant Alzheimer disease: a systematic review
      and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mean onset was 46.2 years for all affected patients in the combined
      dataset, clearly younger than the mean symptom onset of 68 years reported
      in late-onset AD.
    explanation: >-
      Largest meta-analysis of ADAD age at onset, quantifying the shift relative
      to late-onset disease.
  - reference: PMID:24928124
    reference_title: >-
      Symptom onset in autosomal dominant Alzheimer disease: a systematic review
      and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Significant proportions of the observed variance in age at symptom onset in
      ADAD can be explained by family history and mutation type, providing
      empirical support for use of these data to estimate onset in clinical
      research.
    explanation: >-
      Establishes the predictability of onset that makes EYO-based staging and
      secondary-prevention trial design possible.
- phase: Symptomatic course to death
  duration: mean 9.7 years from symptom onset
  notes: >-
    Mean survival from symptom onset to death was 9.7 years, only modestly
    shorter than the ~11.3 years reported for sporadic Alzheimer disease - so the
    common belief that ADAD is uniformly more rapidly progressive is not
    supported. Disease course is non-linear in age at onset, with the very young
    and the very old at onset having the shortest survival.
  evidence:
  - reference: PMID:24928124
    reference_title: >-
      Symptom onset in autosomal dominant Alzheimer disease: a systematic review
      and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The average course from symptom onset to death in our dataset (9.7 years ±
      5.06 SD) was only modestly shorter than the average course of 11.3 years
      from symptom onset to death reported in a large population with sporadic
      AD.
    explanation: >-
      Quantifies disease duration and refutes an assumed uniformly accelerated
      course.
  - reference: PMID:24928124
    reference_title: >-
      Symptom onset in autosomal dominant Alzheimer disease: a systematic review
      and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with early (younger than 35 years) or late (older than 65 years)
      onset each had a shorter disease course than patients with onset in midlife
      (35–65 years).
    explanation: >-
      Documents the inverted-U relationship between age at onset and survival.
- phase: Preclinical biomarker cascade
  notes: >-
    Pathophysiological change begins more than two decades before symptoms.
    Relative to expected symptom onset, CSF Abeta42 declines at about -25 years,
    fibrillar amyloid PET signal and CSF tau become abnormal at about -15 years
    together with hippocampal atrophy, cerebral hypometabolism and impaired
    episodic memory appear at about -10 years, global cognitive impairment at
    about -5 years, and dementia criteria are met about 3 years after expected
    onset.
  evidence:
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Changes begin in the brain at least two decades before the estimated onset
      of clinical symptoms.
    explanation: >-
      Summarises the DIAN finding that measurable pathophysiology long precedes
      symptoms in ADAD.
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the order and magnitude of changes indicate that genetic mutations cause
      increased Aβ42, which is followed by brain amyloidosis, tauopathy, brain
      atrophy, and decreased glucose metabolism
    explanation: >-
      States the observed temporal ordering of the ADAD biomarker cascade, which
      this entry's pathophysiology chain reproduces.
genetic:
- name: PSEN1
  gene_term:
    preferred_term: PSEN1
    term:
      id: hgnc:9508
      label: PSEN1
  association: Pathogenic missense variants (autosomal dominant, deterministic)
  subtype: PSEN1
  notes: >-
    PSEN1 encodes presenilin 1, the catalytic aspartyl protease subunit of the
    gamma-secretase complex that performs the final intramembrane cleavage of the
    APP C-terminal fragment. Pathogenic missense variants reduce the processivity
    of successive carboxypeptidase-like cleavages, releasing longer Abeta species
    and raising the Abeta42:Abeta40 ratio. PSEN1 variants are the most common
    cause of ADAD and are associated with the earliest onset.
  case_fractions:
  - population: French population-based ADEOAD families (Rouen study, n=34)
    case_fraction_percent: 56.0
    cohort_size: 34
    notes: 19 of 34 stringently defined ADEOAD families carried a PSEN1 variant.
    evidence:
    - reference: PMID:10441572
      reference_title: >-
        Early-onset autosomal dominant Alzheimer disease: prevalence, genetic
        heterogeneity, and mutation spectrum.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In 19 (56%) of these families, we identified 16 distinct PSEN1 missense
        mutations
      explanation: Quantifies the PSEN1 share of ADEOAD families in this cohort.
  evidence:
  - reference: PMID:7596406
    reference_title: >-
      Cloning of a gene bearing missense mutations in early-onset familial
      Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic linkage studies have mapped a locus (AD3) associated with
      susceptibility to a very aggressive form of Alzheimer's disease to
      chromosome 14q24.3.
    explanation: >-
      Maps and identifies the PSEN1 (AD3) locus underlying aggressive early-onset
      familial Alzheimer disease.
- name: APP
  gene_term:
    preferred_term: APP
    term:
      id: hgnc:620
      label: APP
  association: >-
    Pathogenic missense variants near the secretase cleavage sites, and
    whole-locus duplication (autosomal dominant, deterministic)
  subtype: APP
  notes: >-
    APP encodes the amyloid precursor protein, the substrate from which
    amyloid-beta is liberated by sequential beta- and gamma-secretase cleavage.
    Pathogenic variants cluster around the cleavage sites flanking the
    amyloid-beta peptide and either shift cleavage toward Abeta42 or increase the
    aggregation propensity of the peptide. Duplication of the entire locus causes
    disease purely by increased gene dosage.
  case_fractions:
  - population: French population-based ADEOAD families (Rouen study, n=34)
    case_fraction_percent: 15.0
    cohort_size: 34
    notes: 5 of 34 stringently defined ADEOAD families carried an APP variant.
    evidence:
    - reference: PMID:10441572
      reference_title: >-
        Early-onset autosomal dominant Alzheimer disease: prevalence, genetic
        heterogeneity, and mutation spectrum.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        APP mutations, including a novel mutation located at codon 715, were
        identified in 5 (15%) of the families.
      explanation: Quantifies the APP share of ADEOAD families in this cohort.
  evidence:
  - reference: PMID:1671712
    reference_title: >-
      Segregation of a missense mutation in the amyloid precursor protein gene
      with familial Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This suggests that some cases of AD could be caused by mutations in the APP
      gene.
    explanation: >-
      Original demonstration of APP as a causal gene for familial Alzheimer
      disease.
  - reference: PMID:16369530
    reference_title: >-
      APP locus duplication causes autosomal dominant early-onset Alzheimer
      disease with cerebral amyloid angiopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Duplication of the APP locus, resulting in accumulation of amyloid-beta
      peptides, causes ADEOAD with CAA.
    explanation: >-
      Establishes gene dosage of APP as sufficient to cause the disease, a
      dose-response argument for the amyloid mechanism.
- name: PSEN2
  gene_term:
    preferred_term: PSEN2
    term:
      id: hgnc:9509
      label: PSEN2
  association: Pathogenic missense variants (autosomal dominant, deterministic)
  subtype: PSEN2
  notes: >-
    PSEN2 encodes presenilin 2, the paralogous catalytic subunit of
    gamma-secretase that can substitute for presenilin 1. Pathogenic variants are
    the rarest cause of ADAD, with the N141I founder variant of the Volga German
    kindreds the best characterised. Onset is significantly later and more
    variable than for PSEN1 or APP.
  evidence:
  - reference: PMID:7638622
    reference_title: Candidate gene for the chromosome 1 familial Alzheimer's disease locus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The presence of missense mutations in AD subjects in two highly similar
      genes strongly supports the hypothesis that mutations in both are
      pathogenic.
    explanation: >-
      Establishes PSEN2 (STM2) as a second presenilin gene causal for familial
      Alzheimer disease.
- name: APOE
  gene_term:
    preferred_term: APOE
    term:
      id: hgnc:613
      label: APOE
  relationship_type: MODIFIER
  association: Onset-modifying locus; the R136S "Christchurch" variant is protective
  notes: >-
    APOE genotype is the dominant risk locus for sporadic late-onset Alzheimer
    disease but is NOT a major determinant of onset age in ADAD as a whole: in
    the largest meta-analysis, APOE genotype and sex did not significantly add to
    the variance in onset explained by mutation type and family history. The
    striking exception is the homozygous APOE3 Christchurch (R136S) variant,
    which delayed cognitive onset by about three decades in a PSEN1 E280A carrier
    despite very high brain amyloid - the single most informative human
    resilience observation in ADAD, and the basis for APOE-directed therapeutic
    strategies.
  evidence:
  - reference: PMID:31686034
    reference_title: >-
      Resistance to autosomal dominant Alzheimer's disease in an APOE3
      Christchurch homozygote: a case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The individual had two copies of the APOE3 Christchurch (R136S) mutation,
      unusually high brain amyloid levels and limited tau and neurodegenerative
      measurements.
    explanation: >-
      Documents a protective APOE genotype uncoupling amyloid burden from tau,
      neurodegeneration, and clinical onset in an ADAD carrier.
mechanistic_hypotheses:
- hypothesis_group_id: deterministic_amyloid_cascade
  hypothesis_label: >-
    Deterministic amyloid cascade: mutation-driven Abeta42 overproduction is the
    sufficient upstream cause of the entire ADAD pathophysiology
  status: CANONICAL
  description: >-
    In ADAD the amyloid cascade is not merely correlative. All three causal genes
    sit on the amyloid-beta biosynthetic axis; APP locus duplication shows a pure
    gene-dosage effect; and the DIAN cross-sectional cascade recovers exactly the
    predicted temporal order (CSF Abeta42 change, then fibrillar amyloid, then
    tau, then atrophy and hypometabolism, then cognition). This entry's
    pathophysiology chain is modelled on that ordering. Downstream causal edges
    that belong to this model opt in via
    hypothesis_groups: [deterministic_amyloid_cascade].
  evidence:
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the order and magnitude of changes indicate that genetic mutations cause
      increased Aβ42, which is followed by brain amyloidosis, tauopathy, brain
      atrophy, and decreased glucose metabolism
    explanation: >-
      Reports the observed sequence of pathophysiological change in ADAD
      carriers, the empirical backbone of this hypothesis.
  - reference: PMID:16369530
    reference_title: >-
      APP locus duplication causes autosomal dominant early-onset Alzheimer
      disease with cerebral amyloid angiopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Duplication of the APP locus, resulting in accumulation of amyloid-beta
      peptides, causes ADEOAD with CAA.
    explanation: >-
      A pure gene-dosage cause is the strongest available human argument that
      increased amyloid-beta production alone is sufficient to cause the disease.
  notes: >-
    Retained as CANONICAL, but the cascade being sufficient to CAUSE the disease
    is not the same as amyloid removal being sufficient to TREAT it: the DIAN-TU
    double-blind period showed target engagement and biomarker change without
    cognitive benefit. See the qualitative-Abeta-profile alternative below and
    the open discussions.
- hypothesis_group_id: qualitative_abeta_profile
  hypothesis_label: >-
    Qualitative Abeta profile, not simply the Abeta42:Abeta40 ratio, determines
    familial Alzheimer pathogenicity
  status: ALTERNATIVE
  description: >-
    An alternative reading of the proximal step. Kinetic dissection of
    gamma-secretase shows that familial Alzheimer disease mutations act through
    at least three distinct mechanisms and change the qualitative spectrum of
    Abeta products, not only the Abeta42 fraction - and that many PSEN variants
    paradoxically IMPAIR gamma-secretase rather than simply activating an
    Abeta42-generating gain of function. This matters therapeutically because it
    predicts that indiscriminate gamma-secretase inhibition (which failed
    clinically) is the wrong intervention, while modulation of the
    carboxypeptidase-like activity is the right one.
  evidence:
  - reference: PMID:22505025
    reference_title: The mechanism of γ-Secretase dysfunction in familial Alzheimer disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we use kinetic studies to demonstrate that FAD mutations affect Aβ
      generation via three different mechanisms, resulting in qualitative changes
      in the Aβ profiles, which are not limited to Aβ42.
    explanation: >-
      Directly states the qualitative-profile alternative to a simple
      Abeta42-quantity model.
  - reference: PMID:22505025
    reference_title: The mechanism of γ-Secretase dysfunction in familial Alzheimer disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      However, many PSEN mutations paradoxically impair γ-secretase and
      'loss-of-function' mechanisms have also been postulated.
    explanation: >-
      Notes the loss-of-function observation that a pure gain-of-toxic-function
      model does not accommodate. Marked PARTIAL because the sentence frames a
      postulate rather than establishing it.
pathophysiology:
- name: Pathogenic APP, PSEN1, or PSEN2 Germline Variant
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    The proximal cause is a heterozygous germline pathogenic variant in one of
    three genes on the amyloid-beta biosynthetic axis: APP (the substrate, by
    missense variant near a secretase cleavage site or by whole-locus
    duplication), PSEN1, or PSEN2 (the catalytic subunit of the gamma-secretase
    that performs the final cleavage). More than 230 such variants are
    catalogued. Because the lesion is present from conception and acts
    constitutively, the entire downstream cascade is deterministic rather than
    probabilistic, and its timing is set largely by which variant is carried.
  genes:
  - preferred_term: APP
    term:
      id: hgnc:620
      label: APP
  - preferred_term: PSEN1
    term:
      id: hgnc:9508
      label: PSEN1
  - preferred_term: PSEN2
    term:
      id: hgnc:9509
      label: PSEN2
  evidence:
  - reference: PMID:24928124
    reference_title: >-
      Symptom onset in autosomal dominant Alzheimer disease: a systematic review
      and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Researchers have identified more than 230 different autosomal dominant
      Alzheimer disease (ADAD) mutations located in the genes for amyloid
      precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2)
    explanation: >-
      Establishes the three-gene allelic architecture that constitutes the
      trigger of this chain.
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in one of three genes (APP, PSEN1, and PSEN2) have been
      identified that cause alterations in Aβ processing
    explanation: >-
      Links the germline variant directly to altered amyloid-beta processing, the
      next node.
  downstream:
  - target: Altered Gamma-Secretase Processing of APP and Increased Abeta42 Fraction
    hypothesis_groups:
    - deterministic_amyloid_cascade
  - target: Increased APP Substrate Dosage
    hypothesis_groups:
    - deterministic_amyloid_cascade
- name: Altered Gamma-Secretase Processing of APP and Increased Abeta42 Fraction
  biological_scale: MOLECULAR
  role: amplifier
  subtypes:
  - PSEN1
  - APP
  - PSEN2
  conforms_to: "amyloidogenesis#Amyloidogenic Precursor Protein"
  description: >-
    The qualitative arm of the proximal lesion, and the mechanism of the
    point-mutation subtypes (PSEN1, PSEN2, and APP missense). Pathogenic variants shift
    the sequential, carboxypeptidase-like gamma-secretase cleavage of the APP
    C-terminal fragment so that longer, more aggregation-prone amyloid-beta
    species are released, raising the Abeta42:Abeta40 ratio. This node is the
    ADAD-specific substitution for the amyloidogenesis module's generic
    "amyloidogenic precursor protein" trigger: the precursor is amyloid-beta, and
    what destabilises it is not aging or somatic mutation but a constitutive
    germline change in how it is generated. A mechanistic caveat is carried by
    the qualitative_abeta_profile hypothesis: kinetic work shows familial
    Alzheimer variants change the qualitative spectrum of Abeta products through
    several distinct mechanisms, not only the Abeta42 quantity, and many PSEN
    variants paradoxically impair the enzyme. The parallel quantitative
    (gene-dosage) arm is modelled as the sibling node "Increased APP Substrate
    Dosage" rather than folded in here, because copy-number gain of APP does not
    alter gamma-secretase processing and does not by itself raise the
    Abeta42:Abeta40 ratio - it raises total substrate.
  biological_processes:
  - preferred_term: amyloid precursor protein catabolic process
    term:
      id: GO:0042987
      label: amyloid precursor protein catabolic process
    modifier: ABNORMAL
  - preferred_term: amyloid-beta metabolic process
    term:
      id: GO:0050435
      label: amyloid-beta metabolic process
    modifier: INCREASED
  molecular_functions:
  - preferred_term: gamma-secretase endopeptidase activity
    term:
      id: GO:0004175
      label: endopeptidase activity
    modifier: ABNORMAL
  evidence:
  - reference: PMID:22505025
    reference_title: The mechanism of γ-Secretase dysfunction in familial Alzheimer disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      FAD mutations increase the release of amyloid β (Aβ)42 relative to Aβ40 by
      an unknown, possibly gain-of-toxic-function, mechanism.
    explanation: >-
      Directly states the shift in the Abeta42:Abeta40 ratio produced by familial
      Alzheimer disease mutations.
  - reference: PMID:40120616
    reference_title: >-
      Safety and efficacy of long-term gantenerumab treatment in dominantly
      inherited Alzheimer's disease: an open-label extension of the phase 2/3
      multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU
      trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dominantly inherited Alzheimer’s disease (DIAD) is caused by autosomal
      dominant mutations in presenilin-1 (PSEN1), presenilin-2 (PSEN2), or the
      amyloid-beta precursor protein (APP) genes that alter APP processing,
      resulting in overproduction of aggregation prone amyloid β
    explanation: >-
      States the causal step from variant to altered APP processing to
      overproduction of aggregation-prone amyloid-beta.
  downstream:
  - target: Amyloid-beta Misfolding and Soluble Oligomer Formation
    hypothesis_groups:
    - deterministic_amyloid_cascade
- name: Increased APP Substrate Dosage
  biological_scale: MOLECULAR
  role: amplifier
  subtypes:
  - APP Duplication
  conforms_to: "amyloidogenesis#Amyloidogenic Precursor Protein"
  description: >-
    The quantitative (gene-dosage) arm of the proximal lesion, and the sibling of
    the gamma-secretase-processing node. Copy-number gain of the whole APP locus
    on chromosome 21 increases the amount of APP substrate presented to the
    normal secretase machinery, so more amyloid-beta is produced without any
    change in the enzyme or in the Abeta42:Abeta40 ratio. It is modelled as a
    distinct node precisely because it is the cleanest human dose-response
    argument for the amyloid hypothesis: no altered peptide chemistry is
    required, only more of the normal precursor. This node is arguably the more
    literal instance of the amyloidogenesis module's "amyloidogenic precursor
    protein" trigger, whose description names overproduction alongside mutation
    as a route to a metastable precursor. It converges with the qualitative arm
    on the shared downstream misfolding node, and its vascular emphasis is
    carried onward by the cerebral amyloid angiopathy node.
  genes:
  - preferred_term: APP
    term:
      id: hgnc:620
      label: APP
  biological_processes:
  - preferred_term: amyloid-beta metabolic process
    term:
      id: GO:0050435
      label: amyloid-beta metabolic process
    modifier: INCREASED
  evidence:
  - reference: PMID:16369530
    reference_title: >-
      APP locus duplication causes autosomal dominant early-onset Alzheimer
      disease with cerebral amyloid angiopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Duplication of the APP locus, resulting in accumulation of amyloid-beta
      peptides, causes ADEOAD with CAA.
    explanation: >-
      States the gene-dosage mechanism explicitly: duplication of the locus, not
      an altered peptide or enzyme, produces amyloid-beta accumulation and
      disease.
  downstream:
  - target: Amyloid-beta Misfolding and Soluble Oligomer Formation
    hypothesis_groups:
    - deterministic_amyloid_cascade
- name: Amyloid-beta Misfolding and Soluble Oligomer Formation
  biological_scale: MOLECULAR
  role: amplifier
  conforms_to: "amyloidogenesis#Protein Misfolding and Beta-Sheet Oligomerization"
  description: >-
    The excess longer amyloid-beta species depart their soluble monomeric
    conformation and self-associate into beta-sheet-rich, proteotoxic soluble
    oligomers that both seed further aggregation and directly impair synaptic
    function. In ADAD this step is read out in vivo as the earliest detectable
    biomarker change: CSF Abeta42 concentration begins to fall about 25 years
    before expected symptom onset as the peptide is sequestered out of the
    soluble pool.
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
    modifier: ABNORMAL
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Beginning 25 years before expected symptom onset, Aβ42 concentrations in
      the CSF in mutation carriers appeared to decline, as compared with those in
      noncarriers.
    explanation: >-
      The falling soluble CSF Abeta42 pool is the in vivo signature of
      amyloid-beta leaving solution, and is the earliest measurable event in the
      ADAD cascade.
  downstream:
  - target: Fibrillar Amyloid-beta Plaque Formation and Deposition
    hypothesis_groups:
    - deterministic_amyloid_cascade
- name: Fibrillar Amyloid-beta Plaque Formation and Deposition
  biological_scale: TISSUE
  role: central_effector
  conforms_to: "amyloidogenesis#Amyloid Fibril Formation and Extracellular Deposition"
  description: >-
    Oligomers nucleate and elongate into insoluble cross-beta amyloid fibrils
    that deposit as extracellular parenchymal plaques. This is the ADAD instance
    of the amyloidogenesis module's central effector. It is directly imaged in
    living carriers with Pittsburgh compound B PET, which becomes abnormal about
    15 years before expected symptom onset, and characteristically shows early
    and prominent neostriatal signal - a feature more typical of ADAD than of
    sporadic disease. No non-carrier in the DIAN cohort had a positive scan, so
    the genotype-to-deposition link is essentially deterministic.
  biological_processes:
  - preferred_term: amyloid fibril formation
    term:
      id: GO:1990000
      label: amyloid fibril formation
    modifier: INCREASED
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As compared with noncarriers, mutation carriers had significant amyloid
      deposition in the precuneus 15 years before expected symptom onset
    explanation: >-
      Times fibrillar amyloid deposition in living ADAD carriers and anchors it in
      the cascade.
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There was no detectable amyloid deposition in noncarriers.
    explanation: >-
      The absence of any deposition in non-carriers of the same pedigrees
      supports a deterministic genotype-to-fibril relationship.
  downstream:
  - target: Progressive Cortical Amyloid Accumulation
    hypothesis_groups:
    - deterministic_amyloid_cascade
  - target: Cerebral Amyloid Angiopathy
- name: Progressive Cortical Amyloid Accumulation
  biological_scale: TISSUE
  role: effector
  conforms_to: "amyloidogenesis#Progressive Tissue Amyloid Accumulation"
  description: >-
    Fibril deposition continues to accumulate as a growing cortical amyloid
    burden, expanding monotonically as the carrier approaches expected symptom
    onset. This is the ADAD instance of the amyloidogenesis module's
    tissue-accumulation effector: it converts the molecular fibril-formation
    event into an organ-level structural lesion and is the quantity that
    anti-amyloid antibody therapy is designed to reverse.
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The amount of amyloid deposition in mutation carriers increased as a
      function of estimated years from expected symptom onset at least until
      clinical symptom onset.
    explanation: >-
      Documents progressive, time-dependent accumulation of the tissue amyloid
      burden.
  downstream:
  - target: Site-Specific Soluble Tau Hyperphosphorylation
    hypothesis_groups:
    - deterministic_amyloid_cascade
  - target: Microglial Activation and Neuroinflammation
- name: Cerebral Amyloid Angiopathy
  biological_scale: TISSUE
  role: consequence
  description: >-
    A parallel vascular arm of the same deposition process: amyloid-beta,
    especially the shorter Abeta40 species, deposits in the walls of
    leptomeningeal and cortical arterioles. This is present to some degree in
    most ADAD but is a defining and severe feature of APP locus duplication,
    where it produces lobar intracerebral haemorrhage. Its clinical importance
    has grown because cerebral amyloid angiopathy is the substrate for
    amyloid-related imaging abnormalities during anti-amyloid antibody therapy.
  subtypes:
  - APP Duplication
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:16369530
    reference_title: >-
      APP locus duplication causes autosomal dominant early-onset Alzheimer
      disease with cerebral amyloid angiopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brains from individuals with APP duplication showed abundant parenchymal
      and vascular deposits of amyloid-beta peptides.
    explanation: >-
      Documents the vascular deposition arm alongside the parenchymal plaque arm
      in the gene-dosage subtype.
  downstream:
  - target: Vessel Wall Fragility and Intracerebral Haemorrhage
- name: Vessel Wall Fragility and Intracerebral Haemorrhage
  biological_scale: TISSUE
  role: consequence
  description: >-
    Amyloid infiltration of the arteriolar media and adventitia weakens the
    vessel wall, so cerebral amyloid angiopathy terminates in haemorrhagic
    events: lobar intracerebral haemorrhage and cortical microhaemorrhage. This
    is the clinical endpoint of the vascular arm, and it is also the substrate
    that makes anti-amyloid antibody therapy hazardous in this disease -
    amyloid-related imaging abnormalities (microhaemorrhage and vasogenic oedema)
    occurred in 53% of participants in the high-dose DIAN-TU gantenerumab
    extension. The evidence cited here is the trial's ARIA safety readout, which
    documents the haemorrhagic events themselves rather than the untreated
    natural history; the untreated-CAA haemorrhage claim in this node's
    description is not separately cited and should be treated as a described
    clinical association pending a properly quotable source.
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:40120616
    reference_title: >-
      Safety and efficacy of long-term gantenerumab treatment in dominantly
      inherited Alzheimer's disease: an open-label extension of the phase 2/3
      multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU
      trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Amyloid-related imaging abnormalities occurred in 53% (39/73) of
      participants: 47% (34/73) with microhaemorrhages, 30% (22/73) with oedema,
      and 6% (5/73) were associated with symptoms.
    explanation: >-
      Documents haemorrhagic events (microhaemorrhage) and vasogenic oedema in
      ADAD carriers. Marked PARTIAL because these were observed under high-dose
      anti-amyloid antibody treatment, so the quote supports the vessel-wall
      vulnerability of this node but not the untreated haemorrhage rate.
- name: Site-Specific Soluble Tau Hyperphosphorylation
  biological_scale: MOLECULAR
  role: amplifier
  description: >-
    The first tau event, roughly two decades before symptoms and separated from
    tangle formation by about 20 years. Cortical amyloid pathology triggers a
    stereotyped, ordered, site-specific rise in soluble tau phosphorylation
    occupancy measurable in CSF: threonine 217 first (about 21 years before
    expected onset, essentially in lockstep with rising amyloid PET signal), then
    threonine 181, then total tau, then threonine 205. This is the mechanistic
    bridge from the amyloid arm into the tau arm, and is why p-tau217 is now the
    leading amyloid-proximal fluid biomarker. It is modelled separately from
    tangle formation because the two events are ~20 years apart and, critically,
    move in OPPOSITE directions once tangles appear (see the downstream node).
  biological_processes:
  - preferred_term: peptidyl-threonine phosphorylation
    term:
      id: GO:0018107
      label: peptidyl-threonine phosphorylation
    modifier: INCREASED
  cell_types:
  - preferred_term: cortical pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  evidence:
  - reference: PMID:32161412
    reference_title: >-
      A soluble phosphorylated tau signature links tau, amyloid and the evolution
      of stages of dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      phosphorylation of tau at threonine 217 (pT217/T217) (which occurred at
      around −21 EYO) was followed by that of threonine 181 (pT181/T181) (−19
      EYO), then t-tau increase (−17 EYO), then phosphorylation of tau at
      threonine 205 (pT205/T205) (−13 EYO)
    explanation: >-
      Establishes the ordered sequence of site-specific soluble tau
      hyperphosphorylation in ADAD and times it two decades before symptoms.
  - reference: PMID:32161412
    reference_title: >-
      A soluble phosphorylated tau signature links tau, amyloid and the evolution
      of stages of dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results suggest that the events initially leading to increased tau
      phosphorylation in AD are probably related to aggregated Aβ pathology
    explanation: >-
      Supports the causal edge from cortical amyloid accumulation to soluble tau
      hyperphosphorylation.
  downstream:
  - target: Neurofibrillary Tangle Formation
    hypothesis_groups:
    - deterministic_amyloid_cascade
- name: Neurofibrillary Tangle Formation
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    Aggregation of hyperphosphorylated tau into intraneuronal paired helical
    filaments and neurofibrillary tangles. In ADAD this is a LATE event: tau-PET
    signal in mutation carriers rises only near the time of symptom onset,
    roughly two decades after soluble p-tau hyperphosphorylation begins. At that
    point soluble pT217 and pT181 occupancy paradoxically FALL - plausibly
    through sequestration into the aggregates - while total tau keeps rising, so
    the soluble and aggregated tau species diverge. That opposite direction of
    change is the reason this is a separate node from the upstream
    hyperphosphorylation event, and it is what makes stage-blind interpretation
    of a p-tau result unsafe.
  biological_processes:
  - preferred_term: neurofibrillary tangle assembly
    term:
      id: GO:1902988
      label: neurofibrillary tangle assembly
    modifier: INCREASED
  cell_types:
  - preferred_term: cortical pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:32161412
    reference_title: >-
      A soluble phosphorylated tau signature links tau, amyloid and the evolution
      of stages of dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      First, we confirmed that tau-PET SUVR in mutation carriers only increased
      near the time of symptom onset
    explanation: >-
      Times aggregated tangle pathology to near symptom onset, ~20 years after
      the upstream soluble hyperphosphorylation node.
  - reference: PMID:32161412
    reference_title: >-
      A soluble phosphorylated tau signature links tau, amyloid and the evolution
      of stages of dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Second, pT217/T217 and pT181/T181 began to decline significantly near the
      time of symptom onset, while phosphorylation at pT205/T205 slowed and t-tau
      levels continued to increase.
    explanation: >-
      Documents the opposite direction of change (falling soluble p-tau as
      tangles form) that requires this to be a node distinct from the upstream
      hyperphosphorylation event.
  downstream:
  - target: Neuronal Loss and Cortical Atrophy
    hypothesis_groups:
    - deterministic_amyloid_cascade
- name: Microglial Activation and Neuroinflammation
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    Plaque-associated microglia and reactive astrocytes mount a chronic innate
    immune response around amyloid deposits. In ADAD this arm is directly
    measurable and pharmacologically reversible: CSF markers of microglial
    activity, other inflammatory markers, and astrocyte activation all improved
    under gantenerumab treatment in DIAN-TU, showing this is a process
    downstream of amyloid rather than an independent one. It is modelled separately
    from synaptic loss, which is its consequence rather than the same event.
  biological_processes:
  - preferred_term: neuroinflammatory response
    term:
      id: GO:0150076
      label: neuroinflammatory response
    modifier: INCREASED
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  evidence:
  - reference: PMID:40120616
    reference_title: >-
      Safety and efficacy of long-term gantenerumab treatment in dominantly
      inherited Alzheimer's disease: an open-label extension of the phase 2/3
      multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU
      trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      gantenerumab treatment significantly improved multiple CSF measures of
      synaptic degeneration, microglial activity, other inflammatory markers, and
      astrocyte activation markers
    explanation: >-
      Shows that the microglial, astrocytic, and inflammatory markers are
      downstream of amyloid in ADAD and move when amyloid is removed.
  downstream:
  - target: Synaptic Loss
- name: Synaptic Loss
  biological_scale: CELLULAR
  role: effector
  description: >-
    Loss of synapses in the neuropil surrounding plaques, driven both by
    proteotoxic soluble amyloid-beta oligomers and by microglial synaptic
    pruning. Synaptic loss is the structural correlate that best tracks cognitive
    impairment in Alzheimer disease, and it sits downstream of - not alongside -
    the microglial/inflammatory response. Like that response, CSF measures of
    synaptic degeneration improved under gantenerumab in DIAN-TU.
  biological_processes:
  - preferred_term: synapse organization
    term:
      id: GO:0050808
      label: synapse organization
    modifier: ABNORMAL
  - preferred_term: synapse pruning
    term:
      id: GO:0098883
      label: synapse pruning
    modifier: INCREASED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:40120616
    reference_title: >-
      Safety and efficacy of long-term gantenerumab treatment in dominantly
      inherited Alzheimer's disease: an open-label extension of the phase 2/3
      multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU
      trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      gantenerumab treatment significantly improved multiple CSF measures of
      synaptic degeneration
    explanation: >-
      Documents synaptic degeneration as a measurable, amyloid-downstream,
      treatment-responsive process in ADAD.
  downstream:
  - target: Neuronal Loss and Cortical Atrophy
- name: Neuronal Loss and Cortical Atrophy
  biological_scale: TISSUE
  role: effector
  description: >-
    Neuronal death producing measurable structural loss. Increased atrophy of the
    bilateral hippocampi is detectable on volumetric MRI about 15 years before
    expected symptom onset, with the precuneus and medial temporal structures
    affected earliest - matching the topography of early amyloid deposition. This
    is modelled separately from cerebral hypometabolism, which the same DIAN
    analysis times five years later.
  biological_processes:
  - preferred_term: neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
    modifier: INCREASED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: hippocampal formation
    term:
      id: UBERON:0002421
      label: hippocampal formation
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Increased atrophy of bilateral hippocampi was detected in mutation carriers
      15 years before expected symptom onset
    explanation: >-
      Times the structural neurodegeneration node at about 15 years before
      expected symptom onset.
  downstream:
  - target: Cerebral Glucose Hypometabolism
    hypothesis_groups:
    - deterministic_amyloid_cascade
  - target: Progressive Dementia
    hypothesis_groups:
    - deterministic_amyloid_cascade
- name: Cerebral Glucose Hypometabolism
  biological_scale: TISSUE
  role: effector
  description: >-
    Regional failure of cerebral glucose utilisation, measured by FDG-PET, in
    territories losing synapses and neurons. In DIAN carriers a significant
    decrease in precuneus metabolism appears about 10 years before expected
    symptom onset - five years after hippocampal atrophy becomes detectable,
    which is why it is a distinct node rather than being bundled with atrophy.
  locations:
  - preferred_term: cerebral cortex
    term:
      id: UBERON:0000956
      label: cerebral cortex
  evidence:
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A significant decrease in cerebral metabolism in the precuneus was detected
      in mutation carriers 10 years before expected symptom onset
    explanation: >-
      Times cerebral hypometabolism at about 10 years before expected symptom
      onset, distinct from the 15-year atrophy timing of the upstream node.
  downstream:
  - target: Progressive Dementia
    hypothesis_groups:
    - deterministic_amyloid_cascade
- name: Progressive Dementia
  biological_scale: ORGANISM
  role: consequence
  conforms_to: "amyloidogenesis#Organ Dysfunction"
  description: >-
    The clinical end state, and the ADAD instance of the amyloidogenesis module's
    organ-dysfunction consequence, with the brain as the affected organ. Impaired
    episodic memory appears about 10 years before expected symptom onset, global
    cognitive impairment about 5 years before, and criteria for mild dementia are
    met about 3 years after expected onset, with progression to death over
    roughly a decade. Non-amnestic and neurological features (myoclonus,
    seizures, spastic paraparesis) are more common than in late-onset disease.
  evidence:
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Global cognitive impairment, as measured by the Mini-Mental State
      Examination and the Clinical Dementia Rating scale, was detected 5 years
      before expected symptom onset, and patients met diagnostic criteria for
      dementia at an average of 3 years after expected symptom onset.
    explanation: >-
      Times the clinical consequence node relative to the rest of the cascade.
phenotypes:
- category: Neurologic
  name: Progressive Dementia
  description: >-
    Progressive multidomain cognitive decline meeting criteria for dementia,
    reached on average about three years after the family-expected age at symptom
    onset and roughly two decades earlier than in sporadic Alzheimer disease.
  phenotype_term:
    preferred_term: Dementia
    term:
      id: HP:0000726
      label: Dementia
    clinical_course: PROGRESSIVE
  frequency: OBLIGATE
  evidence:
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients met diagnostic criteria for dementia at an average of 3 years
      after expected symptom onset
    explanation: >-
      Documents progression to dementia in mutation carriers at a predictable
      time relative to expected onset. Frequency is OBLIGATE because ADAD
      variants are essentially fully penetrant for dementia by the
      family-expected age (see the inheritance block and PMID:10441572).
- category: Neurologic
  name: Episodic Memory Impairment
  description: >-
    Impaired delayed recall is the earliest reliably detectable cognitive
    deficit, separating carriers from non-carriers about 10 years before expected
    symptom onset - well before global cognitive measures change.
  phenotype_term:
    preferred_term: Impaired episodic memory
    term:
      id: HP:0002354
      label: Memory impairment
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cerebral hypometabolism and impaired episodic memory were observed 10 years
      before expected symptom onset.
    explanation: >-
      Directly establishes impaired episodic memory in ADAD mutation carriers and
      times it at about 10 years before expected symptom onset.
  - reference: PMID:27777022
    reference_title: >-
      Clinical phenotype and genetic associations in autosomal dominant familial
      Alzheimer's disease: a case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      71 (84%) individuals with PSEN1 mutations and 35 (97%) with APP mutations
      presented with amnestic symptoms
    explanation: >-
      Supports the VERY_FREQUENT band directly: 84% of PSEN1 and 97% of APP
      carriers presented with amnestic symptoms, both within the 80-100% range,
      so the frequency is evidenced by quoted counts rather than inferred.
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The typical clinical presentation is progressive loss of memory and
      cognitive function, ultimately leading to a loss of independence
    explanation: >-
      Establishes progressive memory loss as the typical presenting deficit of
      Alzheimer disease, the clinical form the ADAD deficit takes.
- category: Neuroimaging
  name: Cerebral Atrophy
  description: >-
    Progressive brain atrophy, earliest and most marked in the hippocampi and
    precuneus, detectable on volumetric MRI about 15 years before expected
    symptom onset.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
    clinical_course: PROGRESSIVE
  notes: >-
    `frequency:` deliberately omitted. The cited evidence establishes that
    hippocampal atrophy is detectable at the group level in carriers 15 years
    before onset, which is a timing claim rather than a proportion, and
    docs/frequency-evidence-guidelines.md prefers omission over a band inferred
    from reasoning.
  evidence:
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Increased atrophy of bilateral hippocampi was detected in mutation carriers
      15 years before expected symptom onset
    explanation: >-
      Documents structural atrophy and its preclinical timing. Frequency
      VERY_FREQUENT because atrophy was detectable at the group level in carriers
      well before symptoms and is universal by the dementia stage.
- category: Neuropathologic
  name: Neurofibrillary Tangles
  description: >-
    Intraneuronal aggregates of hyperphosphorylated tau in paired helical
    filaments, the defining tauopathy component of Alzheimer neuropathology. In
    ADAD, aggregated tangle pathology measurable by tau PET appears late - only
    near the time of symptom onset - despite tau hyperphosphorylation beginning
    two decades earlier.
  phenotype_term:
    preferred_term: Neurofibrillary tangles
    term:
      id: HP:0002185
      label: Neurofibrillary tangles
  notes: >-
    `frequency:` deliberately omitted. Neurofibrillary tangles are a required
    neuropathological criterion for Alzheimer disease, which would make OBLIGATE
    correct by definition, but the cited snippet reports the timing of tau-PET
    signal rather than a proportion of carriers, so the band would be inferred
    rather than evidenced.
  evidence:
  - reference: PMID:32161412
    reference_title: >-
      A soluble phosphorylated tau signature links tau, amyloid and the evolution
      of stages of dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      First, we confirmed that tau-PET SUVR in mutation carriers only increased
      near the time of symptom onset
    explanation: >-
      Documents aggregated tangle pathology in ADAD carriers and its late timing
      relative to the soluble p-tau changes. Frequency is OBLIGATE because
      neurofibrillary tangles are a required neuropathological criterion for
      Alzheimer disease, which all ADAD carriers develop.
- category: Neuropathologic
  name: Amyloid-beta Plaque Deposition
  description: >-
    Abundant extracellular parenchymal deposits immunoreactive to amyloid-beta,
    present in essentially all mutation carriers and detectable in vivo by
    amyloid PET more than a decade before symptoms.
  phenotype_term:
    preferred_term: Deposits immunoreactive to beta-amyloid protein
    term:
      id: HP:0003791
      label: Deposits immunoreactive to beta-amyloid protein
  frequency: OBLIGATE
  evidence:
  - reference: PMID:16369530
    reference_title: >-
      APP locus duplication causes autosomal dominant early-onset Alzheimer
      disease with cerebral amyloid angiopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brains from individuals with APP duplication showed abundant parenchymal
      and vascular deposits of amyloid-beta peptides.
    explanation: >-
      Neuropathological confirmation of abundant amyloid-beta deposits in ADAD
      brain.
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      our data suggest that amyloid deposition will develop and be detectable in
      all persons with a mutation while still asymptomatic, whereas no
      noncarriers had positive scans for amyloid deposition
    explanation: >-
      Directly supports the OBLIGATE frequency: amyloid deposition is expected in
      all mutation carriers and in no non-carriers.
- category: Neurologic
  name: Cerebral Amyloid Angiopathy
  description: >-
    Amyloid-beta deposition in the walls of leptomeningeal and cortical vessels.
    Present to some degree across ADAD but severe and clinically dominant in APP
    locus duplication, where it causes lobar intracerebral haemorrhage.
  phenotype_term:
    preferred_term: Cerebral amyloid angiopathy
    term:
      id: HP:0011970
      label: Cerebral amyloid angiopathy
  subtype: APP Duplication
  evidence:
  - reference: PMID:16369530
    reference_title: >-
      APP locus duplication causes autosomal dominant early-onset Alzheimer
      disease with cerebral amyloid angiopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report duplication of the APP locus on chromosome 21 in five families
      with autosomal dominant early-onset Alzheimer disease (ADEOAD) and cerebral
      amyloid angiopathy (CAA).
    explanation: >-
      Documents cerebral amyloid angiopathy as a defining feature of the APP
      duplication subtype. No `frequency` is asserted because the source reports
      a five-family series rather than a frequency band.
- category: Neurologic
  name: Myoclonus
  description: >-
    Brief involuntary muscle jerks - together with seizures, the most common
    additional neurological feature of ADAD and markedly over-represented
    relative to late-onset Alzheimer disease. In the largest single-centre ADAD
    series myoclonus affected 47% of PSEN1 and 33% of APP mutation carriers, and
    carriers with myoclonus were significantly more likely to go on to develop
    seizures.
  phenotype_term:
    preferred_term: Myoclonus
    term:
      id: HP:0001336
      label: Myoclonus
  notes: >-
    `frequency:` is deliberately omitted even though the source reports 47%
    (PSEN1) and 33% (APP), which would map to FREQUENT. The reference validator
    strips square-bracketed content from snippets, so the bracketed percentages
    in the source sentence cannot be quoted verbatim, and per
    docs/frequency-evidence-guidelines.md a band should be omitted rather than
    asserted on a snippet that does not carry the number. The figures are
    recorded here and in the description, both attributable to PMID:27777022.
  evidence:
  - reference: PMID:27777022
    reference_title: >-
      Clinical phenotype and genetic associations in autosomal dominant familial
      Alzheimer's disease: a case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myoclonus and seizures were the most common additional neurological
      features
    explanation: >-
      Establishes myoclonus as the most common additional neurological feature of
      ADAD in the largest single-centre series.
- category: Neurologic
  name: Seizures
  description: >-
    Epileptic seizures, affecting roughly a quarter of symptomatic ADAD carriers
    of either gene - substantially more than in late-onset Alzheimer disease.
    Preceding myoclonus is a significant predictor of subsequent seizures, so the
    two cluster together clinically. Their frequency is one of the practical
    reasons to consider genetic testing in a young patient with dementia plus
    additional neurological features.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:27777022
    reference_title: >-
      Clinical phenotype and genetic associations in autosomal dominant familial
      Alzheimer's disease: a case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      which affected around a quarter of the patients in each group
    explanation: >-
      Quantifies seizures at around a quarter of symptomatic ADAD carriers in
      both the PSEN1 and APP groups, which falls in the OCCASIONAL band (5-29%),
      so the frequency is directly evidenced rather than inferred.
- category: Neurologic
  name: Pyramidal Signs
  description: >-
    Corticospinal-tract signs (spasticity, hyperreflexia, extensor plantar
    responses), reported in 25% of PSEN1 mutation carriers in the largest ADAD
    series and essentially restricted to PSEN1. At the severe end of this
    spectrum sits the distinctive "variant AD with spastic paraparesis"
    presentation associated with particular PSEN1 variants, often those producing
    cotton-wool plaques. The phenotype is bound to the general pyramidal-sign
    term rather than to a spastic-paraparesis term because that is what the cited
    series actually counted.
  phenotype_term:
    preferred_term: Pyramidal signs (including spastic paraparesis)
    term:
      id: HP:0007256
      label: Abnormal pyramidal sign
  subtype: PSEN1
  notes: >-
    `frequency:` omitted for the same reason as myoclonus - the source reports
    25% but only inside square brackets, which the reference validator strips, so
    the band cannot be carried by a verbatim snippet.
  evidence:
  - reference: PMID:27777022
    reference_title: >-
      Clinical phenotype and genetic associations in autosomal dominant familial
      Alzheimer's disease: a case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A number of patients with PSEN1 mutations had ... pyramidal ... signs.
    explanation: >-
      Documents pyramidal signs specifically in PSEN1 mutation carriers,
      supporting both the phenotype and its PSEN1 subtype restriction.
- category: Neurologic
  name: Extrapyramidal Signs
  description: >-
    Parkinsonian and other extrapyramidal motor signs, reported in 14% of PSEN1
    mutation carriers in the largest ADAD series.
  phenotype_term:
    preferred_term: Abnormality of extrapyramidal motor function
    term:
      id: HP:0002071
      label: Abnormality of extrapyramidal motor function
  subtype: PSEN1
  notes: >-
    `frequency:` omitted - the reported 14% appears only inside square brackets
    in the source sentence, which the reference validator strips from snippets.
  evidence:
  - reference: PMID:27777022
    reference_title: >-
      Clinical phenotype and genetic associations in autosomal dominant familial
      Alzheimer's disease: a case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A number of patients with PSEN1 mutations had ... extrapyramidal ... signs.
    explanation: >-
      Documents extrapyramidal signs in PSEN1 mutation carriers.
- category: Neurologic
  name: Cerebellar Signs
  description: >-
    Cerebellar signs, the rarest of the additional neurological features,
    reported in 4% of PSEN1 mutation carriers in the largest ADAD series.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  subtype: PSEN1
  notes: >-
    `frequency:` omitted - the reported 4% appears only inside square brackets in
    the source sentence, which the reference validator strips from snippets.
  evidence:
  - reference: PMID:27777022
    reference_title: >-
      Clinical phenotype and genetic associations in autosomal dominant familial
      Alzheimer's disease: a case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A number of patients with PSEN1 mutations had ... cerebellar ... signs.
    explanation: Documents cerebellar signs in PSEN1 mutation carriers.
- category: Neurologic
  name: Atypical Non-Amnestic Cognitive Presentation
  description: >-
    Presentation with a leading non-memory cognitive or behavioural syndrome
    (language, visuospatial, dysexecutive, or behavioural) rather than the usual
    amnestic onset. Significantly more common in PSEN1 than APP carriers - 16%
    versus 3% by complement of the reported amnestic proportions - and one of the
    features that makes ADAD diagnostically harder than late-onset disease.
  phenotype_term:
    preferred_term: Atypical (non-amnestic) cognitive presentation
    term:
      id: HP:0000708
      label: Atypical behavior
  subtype: PSEN1
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:27777022
    reference_title: >-
      Clinical phenotype and genetic associations in autosomal dominant familial
      Alzheimer's disease: a case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      71 (84%) individuals with PSEN1 mutations and 35 (97%) with APP mutations
      presented with amnestic symptoms, making atypical cognitive presentations
      significantly more common in PSEN1 mutation carriers
    explanation: >-
      The complement of the quoted amnestic proportions gives 16% non-amnestic
      presentation in PSEN1 and 3% in APP; the PSEN1 figure falls in the
      OCCASIONAL band (5-29%), so the frequency is derived from the quoted counts
      rather than inferred. The bound HP term is broader than the intended
      concept - HPO has no single term for "non-amnestic cognitive presentation"
      - so the preferred_term carries the intended meaning.
biochemical:
- name: CSF Amyloid-beta 42
  presence: Decreased
  context: >-
    Cerebrospinal fluid. The earliest measurable biomarker change in ADAD: CSF
    Abeta42 concentration begins to decline about 25 years before expected
    symptom onset as the peptide is sequestered into plaques, reaching clearly
    abnormal levels about 10 years before onset. The magnitude of the decrease is
    similar to that seen in sporadic late-onset disease.
  biomarker_term:
    preferred_term: Decreased amyloid beta 42 peptide CSF concentration
    term:
      id: HP:0025684
      label: Decreased amyloid beta 42 peptide CSF concentration
  specificity: >-
    Not specific to ADAD - shared with sporadic Alzheimer disease. Its value in
    ADAD is that carrier status makes it interpretable decades before symptoms.
  evidence:
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25
      years before expected symptom onset.
    explanation: >-
      Establishes the direction and preclinical timing of the CSF Abeta42 change
      in ADAD.
- name: CSF Amyloid-beta 42/40 Ratio
  presence: Decreased
  context: >-
    Cerebrospinal fluid. The ratio is preferred over Abeta42 alone because it
    normalises for individual differences in total amyloid-beta production, which
    matters especially in APP duplication carriers. It is used in DIAN as the
    dichotomising amyloid-status variable.
  specificity: >-
    Reflects cerebral amyloid status generally rather than the dominant genotype.
  reference_ranges:
  - lower_bound: 0.0776
    unit: "1"
    population: >-
      DIAN autosomal dominant Alzheimer disease cohort; mass-spectrometry CSF
      assay. Values at or above the bound are amyloid-negative; values below are
      amyloid-positive.
    notes: >-
      Dimensionless ratio, so the UCUM unit is "1" and there is no upper bound.
      No `loinc_term` is asserted: this curator could not verify a LOINC code for
      the CSF Abeta42/Abeta40 ratio against an authoritative source, and LOINC is
      not in the dismech OAK validation config (conf/oak_config.yaml), so an
      unverified code would be an undetectable error. Adding the verified LOINC
      code later is a welcome improvement.
    evidence:
    - reference: PMID:32161412
      reference_title: >-
        A soluble phosphorylated tau signature links tau, amyloid and the
        evolution of stages of dominantly inherited Alzheimer's disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        classifying participants as amyloid positive (Aβ 42/40 ≥ 0.0776) or
        amyloid negative (Aβ 42/40 < 0.0776)
      explanation: >-
        Source of the 0.0776 amyloid-positivity cutoff used to define these
        bands.
    interpretation_bands:
    - name: Amyloid positive
      upper_bound: 0.0776
      unit: "1"
      abnormal_flag: LOW
      interpretation: >-
        CSF amyloid-beta 42/40 ratio below the cutoff indicates cerebral amyloid
        pathology.
      phenotype_term:
        preferred_term: Decreased amyloid beta 42 peptide CSF concentration
        term:
          id: HP:0025684
          label: Decreased amyloid beta 42 peptide CSF concentration
    - name: Amyloid negative
      lower_bound: 0.0776
      unit: "1"
      abnormal_flag: NORMAL
      interpretation: >-
        CSF amyloid-beta 42/40 ratio at or above the cutoff indicates no
        significant cerebral amyloid pathology.
  evidence:
  - reference: PMID:32161412
    reference_title: >-
      A soluble phosphorylated tau signature links tau, amyloid and the evolution
      of stages of dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When using CSF-soluble Aβ in DIAD to determine abnormal amyloid levels, we
      found the same order for the soluble tau measures in classifying
      participants as amyloid positive (Aβ 42/40 ≥ 0.0776) or amyloid negative
      (Aβ 42/40 < 0.0776)
    explanation: >-
      Documents the use of the CSF Abeta42/40 ratio with an explicit cutoff to
      define amyloid status in the DIAN ADAD cohort.
- name: CSF Phospho-tau 217 (pT217/T217 occupancy)
  presence: Increased
  context: >-
    Cerebrospinal fluid, measured as phosphorylation occupancy by mass
    spectrometry. The most amyloid-proximal tau marker: occupancy begins to rise
    about 21 years before expected symptom onset, essentially in lockstep with
    the first rise in amyloid PET signal, and near-perfectly discriminates
    amyloid-positive from amyloid-negative carriers. It then falls again around
    symptom onset as tangle pathology accumulates, so its trajectory is
    non-monotonic and must be interpreted with disease stage.
  specificity: >-
    Highly specific for amyloid pathology (AUC 0.97 against amyloid PET status in
    the DIAN cohort), and now the leading fluid biomarker of Alzheimer pathology
    generally.
  evidence:
  - reference: PMID:32161412
    reference_title: >-
      A soluble phosphorylated tau signature links tau, amyloid and the evolution
      of stages of dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is a near-perfect association with Aβ pathology for pT217/T217
      (purple; AUC = 0.97).
    explanation: >-
      Quantifies the discriminative performance of CSF pT217 occupancy for
      amyloid pathology in ADAD.
  - reference: PMID:32161412
    reference_title: >-
      A soluble phosphorylated tau signature links tau, amyloid and the evolution
      of stages of dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Second, pT217/T217 and pT181/T181 began to decline significantly near the
      time of symptom onset, while phosphorylation at pT205/T205 slowed and t-tau
      levels continued to increase.
    explanation: >-
      Documents the non-monotonic trajectory that complicates stage-blind
      interpretation of pT217 and pT181.
- name: CSF Phospho-tau 181
  presence: Increased
  context: >-
    Cerebrospinal fluid. Rises about 19 years before expected symptom onset,
    shortly after pT217. It is the tau marker with the longest clinical assay
    history and was one of the biomarkers significantly lowered by gantenerumab
    in the DIAN-TU trial, making it a usable pharmacodynamic readout in ADAD.
  evidence:
  - reference: PMID:34155411
    reference_title: >-
      A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's
      disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid
      total tau, and phospho-tau181 and attenuated increases of neurofilament
      light chain.
    explanation: >-
      Demonstrates CSF phospho-tau181 as an amyloid-downstream,
      treatment-responsive biomarker in ADAD.
- name: CSF Total Tau
  presence: Increased
  context: >-
    Cerebrospinal fluid. Rises about 15-17 years before expected symptom onset
    and continues to increase monotonically as cognition declines, making it the
    tau measure that tracks neurodegeneration most directly.
  evidence:
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In mutation carriers, levels of tau in the CSF were increased 15 years
      before expected symptom onset
    explanation: Times the rise in CSF total tau within the ADAD biomarker cascade.
- name: Fibrillar Amyloid PET (PiB) Standardised Uptake Value Ratio
  presence: Increased
  context: >-
    Imaging biomarker (11C-Pittsburgh compound B PET), reported as a cortical
    composite standardised uptake value ratio. Becomes abnormal about 15 years
    before expected symptom onset; no DIAN non-carrier had a positive scan. It is
    the primary pharmacodynamic endpoint for anti-amyloid antibody therapy in
    ADAD.
  specificity: >-
    Positive amyloid PET in an at-risk pedigree member is effectively
    genotype-informative, since non-carriers in the DIAN cohort were uniformly
    negative.
  reference_ranges:
  - upper_bound: 1.25
    unit: "1"
    population: >-
      DIAN cohort; cortical PiB-PET composite. The normal cutoff was derived from
      the 95th percentile of asymptomatic non-carriers.
    notes: >-
      Dimensionless uptake ratio, so the UCUM unit is "1" and there is no
      meaningful lower bound. No `loinc_term` is asserted because amyloid PET
      SUVR is an imaging-derived quantity rather than a LOINC-coded clinical
      laboratory analyte.
    evidence:
    - reference: PMID:40120616
      reference_title: >-
        Safety and efficacy of long-term gantenerumab treatment in dominantly
        inherited Alzheimer's disease: an open-label extension of the phase 2/3
        multicentre, randomised, double-blind, placebo-controlled platform
        DIAN-TU trial.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The DIAN normal cutoff was 1.25 PiB-PET SUVR
      explanation: >-
        Source of the 1.25 SUVR amyloid-positivity threshold used to define these
        bands.
    interpretation_bands:
    - name: Amyloid negative
      upper_bound: 1.25
      unit: "1"
      abnormal_flag: NORMAL
      interpretation: >-
        Cortical PiB-PET SUVR below the DIAN cutoff indicates no significant
        fibrillar amyloid burden.
    - name: Amyloid positive
      lower_bound: 1.25
      unit: "1"
      abnormal_flag: HIGH
      interpretation: >-
        Cortical PiB-PET SUVR at or above the DIAN cutoff indicates significant
        fibrillar cerebral amyloid pathology.
      phenotype_term:
        preferred_term: Deposits immunoreactive to beta-amyloid protein
        term:
          id: HP:0003791
          label: Deposits immunoreactive to beta-amyloid protein
  evidence:
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aβ deposition, as measured by positron-emission tomography with the use of
      Pittsburgh compound B, was detected 15 years before expected symptom onset.
    explanation: Times the amyloid PET biomarker within the preclinical cascade.
- name: CSF Neurofilament Light Chain
  presence: Increased
  context: >-
    Cerebrospinal fluid (and plasma). A non-specific marker of axonal
    neurodegeneration whose rate of increase tracks disease progression in ADAD
    and was attenuated by gantenerumab, providing evidence that anti-amyloid
    treatment slows the neurodegenerative arm even where cognitive endpoints did
    not move.
  specificity: >-
    Not disease-specific; elevated across many neurodegenerative and neuroaxonal
    injury states.
  evidence:
  - reference: PMID:34155411
    reference_title: >-
      A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's
      disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: attenuated increases of neurofilament light chain
    explanation: >-
      Documents neurofilament light chain as a treatment-responsive
      neurodegeneration marker in ADAD.
diagnosis:
- name: Molecular Genetic Testing of APP, PSEN1, and PSEN2
  presence: Definitive
  notes: >-
    The definitive diagnostic test. Because the disease is monogenic and
    deterministic, identifying a pathogenic variant in one of the three genes
    establishes the diagnosis in a symptomatic proband and, in an asymptomatic
    at-risk relative, is predictive rather than merely probabilistic. More than
    230 pathogenic variants are catalogued across the three genes, and the
    specific variant is the strongest single predictor of age at onset, so
    genotype has direct prognostic value. Testing should be offered with formal
    genetic counselling (see the Predictive Genetic Testing and Genetic
    Counselling treatment entry) and is a practical prerequisite for entry into
    secondary-prevention trials. A negative result does not exclude the disease:
    in a stringently ascertained population series no PSEN1, PSEN2, or APP
    variant was identified in 10 of 34 ADEOAD families, so roughly 29% of
    clinically dominant early-onset pedigrees remain genetically unexplained.
  evidence:
  - reference: PMID:24928124
    reference_title: >-
      Symptom onset in autosomal dominant Alzheimer disease: a systematic review
      and meta-analysis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Researchers have identified more than 230 different autosomal dominant
      Alzheimer disease (ADAD) mutations located in the genes for amyloid
      precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2)
    explanation: >-
      Defines the three-gene testing panel that constitutes the definitive
      molecular diagnosis.
  - reference: PMID:10441572
    reference_title: >-
      Early-onset autosomal dominant Alzheimer disease: prevalence, genetic
      heterogeneity, and mutation spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the 10 remaining ADEOAD families and in 9 additional autosomal dominant
      Alzheimer disease families that did not fulfill the strict criteria for
      ADEOAD, no PSEN1, PSEN2, or APP mutation was identified.
    explanation: >-
      Documents the diagnostic limitation of the three-gene panel: a substantial
      minority of clinically dominant early-onset pedigrees are variant-negative.
      Marked PARTIAL because it qualifies rather than supports the test's
      sensitivity.
  - reference: PMID:27777022
    reference_title: >-
      Clinical phenotype and genetic associations in autosomal dominant familial
      Alzheimer's disease: a case series.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This highlights the importance of considering genetic testing in young
      patients with dementia and additional neurological features in order to
      appropriately diagnose and treat their symptoms
    explanation: >-
      States the clinical indication for genetic testing: young-onset dementia
      with additional neurological features (myoclonus, seizures, pyramidal
      signs).
- name: Pedigree Criterion for Autosomal Dominant Early-Onset Alzheimer Disease
  notes: >-
    The clinical/pedigree definition used to ascertain ADEOAD before or without
    molecular confirmation: at least three early-onset (age <61 years) Alzheimer
    disease cases across three generations. This is the stringent
    epidemiological criterion behind this entry's prevalence record. It is
    deliberately conservative and will miss de novo variants, small pedigrees,
    non-paternity, and the later-onset PSEN2 families; it is an ascertainment
    criterion, not a substitute for molecular testing.
  evidence:
  - reference: PMID:10441572
    reference_title: >-
      Early-onset autosomal dominant Alzheimer disease: prevalence, genetic
      heterogeneity, and mutation spectrum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      EOAD was defined as onset of disease at age <61 years, and ADEOAD was
      defined as the occurrence of at least three EOAD cases in three
      generations.
    explanation: >-
      States the pedigree criterion verbatim, including the age threshold and the
      three-generation requirement.
- name: CSF Amyloid and Tau Biomarker Profile
  markers: >-
    CSF Amyloid-beta 42/40 Ratio; CSF Phospho-tau 217 (pT217/T217 occupancy);
    CSF Phospho-tau 181; CSF Total Tau
  notes: >-
    Cerebrospinal fluid Abeta42/Abeta40 ratio plus phosphorylated and total tau.
    In ADAD these establish that the Alzheimer pathological process is under way
    and stage it, rather than establishing the genetic diagnosis: the Abeta42/40
    ratio dichotomises amyloid status at 0.0776 in the DIAN cohort, and
    site-specific p-tau (pT217, pT181) rises in a stereotyped order two decades
    before symptoms. See the corresponding `biochemical` entries for the
    reference ranges and interpretation bands. Note that p-tau trajectories are
    non-monotonic - pT217 and pT181 fall again around symptom onset - so a result
    must be read together with disease stage.
  evidence:
  - reference: PMID:32161412
    reference_title: >-
      A soluble phosphorylated tau signature links tau, amyloid and the evolution
      of stages of dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      classifying participants as amyloid positive (Aβ 42/40 ≥ 0.0776) or amyloid
      negative (Aβ 42/40 < 0.0776)
    explanation: >-
      Documents the CSF Abeta42/40 cutoff used to dichotomise amyloid status in
      the DIAN ADAD cohort.
  - reference: PMID:32161412
    reference_title: >-
      A soluble phosphorylated tau signature links tau, amyloid and the evolution
      of stages of dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is a near-perfect association with Aβ pathology for pT217/T217
      (purple; AUC = 0.97).
    explanation: >-
      Quantifies the diagnostic performance of CSF pT217 occupancy against
      amyloid pathology in ADAD.
- name: Amyloid PET Imaging
  markers: Fibrillar Amyloid PET (PiB) Standardised Uptake Value Ratio
  notes: >-
    11C-Pittsburgh compound B (or an 18F equivalent) PET, reported as a cortical
    composite standardised uptake value ratio with the DIAN normal cutoff at
    1.25. In ADAD its diagnostic value is unusually high because carrier status
    and scan status are almost perfectly concordant: amyloid deposition becomes
    detectable about 15 years before expected symptom onset in carriers and no
    non-carrier in the DIAN cohort had a positive scan. It is also the primary
    pharmacodynamic endpoint for anti-amyloid therapy.
  evidence:
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      our data suggest that amyloid deposition will develop and be detectable in
      all persons with a mutation while still asymptomatic, whereas no
      noncarriers had positive scans for amyloid deposition
    explanation: >-
      Establishes the near-perfect concordance between mutation carrier status
      and amyloid PET positivity that underpins the test's diagnostic value in
      ADAD pedigrees.
treatments:
- name: Gantenerumab
  description: >-
    A fully human IgG1 monoclonal antibody that binds aggregated amyloid-beta and
    promotes microglial plaque clearance. Gantenerumab is the anti-amyloid
    therapy with the most ADAD-specific evidence: in the DIAN-TU-001 double-blind
    period it engaged its target and significantly lowered amyloid plaques, CSF
    total tau and phospho-tau181, and attenuated the rise in neurofilament light
    chain, but did not slow cognitive decline. In the subsequent 3-year
    open-label extension at substantially higher doses, PiB-PET SUVR fell by 0.71
    and the longest-treated participants showed a hazard ratio for CDR-SB
    progression of 0.53, suggesting - but not establishing - that long-term
    complete amyloid removal may delay symptom onset. Amyloid-related imaging
    abnormalities were common (53% overall in the extension). Development was
    discontinued for lack of a regulatory path, so this agent is not clinically
    available; its value here is as the definitive test of the amyloid hypothesis
    in the deterministic form of the disease.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: gantenerumab
      term:
        id: NCIT:C88580
        label: Gantenerumab
  target_mechanisms:
  - target: Progressive Cortical Amyloid Accumulation
    treatment_effect: INHIBITS
    description: >-
      Binds and opsonises aggregated amyloid-beta, driving microglial removal of
      established plaques and thereby reducing the accumulated cortical amyloid
      burden.
  evidence:
  - reference: PMID:34155411
    reference_title: >-
      A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's
      disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid
      total tau, and phospho-tau181 and attenuated increases of neurofilament
      light chain.
    explanation: >-
      Demonstrates target engagement and downstream biomarker effect in ADAD
      mutation carriers.
  - reference: PMID:34155411
    reference_title: >-
      A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's
      disease.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gantenerumab and solanezumab did not slow cognitive decline in symptomatic
      DIAD.
    explanation: >-
      Refutes a clinical (cognitive) benefit of gantenerumab in symptomatic ADAD
      in the double-blind period, despite biomarker engagement.
  - reference: PMID:40120616
    reference_title: >-
      Safety and efficacy of long-term gantenerumab treatment in dominantly
      inherited Alzheimer's disease: an open-label extension of the phase 2/3
      multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU
      trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Partial or short-term amyloid removal did not show significant clinical
      effects. However, long-term full amyloid removal potentially delayed
      symptom onset and dementia progression.
    explanation: >-
      Supports a possible clinical benefit of sustained complete amyloid removal
      in ADAD. Marked PARTIAL because the finding comes from an open-label
      extension with external controls, which the authors themselves flag as
      limiting.
  - reference: PMID:40120616
    reference_title: >-
      Safety and efficacy of long-term gantenerumab treatment in dominantly
      inherited Alzheimer's disease: an open-label extension of the phase 2/3
      multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU
      trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Amyloid-related imaging abnormalities occurred in 53% (39/73) of
      participants: 47% (34/73) with microhaemorrhages, 30% (22/73) with oedema,
      and 6% (5/73) were associated with symptoms.
    explanation: >-
      Quantifies the principal safety liability of high-dose anti-amyloid
      antibody therapy in ADAD, relevant because cerebral amyloid angiopathy is
      part of the disease.
- name: Solanezumab
  description: >-
    A humanised monoclonal antibody directed at the mid-domain of SOLUBLE
    monomeric amyloid-beta rather than aggregated plaque. Tested head-to-head
    with gantenerumab in DIAN-TU-001. It engaged its soluble target but produced
    no downstream biomarker benefit and was associated with greater cognitive
    decline on some measures - an informative negative result arguing that
    clearing soluble monomer is not therapeutically equivalent to clearing
    aggregated amyloid. Included here for that mechanistic contrast, not as a
    therapy.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: solanezumab
      term:
        id: NCIT:C88585
        label: Solanezumab
  evidence:
  - reference: PMID:34155411
    reference_title: >-
      A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's
      disease.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The solanezumab-treated group showed a greater cognitive decline on some
      measures and did not show benefits on downstream biomarkers.
    explanation: >-
      Refutes clinical or biomarker benefit of solanezumab in ADAD and supports
      the aggregate-versus-monomer distinction.
- name: Lecanemab
  description: >-
    A humanised IgG1 monoclonal antibody with high affinity for amyloid-beta
    protofibrils, approved for early symptomatic sporadic Alzheimer disease on
    the basis of the Clarity AD trial, where it lowered amyloid burden and
    modestly slowed decline. IMPORTANT SCOPE CAVEAT: the pivotal evidence is in
    sporadic early Alzheimer disease, NOT in autosomal dominant disease; efficacy
    specifically in ADAD carriers has not been established, and the failure of
    gantenerumab and solanezumab to move cognition in DIAN-TU-001 means
    extrapolation should not be assumed. It is listed here because
    protofibril-directed removal of aggregated amyloid is the same mechanistic
    strategy as gantenerumab and is the class currently available to clinicians
    caring for ADAD carriers.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: lecanemab
      term:
        id: NCIT:C175105
        label: Lecanemab
  target_mechanisms:
  - target: Progressive Cortical Amyloid Accumulation
    treatment_effect: INHIBITS
    description: >-
      Binds amyloid-beta protofibrils and promotes clearance of aggregated
      amyloid, reducing cortical amyloid burden.
  evidence:
  - reference: PMID:36449413
    reference_title: Lecanemab in Early Alzheimer's Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lecanemab reduced markers of amyloid in early Alzheimer's disease and
      resulted in moderately less decline on measures of cognition and function
      than placebo at 18 months but was associated with adverse events.
    explanation: >-
      Establishes amyloid lowering and modest clinical benefit in EARLY SPORADIC
      Alzheimer disease. Marked PARTIAL because the trial population was not
      autosomal dominant carriers, so it supports the mechanism class but not
      ADAD-specific efficacy.
- name: Donanemab
  description: >-
    A monoclonal antibody targeting the N-terminal pyroglutamate-modified
    amyloid-beta epitope found only in established plaque, approved for early
    symptomatic sporadic Alzheimer disease after the TRAILBLAZER-ALZ 2 trial. The
    same scope caveat as lecanemab applies: the pivotal evidence is in sporadic
    disease and ADAD-specific efficacy is unestablished.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: donanemab
      term:
        id: NCIT:C166484
        label: Donanemab
  target_mechanisms:
  - target: Progressive Cortical Amyloid Accumulation
    treatment_effect: INHIBITS
    description: >-
      Binds pyroglutamate-modified amyloid-beta present only in deposited plaque,
      driving microglial plaque removal.
  evidence:
  - reference: PMID:37459141
    reference_title: >-
      Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2
      Randomized Clinical Trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among participants with early symptomatic Alzheimer disease and amyloid and
      tau pathology, donanemab significantly slowed clinical progression at 76
      weeks in those with low/medium tau and in the combined low/medium and high
      tau pathology population.
    explanation: >-
      Establishes clinical benefit in EARLY SPORADIC Alzheimer disease. Marked
      PARTIAL because the trial did not enrol autosomal dominant carriers.
- name: Predictive Genetic Testing and Genetic Counselling
  description: >-
    Because ADAD is deterministic and 50% of a carrier's children are at risk,
    formal genetic counselling with the option of presymptomatic predictive
    testing is a core, non-pharmacological part of care. It also enables
    reproductive options and, practically, is a prerequisite for participation in
    secondary-prevention trials such as the DIAN-TU open-label extension, which
    required participants to know their mutation status.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:40120616
    reference_title: >-
      Safety and efficacy of long-term gantenerumab treatment in dominantly
      inherited Alzheimer's disease: an open-label extension of the phase 2/3
      multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU
      trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For inclusion in the OLE, participants at risk for DIAD had participated in
      the double-blind period of DIAN-TU-001 and were required to know their
      mutation status.
    explanation: >-
      Documents genotype disclosure - and therefore predictive genetic testing
      with counselling - as an operational requirement of ADAD trial
      participation.
clinical_trials:
- name: NCT01760005
  phase: PHASE_III
  status: COMPLETED
  description: >-
    DIAN-TU-001, the first secondary-prevention platform trial in autosomal
    dominant Alzheimer disease. Randomised, double-blind, placebo-controlled,
    multi-arm, enrolling mutation carriers from 15 years before to 10 years after
    their estimated years to symptom onset. Registered as a phase 2/3 trial; the
    gantenerumab and solanezumab arms ran from 2012 to 2019, and the gantenerumab
    open-label extension (2020-2023, NCT06424236) escalated to substantially
    higher doses.
  target_phenotypes:
  - preferred_term: Dementia
    term:
      id: HP:0000726
      label: Dementia
  - preferred_term: Impaired episodic memory
    term:
      id: HP:0002354
      label: Memory impairment
  evidence:
  - reference: clinicaltrials:NCT01760005
    reference_title: >-
      A Phase II/III Multicenter Randomized, Double-Blind, Placebo-Controlled
      Platform Trial of Potential Disease Modifying Therapies Utilizing
      Biomarker, Cognitive, and Clinical Endpoints in Dominantly Inherited
      Alzheimer's Disease
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The purpose of this study is to assess the safety, tolerability, biomarker,
      cognitive and clinical efficacy of investigational products in participants
      with an Alzheimer's disease-causing mutation
    explanation: >-
      ClinicalTrials.gov record confirming that this platform trial enrols
      carriers of Alzheimer disease-causing mutations, i.e. the ADAD population.
  - reference: PMID:34155411
    reference_title: >-
      A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's
      disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fifty-two participants carrying a mutation were assigned to receive
      gantenerumab, 52 solanezumab and 40 placebo.
    explanation: >-
      Reports the randomised allocation of the DIAN-TU-001 double-blind period.
- name: NCT00869817
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    The Dominantly Inherited Alzheimer Network (DIAN) observational study: a
    longitudinal, multi-site natural-history and biomarker cohort of members of
    ADAD pedigrees, both carriers and non-carriers. It produced the canonical
    preclinical biomarker cascade that this entry's pathophysiology chain is
    built on, and supplies the participants and the estimated-years-to-onset
    staging used by DIAN-TU. Observational, so no trial phase applies.
  evidence:
  - reference: clinicaltrials:NCT00869817
    reference_title: Dominantly Inherited Alzheimer Network (DIAN)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The purpose of this study is to identify potential biomarkers that may
      predict the development of Alzheimer's disease in people who carry an
      Alzheimer's mutation.
    explanation: >-
      ClinicalTrials.gov record confirming the observational biomarker aim and
      the mutation-carrier population of the DIAN cohort.
  - reference: PMID:22784036
    reference_title: Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Participants at risk for carrying a mutation for autosomal dominant
      Alzheimer’s disease were enrolled in the Dominantly Inherited Alzheimer
      Network (DIAN) study at 1 of 10 sites.
    explanation: >-
      Describes the DIAN observational cohort whose baseline data produced the
      biomarker cascade.
discussions:
- discussion_id: gap_adad_amyloid_removal_clinical_benefit
  prompt: >-
    Does complete, sustained removal of cerebral amyloid before symptom onset
    prevent or delay dementia in autosomal dominant Alzheimer disease carriers,
    or is the amyloid cascade causally sufficient to initiate the disease but no
    longer the rate-limiting step once tau pathology and neurodegeneration are
    established?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Progressive Cortical Amyloid Accumulation
  - pathophysiology#Site-Specific Soluble Tau Hyperphosphorylation
  - pathophysiology#Neurofibrillary Tangle Formation
  rationale: >-
    ADAD is the cleanest available test of the amyloid hypothesis: causation is
    monogenic and deterministic, onset is predictable, and asymptomatic carriers
    can be treated years before symptoms. Yet the DIAN-TU-001 double-blind period
    showed unambiguous target engagement and downstream biomarker movement
    (plaques, total tau, phospho-tau181, neurofilament light chain) with NO
    cognitive benefit. The open-label extension hints at a benefit from long-term
    complete removal (hazard ratio 0.53 in the longest-treated group), but it is
    open-label with external controls, was terminated early by the sponsor, and
    the authors explicitly caution against over-reading it. The gap is therefore
    not whether amyloid causes ADAD - the genetics settle that - but whether
    amyloid removal is a sufficient intervention, and at what point in the
    cascade it stops being one. This is a genuine absence of evidence rather than
    a model-system translation problem, hence KNOWLEDGE_GAP.
  proposed_experiments:
  - experiment_id: exp_adad_primary_prevention_full_removal
    name: >-
      Randomised, controlled primary-prevention trial of sustained complete
      amyloid removal in far-presymptomatic ADAD carriers
    description: >-
      Enrol mutation carriers substantially earlier than DIAN-TU-001 did - before
      amyloid PET positivity, i.e. more than 15 years before expected symptom
      onset - and treat to and maintain amyloid-negative status with an internal
      randomised control arm rather than external controls. Primary endpoint:
      time to first CDR progression; key secondary: whether tau PET and CSF pT217
      trajectories are prevented from ever diverging from non-carriers. A
      negative result under these conditions would constrain the amyloid
      hypothesis far more sharply than any trial to date.
  evidence:
  - reference: PMID:40120616
    reference_title: >-
      Safety and efficacy of long-term gantenerumab treatment in dominantly
      inherited Alzheimer's disease: an open-label extension of the phase 2/3
      multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU
      trial.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Conclusions are limited due to the OLE design and use of external controls
      and need to be confirmed in long term trials.
    explanation: >-
      The trialists themselves state that the question of clinical benefit from
      long-term amyloid removal in ADAD remains open.
- discussion_id: gap_adad_apoe_christchurch_resilience
  prompt: >-
    By what mechanism does homozygous APOE3 Christchurch (R136S) uncouple very
    high cerebral amyloid burden from tau pathology, neurodegeneration, and
    cognitive onset in a PSEN1 E280A carrier, and can that mechanism be
    pharmacologically reproduced?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Site-Specific Soluble Tau Hyperphosphorylation
  - pathophysiology#Neurofibrillary Tangle Formation
  rationale: >-
    A single PSEN1 E280A carrier homozygous for APOE3 Christchurch remained free
    of mild cognitive impairment until her seventies - three decades past the
    expected onset for that variant - despite unusually high brain amyloid. This
    is a human experiment showing that the amyloid-to-tau edge in this entry's
    pathograph is not obligate and can be broken downstream of amyloid. What is
    not known is which APOE function (lipidation, heparan sulfate proteoglycan
    binding, astrocytic or microglial signalling) is responsible, whether the
    effect generalises beyond a single individual and genotype, and whether an
    APOE-directed drug could reproduce it. Resolving this would identify a
    tau-arm target that acts even when amyloid removal has failed.
  evidence:
  - reference: PMID:31686034
    reference_title: >-
      Resistance to autosomal dominant Alzheimer's disease in an APOE3
      Christchurch homozygote: a case report.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a PSEN1 (presenilin 1) mutation carrier from the world's
      largest autosomal dominant Alzheimer's disease kindred, who did not develop
      mild cognitive impairment until her seventies, three decades after the
      expected age of clinical onset.
    explanation: Documents the resilience observation that defines this gap.
- discussion_id: gap_adad_gamma_secretase_mechanism_heterogeneity
  prompt: >-
    Given that familial Alzheimer disease variants alter the qualitative spectrum
    of amyloid-beta products through at least three distinct mechanisms - with
    many PSEN variants paradoxically IMPAIRING gamma-secretase rather than
    activating an Abeta42-generating gain of function - does a single
    Abeta42:Abeta40-ratio model adequately describe the proximal lesion across
    all ADAD genotypes?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Altered Gamma-Secretase Processing of APP and Increased Abeta42 Fraction
  rationale: >-
    This entry's second pathophysiology node is written around an increased
    Abeta42 fraction, which is the standard formulation and is what the DIAN
    biomarker data are consistent with at the level of the whole cohort. But the
    kinetic dissection of gamma-secretase shows the proximal step is
    mechanistically heterogeneous across variants, so a per-genotype description
    may be required - which matters directly for drug design, since it is the
    reason indiscriminate gamma-secretase inhibitors failed while modulators
    remain of interest. Whether the mechanistic subclasses map onto differences
    in age at onset, biomarker trajectory, or treatment response in living
    carriers is untested.
  evidence:
  - reference: PMID:22505025
    reference_title: The mechanism of γ-Secretase dysfunction in familial Alzheimer disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Overall, we provide a coherent explanation for the effect of different FAD
      mutations, demonstrating the importance of qualitative rather than
      quantitative changes in the Aβ products, and suggest fundamental
      improvements for current drug development efforts.
    explanation: >-
      States the qualitative-versus-quantitative mechanistic question that this
      gap records as unresolved in vivo.
references:
- reference: PMID:20301340
  title: Alzheimer Disease Overview.
  tags:
  - GeneReviews

📚

References & Deep Research

References

1

PMID:20301340

Alzheimer Disease Overview.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

Early-Onset Autosomal Dominant Alzheimer Disease (ADAD/EOFAD): Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 46 citations 2026-07-31T15:11:38.813570

Early-Onset Autosomal Dominant Alzheimer Disease (ADAD/EOFAD): Comprehensive Research Report

1. Disease Information

Overview: Early-Onset Autosomal Dominant Alzheimer Disease (ADAD, also called Early-Onset Familial Alzheimer Disease, EOFAD) is a fully penetrant, Mendelian form of Alzheimer's disease caused by pathogenic variants in APP, PSEN1, or PSEN2. It produces the same core neuropathological and clinical phenotype as sporadic late-onset AD (amyloid-β plaques, neurofibrillary tangles, progressive dementia) but with a much earlier, highly predictable age of onset — typically before age 65, and often in the 30s–50s — and with a family history consistent with autosomal dominant transmission across generations. ADAD accounts for a small minority of all AD (~1% of total AD cases; ~5–10% of early-onset AD, EOAD), but it has been disproportionately important to AD research because carriers can be identified presymptomatically decades before expected symptom onset, enabling prospective study of the full preclinical-to-symptomatic biomarker cascade (the basis of the Dominantly Inherited Alzheimer Network, DIAN).

Key Identifiers: - MONDO: MONDO:0015140 (early-onset autosomal dominant Alzheimer disease) - Orphanet: ORPHA:1020 - OMIM (gene-specific subtypes): - AD1 — OMIM:104300 (APP, 21q21.3) - AD3 — OMIM:607822 (PSEN1, 14q24.2) - AD4 — OMIM:606889 (PSEN2, 1q42.13) - Additional related OMIM entries returned by Orphanet cross-reference include 104310, 602096, 604154, 605055 (familial early-onset AD with coexisting amyloid and prion pathology), 605526, 606187, 607116, 609636, 609790, 611073, 611152, 611154 (locus/phenotype variant entries) - ICD-11: 8A20.00 (Alzheimer disease, early onset) — ICD-10: G30.0 - MeSH: D000544 (Alzheimer Disease); no distinct MeSH term for the familial subtype specifically, indexed under "Alzheimer Disease" + genetic subheadings - HPO (disease-level phenotype set anchor): HP:0002511 (Alzheimer disease); HP:0031060 (early-onset Alzheimer disease, if present in current HPO builds)

Synonyms: Early-onset familial Alzheimer disease (EOFAD); Familial Alzheimer disease (FAD); Autosomal dominant Alzheimer disease (ADAD); Dominantly Inherited Alzheimer Disease (DIAD, used specifically by the DIAN consortium); Presenilin-related familial Alzheimer disease.

Data provenance: Nearly all mechanistic and biomarker knowledge for ADAD is aggregated disease-level knowledge synthesized from large observational cohorts (DIAN Observational Study, the Colombian PSEN1 E280A "Paisa" kindred cohort, the UK/European ADAD case series) rather than isolated EHR mining — this is a rare-disease field built on international, prospectively phenotyped, longitudinally followed multi-generational kindreds. (Orphanet: Early onset autosomal dominant Alzheimer disease; GARD: Early-onset autosomal dominant Alzheimer disease)

2. Etiology

Disease causal factors: ADAD is caused by heterozygous, fully penetrant (or near-fully penetrant) pathogenic variants in one of three genes, each converging on abnormal amyloid-β (Aβ) generation: - PSEN1 (presenilin-1, the catalytic subunit of γ-secretase) — the most common cause, accounting for ~69–70% of genetically-solved ADAD; over 300 pathogenic variants reported (missense predominant). - APP (amyloid precursor protein) — missense variants near the β- or γ-secretase cleavage sites, or whole-gene duplication (as in Down syndrome trisomy 21, which produces an ADAD-like phenotype via APP gene-dosage) — ~13–16% of cases (variants) plus ~7.5% (duplications). - PSEN2 (presenilin-2, homologous γ-secretase subunit) — rarest cause (~2%), notably enriched in the Volga German kindreds (N141I variant).

Genetic screening studies place combined APP/PSEN1/PSEN2 solve rates at roughly 60–70% of clinically defined familial (autosomal-dominant pedigree) early-onset AD (PLOS Medicine genetic screening study).

Risk factors: - Genetic: Inheriting one causal variant is both necessary and (with near-complete penetrance) sufficient — this is a monogenic disorder, not a polygenic-susceptibility one. Modifier loci shift age of onset but do not determine disease occurrence: APOE genotype (ε4 accelerates amyloid accumulation timing in some cohorts, though effects are more modest/variable than in sporadic AD — PSEN1 E280A ε4 carriers showed amyloid-PET-positivity ~3 years earlier than non-carriers); DAOA rs2391191 (A/A genotype associated with later onset in PSEN1 A431E carriers, PMC12387094); specific γ-secretase "Aβ profile" generated by a given PSEN1/PSEN2/APP variant (ratio and composition of Aβ37/38/40/42/43 species correlates linearly with age at onset across all three genes — PMC12032737, unifying "spectrum of γ-secretase dysfunction" model). - Environmental: Age is the dominant non-genetic modifier of symptom expression (variant-specific mean onset age, but individual variance of years-to-decades exists even within families carrying the identical variant). Educational attainment is protective/moderating for cognitive trajectory independent of neuropathological burden (cognitive reserve effect; Nature Communications, PMC10447560). Head trauma and cardiovascular risk factors are implicated as accelerants in sporadic AD but are less well-characterized as modifiers specifically in ADAD. - Reduced penetrance exceptions: Rare variants such as PSEN1 H163Y show documented reduced penetrance with symptom-free survival into advanced age in some carriers (22-year follow-up study, PMC5944151), indicating unmeasured genetic/epigenetic/environmental modifiers exist even in "fully penetrant" genes.

Protective factors: APOE ε2 has been associated with delayed cognitive decline/onset in some ADAD cohorts (contrasted with ε4 acceleration). No validated environmental protective factor is specific to ADAD; general cognitive-reserve/educational-attainment effects (moderating clinical expression of a fixed pathological burden) are the best-supported protective modifiers.

Gene-environment interactions: Formal GxE studies in ADAD are sparse given the small, geographically dispersed kindred sizes; the strongest documented interaction is the education × APOE interaction on cognitive trajectory (education moderates but does not eliminate the negative effect of APOE ε4 on cognition in mutation carriers).

3. Phenotypes

ADAD presents the core sporadic-AD phenotype (progressive episodic memory impairment leading to global dementia) plus a materially higher rate of "atypical"/non-amnestic and neurological accompaniments than late-onset sporadic AD, particularly with PSEN1 variants.

Core cognitive/behavioral phenotype: - Episodic memory impairment (initial and near-universal presenting symptom) — HP:0002354 (Memory impairment) / HP:0031830 (?) — best mapped to HP:0002354. - Progressive dementia — HP:0000726 (Dementia) - Behavioral/personality change (frequently an early presenting feature alongside or preceding memory loss) — HP:0000708 (Behavioral abnormality) / HP:0000722 (Irritability) / HP:0100716 (Self-injurious behavior, situational) - Language impairment / aphasia — HP:0002381 (Aphasia) - Executive dysfunction — HP:0002357 (?), best represented as HP:0002344 (Attention deficit) or a general HP:0031466 executive-function term depending on HPO build.

Neurological accompaniments enriched in ADAD (especially PSEN1): - Myoclonus — HP:0001336 — onset relatively early in disease course in ~70% of those affected; strong predictor of subsequent seizures. - Seizures — HP:0001250 — early-onset seizures in ~30% of affected individuals with myoclonus, late-onset in ~50%; individuals with myoclonus are 40% (PSEN1) to 50% (APP) more likely to develop seizures than those without (Lancet Neurology case series; ScienceDirect DIAN-OBS comparison, S1474442216302290). - Spastic paraparesis — HP:0007256 (Progressive spastic paraparesis) — variably associated with specific PSEN1 variants (e.g., the "spastic paraparesis variant" phenotype); pyramidal signs seen in ~25% of PSEN1 carriers in some series, restricted to PSEN1 (not seen with APP/PSEN2) — a genotype-phenotype correlation. - Extrapyramidal signs (parkinsonism) — HP:0002548 (Extrapyramidal sign) - Cerebellar ataxia — HP:0001251 — rare/exceptional. - Intracerebral hemorrhage — HP:0001342 — associated particularly with certain APP variants causing cerebral amyloid angiopathy (CAA), e.g., Dutch/Iowa-type variants. - Visual disturbance / posterior cortical features — HP:0000505 (Visual impairment)

Phenotype characteristics: - Age of onset: Highly variant-specific. PSEN1 mutations cause the earliest onset overall (mean often 30s–50s; documented range from as young as ~24 years to the 60s). PSEN2 and APP variants show delayed onset relative to PSEN1 — recent quantitative work estimates mean delays of ~27 years for PSEN2 and ~8 years for APP relative to PSEN1 (2025 study cited above). - Severity/progression: Uniformly progressive; disease course pattern is relentlessly progressive (not relapsing-remitting), typically over 8–10 years from symptom onset to death, though this varies by variant. - Frequency of specific neurological signs: Varies substantially by variant and gene (see above percentages); a UK case series and DIAN-OBS comparison found systematic differences between published literature phenotype summaries and directly-observed DIAN-OBS cohort data, cautioning against over-generalizing single-kindred phenotype reports (PMC12738114).

Quality of life impact: Progressive loss of independent function (activities of daily living), caregiver burden, and — because of early working-age onset — substantial socioeconomic and family-planning impact distinct from late-onset AD (loss of employment/income during peak career/parenting years; documented psychological burden and elevated suicidal ideation risk in at-risk relatives undergoing predictive testing, PMC10046467).

4. Genetic/Molecular Information

Causal genes: | Gene | HGNC | OMIM (gene) | Locus | Approx. % of solved ADAD | |---|---|---|---|---| | PSEN1 | HGNC:9508 | 104311 | 14q24.2 | ~69% | | APP | HGNC:620 | 104760 | 21q21.3 | ~13% (point variants) + ~7.5% (duplication) | | PSEN2 | HGNC:9509 | 600759 | 1q42.13 | ~2% |

Pathogenic variants: - PSEN1 — >300 reported pathogenic missense variants distributed across all 9 transmembrane domains; classified pathogenic/likely pathogenic per ACMG/AMP in ClinVar. Loss of normal γ-secretase substrate-processivity (rather than simple gain- or loss-of-function) is now understood as the shared mechanism: variants shift the ratio of Aβ species toward longer, more amyloidogenic forms (Aβ42, Aβ43) relative to Aβ40. Example founder variants: E280A (Colombian "Paisa" kindred, the largest single-family ADAD cohort in the world), A431E (Jalisco, Mexico, founder variant). - APP — Variants cluster near the β-secretase (Swedish, KM670/671NL), α-secretase (e.g., London V717I), and γ-secretase cleavage sites, shifting APP processing toward increased total Aβ production or toward the more aggregation-prone Aβ42 species; the APP locus duplication (as in trisomy 21 / Down syndrome) causes ADAD-like early-onset AD purely through increased gene dosage/protein level, without any coding variant — direct evidence that increased Aβ production alone is sufficient to cause the disease. - PSEN2 — Fewer variants known; N141I is the classic Volga German founder variant; generally later, more variable onset and comparatively reduced penetrance versus PSEN1. - Variant type spectrum: Predominantly missense for PSEN1/PSEN2; missense and structural (duplication) for APP. Frameshift/nonsense variants are rare/atypical since loss-of-function null alleles of PSEN1 generally do not cause the classical ADAD phenotype (informing a "partial loss of normal function / gain of abnormal function" model for missense variants rather than simple haploinsufficiency). - Allele frequency: Pathogenic ADAD-causing variants are essentially absent or present at extremely low frequency (rarely >1 allele) in population reference databases (gnomAD), consistent with strong negative selection against a childhood/reproductive-age-compatible but ultimately lethal, fully penetrant dominant disease. - Somatic vs. germline: Germline in essentially all classical ADAD kindreds; no established somatic-mosaicism mechanism is a primary ADAD cause (contrast with some other neurogenetic disorders), though germline mosaicism has been raised as a genetic-counseling consideration for apparent de novo cases. - Functional consequence: The unifying functional theme (PMC12032737, "spectrum of γ-secretase dysfunction") is altered γ-secretase processivity of APP substrate, producing a quantitatively predictable shift in the Aβ42(43)/Aβ40 ratio that correlates linearly with age at onset across PSEN1, PSEN2, and APP variants — a genotype→biochemistry→age-of-onset relationship that is one of the most quantitatively robust genotype-phenotype correlations in neurodegenerative disease.

Modifier genes: APOE (ε2/ε3/ε4), DAOA (rs2391191), with ongoing multiomic work (PMC11699654) identifying "common endotypes" across PSEN1/PSEN2/APP mutation carriers suggesting shared downstream modifier pathways (inflammatory/astrocytic) independent of the specific causal gene.

Epigenetic information: No established disease-defining epigenetic lesion in ADAD itself (unlike, e.g., imprinting disorders); epigenetic dysregulation (DNA methylation changes at AD-associated loci, histone modification changes) is an active downstream/consequence research area in both sporadic and familial AD but is not established as causal.

Chromosomal abnormalities: The APP locus duplication (21q21.3) is the clearest chromosomal/structural mechanism; complete trisomy 21 (Down syndrome) produces an obligate ADAD-like phenotype via 3-copy APP dosage, with virtually universal AD neuropathology by the 40s and clinical dementia in a majority of individuals with Down syndrome by their 50s–60s — this is a widely used "genetically determined AD" comparator model in the field.

5. Environmental Information

ADAD is, by definition, monogenically determined with near-complete penetrance, so environmental/lifestyle factors are best understood as modifiers of the timing and expression of an essentially inevitable disease rather than determinants of whether disease occurs. - Environmental toxin/occupational factors: No ADAD-specific toxin exposure has been established as a modifier; general AD-epidemiology environmental factors (air pollution, pesticide exposure) are studied in sporadic AD but not specifically validated in ADAD cohorts. - Lifestyle factors: Educational attainment/cognitive reserve is the best-evidenced modifier of clinical (not necessarily pathological) trajectory in ADAD mutation carriers (Nature Communications, PMC10447560). Cardiovascular risk-factor management (as in sporadic AD) is plausibly beneficial but not specifically validated as modifying ADAD's core amyloid-driven course. - Infectious agents: Not implicated as a cause of ADAD. (The broader "infectious hypothesis" of sporadic AD, e.g., HSV-1, periodontal pathogens, remains investigational and is not part of the ADAD causal model, which is fully explained by the monogenic amyloidogenic mechanism.)

6. Mechanism / Pathophysiology

Overview causal chain (the amyloid cascade hypothesis, as directly demonstrated by ADAD genetics):

Trigger (molecular scale): Pathogenic PSEN1/PSEN2 variant alters γ-secretase complex processivity, OR pathogenic APP variant/duplication alters substrate availability or cleavage-site accessibility → shift in the ratio and length distribution of Aβ peptides generated from sequential β- and γ-secretase cleavage of APP, favoring longer, more aggregation-prone species (Aβ42, Aβ43) over Aβ40.
Aβ aggregation and amyloidosis (molecular→cellular): Increased relative Aβ42/43 production → oligomerization → fibrillization → extracellular amyloid plaque deposition (diffuse and neuritic plaques) and, for certain APP variants, cerebral amyloid angiopathy (vascular Aβ deposition). This is the earliest detectable biomarker change, beginning ~20–25 years before expected symptom onset in DIAN cohort data (Bateman et al., NEJM 2012 — landmark longitudinal biomarker cascade paper; NEJM full text).
Downstream tauopathy: Amyloid pathology precipitates (via still partially defined mechanisms involving synaptic dysfunction, oxidative stress, and kinase dysregulation) hyperphosphorylation of microtubule-associated protein tau by kinases including GSK-3β; presenilins themselves (via γ-secretase-dependent and -independent roles) normally help regulate GSK-3β subcellular localization and restrain tau hyperphosphorylation, so presenilin dysfunction can directly promote tauopathy in addition to its Aβ-generating effect. Hyperphosphorylated tau detaches from microtubules, impairing axonal transport, and self-aggregates into paired helical filaments forming intraneuronal neurofibrillary tangles — occurring downstream of and temporally after amyloid changes in the DIAN cascade (tau PET/CSF changes emerge and progress after amyloid positivity).
Neuroinflammation / microglial dysfunction (cellular): Aβ plaques and early oligomers activate microglia; TREM2 (via DAP12-SYK signaling) mediates microglial phagocytic clearance of Aβ and, together with complement (C1q) and APOE, mediates aberrant microglial synaptic pruning/engulfment. Chronic activation produces a maladaptive, disease-associated microglial (DAM) state contributing to a self-perpetuating neuroinflammatory milieu rather than effective clearance.
Synaptic and neuronal injury (cellular→tissue): Soluble Aβ oligomers directly impair synaptic function and induce neuronal hyperactivity; combined amyloid/tau/neuroinflammatory burden drives synaptic loss (the pathological correlate best correlated with cognitive impairment), followed by neuronal loss.
Neurodegeneration and atrophy (tissue→organism): Progressive regional brain atrophy (starting in medial temporal lobe/hippocampus, later diffuse), declining cerebral glucose metabolism (FDG-PET hypometabolism), and clinical cognitive decline — occurring last in the DIAN cascade, ~10–20 years after the earliest amyloid biomarker changes.

Suggested GO terms (biological processes): - GO:0034205 amyloid-beta formation - GO:1902430 negative regulation of amyloid-beta formation (relevant to pathway perturbation) - GO:0007172 signal complex assembly (γ-secretase complex context) / GO:0070765 gamma-secretase complex - GO:0006338 chromatin remodeling (epigenetic downstream, if modeled) - GO:0050890 cognition (phenotypic endpoint) - GO:0001764 neuron migration / GO:0007399 nervous system development (not primary) - GO:0043523 regulation of neuron apoptotic process - GO:0045087 innate immune response (microglial activation) - GO:0006979 response to oxidative stress

Suggested CL terms (cell types): - CL:0000540 neuron (generic); CL:0000031 (neuroblast, not relevant) - CL:0000679 glutamatergic neuron (pyramidal/cortical neurons preferentially affected) - CL:0000129 microglial cell - CL:0000127 astrocyte (reactive astrogliosis) - CL:0002453 oligodendrocyte precursor cell (secondary white-matter involvement, less central)

Molecular functions/UniProt/PDB: APP (UniProt P05067); PSEN1 (UniProt P49768); PSEN2 (UniProt P49810); γ-secretase complex structures resolved by cryo-EM (PDB entries exist for human γ-secretase, e.g., 5A63, 5FN2).

Metabolic/biochemical: Downstream mitochondrial dysfunction and impaired glucose metabolism (FDG-PET hypometabolism is a core biomarker); altered lipid metabolism (cholesterol trafficking) links to APOE modifier effects.

Molecular profiling / advanced technologies: Multi-omic integration work across PSEN1/PSEN2/APP carriers has identified convergent ("common endotype") transcriptomic/proteomic signatures independent of the specific causal gene (PMC11699654), and iPSC-derived astrocyte models of PSEN1 variants show disrupted regulated intramembrane proteolysis predisposing to inflammatory phenotypes (PMC12181884) — evidence that presenilin dysfunction has γ-secretase-independent, immune-relevant cellular consequences beyond simple amyloidogenesis.

7. Anatomical Structures Affected

Organ level: Primary organ — brain (UBERON:0000955). Body system — nervous system (UBERON:0001016). Secondary/complication involvement: cerebral vasculature (in APP-variant-associated cerebral amyloid angiopathy, risk of intracerebral hemorrhage); spinal cord/corticospinal tract involvement clinically manifesting as spastic paraparesis in specific PSEN1 variants.

Tissue/cell level: - Cerebral cortex (UBERON:0000956), especially medial temporal lobe / hippocampus (UBERON:0002421) — earliest and most severe atrophy. - Entorhinal cortex (UBERON:0002728) — early tau pathology site (Braak staging origin). - Precuneus/posterior cingulate — early amyloid-PET/FDG-PET signal. - Cell populations: large glutamatergic pyramidal neurons (CL:0000679) selectively vulnerable; microglia (CL:0000129) and astrocytes (CL:0000127) reactively involved; cerebrovascular smooth muscle/endothelium involved in CAA.

Subcellular level: Extracellular amyloid plaques (GO:0097418 neurofibrillary tangle for the intracellular counterpart); GO:0005789 endoplasmic reticulum membrane and GO:0031090 organelle membrane (site of γ-secretase activity — PSEN1/2 are ER/Golgi/plasma-membrane transmembrane proteins); GO:0005739 mitochondrion (downstream dysfunction); GO:0045202 synapse (site of Aβ oligomer toxicity and microglial synaptic pruning).

Localization: Bilateral, generally symmetric involvement (contrast with focal neurodegenerative syndromes); progresses from medial temporal to diffuse neocortical involvement per Braak/Thal staging schemes, mirrored in amyloid-PET (Thal phases) and tau-PET (Braak-like patterns) in DIAN cohort imaging.

8. Temporal Development

Onset: Adult onset, defined as pre-senile (<65 years) and typically much earlier — commonly 30s–50s, occasionally younger depending on variant (as young as mid-20s reported for some aggressive PSEN1 variants). Onset pattern is insidious, not acute — a subtle prodromal decline over months to a few years before diagnosis.

Progression (the DIAN biomarker cascade — a hallmark, extensively validated natural-history finding): 1. Aβ42 CSF changes and amyloid-PET positivity — begin ~20–25 years before expected symptom onset (estimated from parental age at onset within a kindred). 2. Cerebral glucose hypometabolism (FDG-PET) — begins ~10–15 years before onset (~7–10 years after earliest amyloid change). 3. Hippocampal/structural atrophy and initial subtle cognitive decline — begin roughly 10–15 years, becoming clearly measurable ~5 years before clinical onset. 4. Clinical Dementia Rating (CDR) transition to symptomatic/impaired — the defined "onset." 5. Progressive dementia over subsequent years to death (variable, commonly 8–10 years post-diagnosis, similar to sporadic AD trajectory once symptomatic).

(Bateman et al. 2012 NEJM, "Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease"; subsequent DIAN longitudinal work confirming and refining timing, e.g., Neurology 2018 "Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease," and the 2025 "15 years of longitudinal…measures in DIAN" (npj Dementia) update.)

Disease stages: Preclinical (biomarker-positive, cognitively normal) → prodromal/MCI (mild cognitive impairment due to AD) → mild dementia → moderate dementia → severe/end-stage dementia — the CDR and DIAN "Estimated Years to Symptom Onset" (EYO) framework are the field-standard staging tools, distinct from generic AJCC-style staging (not applicable to a non-oncologic disease).

Progression rate/course: Once symptomatic, relentlessly progressive, non-remitting; among the more rapid dementia trajectories compared with typical sporadic late-onset AD, partly reflecting younger baseline health and higher pathological burden at a given clinical stage in some series, though this is debated.

Patterns: No spontaneous or treatment-induced remission is described; anti-amyloid immunotherapy trials (below) aim to slow but not yet reverse progression. The presymptomatic ~20-year biomarker-positive window is the field's key "critical period" for intervention — the rationale for the DIAN-TU prevention trials targeting mutation carriers before symptom onset.

9. Inheritance and Population

Epidemiology: - EOAD overall (<65y onset, all causes) prevalence ≈ 41.2 per 100,000 persons at risk in population-based estimates; incidence in the 45–64 age band ≈ 6.3/100,000/year, prevalence ≈ 24.2/100,000, rising steeply approaching age 65. - ADAD specifically (autosomal-dominant EOAD, ADEOAD): population prevalence ≈ 5.3 per 100,000 persons at risk (same population-based study cited above). - ADAD is estimated to account for ~1% of all AD cases overall, and ~5–10% of early-onset AD cases are attributable to dominantly inherited mutations, with the remainder of EOAD considered sporadic/complex/oligogenic. - Among familial EOAD (patients with ≥1 affected first-degree relative, 35–60% of EOAD), only 10–15% show a clear autosomal-dominant transmission pattern solvable by APP/PSEN1/PSEN2 testing.

Inheritance pattern: Autosomal dominant (HP:0000006). Penetrance is near-complete/"fully penetrant" for the great majority of PSEN1 variants and the APP variants/duplication; documented exceptions with reduced/age-dependent penetrance exist (e.g., PSEN1 H163Y). PSEN2 variants (e.g., N141I) show somewhat more variable, occasionally incomplete penetrance and later/more variable onset than PSEN1.

Expressivity: Variable — age of onset varies not only between genes and between different variants within a gene, but also between individuals carrying the identical variant within the same family, implicating modifier genes (APOE, DAOA) and other unmeasured factors.

Genetic anticipation: Not a defined feature of ADAD (unlike repeat-expansion disorders); no systematic earlier-onset-in-successive-generations pattern is established.

Germline mosaicism: A recognized genetic-counseling consideration for apparent de novo PSEN1/APP cases (parental germline mosaicism can produce unaffected parents with an affected child and residual recurrence risk for future pregnancies), though formally documented cases specific to ADAD genes are limited in the literature relative to other dominant disorders.

Founder effects: Well documented — PSEN1 E280A in the Colombian "Paisa" kindred (~6,000-member, ~1,200 carrier-lineage pedigree, the world's largest single ADAD kindred, central to the Colombia-API prevention trial); PSEN1 A431E in the Jalisco, Mexico population; PSEN2 N141I in Volga German-descended families in the United States.

Consanguinity: Not a relevant risk factor for this autosomal dominant disorder (in contrast to recessive conditions) — a single inherited or de novo copy is sufficient.

Carrier frequency: Population carrier frequency of any single pathogenic ADAD variant is extremely low (rare/private variants, or locally elevated only within founder-effect populations/kindreds); no meaningful general-population carrier screening frequency exists comparable to recessive-disease carrier screening.

Population demographics: No strong evidence for differential susceptibility by ethnicity beyond the founder-population enrichments noted above (Colombian, Mexican, Volga German lineages) — these reflect genealogical founder effects, not differential biological susceptibility. Sex ratio: approximately equal (autosomal, not sex-linked), consistent with Mendelian expectation, though APOE-related modifier effects (and sporadic-AD female-predominance patterns) may subtly influence age-of-onset/progression statistics by sex in some analyses. Age distribution of affected individuals is, by definition, the defining "early-onset" feature (predominantly 30s–50s at symptom onset, contrasted with the ≥65y peak of sporadic AD).

10. Diagnostics

Clinical tests: - Biomarkers (CSF): CSF Aβ42/Aβ40 ratio (decreased) and phosphorylated tau (p-tau181, increasingly p-tau217, p-tau231) are core, guideline-incorporated AD biomarkers; CSF p-tau217/Aβ42 ratio and p-tau217 phosphorylation occupancy show improved performance over p-tau181 for detecting amyloid and tau pathology (Nature Aging, PMC study cited above). - Blood-based biomarkers: Plasma p-tau217 and the p-tau217/Aβ1-42 ratio now show AUC 0.94–0.97 for detecting amyloid pathology against CSF/PET reference standards, a major recent (2024–2025) advance enabling non-invasive, scalable case detection and monitoring — highly relevant for at-risk ADAD family members considering testing and for trial screening/enrollment. - Imaging: Amyloid-PET (e.g., florbetapir, Pittsburgh compound B) — earliest positive biomarker in the DIAN cascade; tau-PET (flortaucipir) — shows variant-specific signatures, e.g., a characterized flortaucipir signature specific to PSEN1 A431E carriers (PMC12740027); structural MRI for hippocampal/cortical atrophy; FDG-PET for regional hypometabolism. - Neurophysiology: EEG may show abnormalities correlating with myoclonus/seizure activity, which are enriched in ADAD relative to sporadic AD. - Neuropathology (postmortem/rare biopsy): Amyloid plaques (neuritic and diffuse), neurofibrillary tangles (Braak staging), cerebral amyloid angiopathy (especially with certain APP variants); the OMIM:605055 entry specifically flags documented coexisting amyloid and prion pathology in some familial early-onset AD cases, an important differential/comorbidity note.

Genetic testing: - Recommended approach: targeted sequencing (single-gene or small panel) of APP, PSEN1, PSEN2 in individuals with early-onset dementia (<65y) and/or a family history consistent with autosomal dominant inheritance; panel/gene-panel testing is standard of care (per GeneReviews/ClinGen-informed protocols) rather than routine WGS/WES as first-line, though WES/WGS is used when panel testing is uninformative or the phenotype is atypical. - Predictive (presymptomatic) testing in at-risk, asymptomatic relatives follows Huntington-disease-style genetic counseling protocols (given the comparably severe, currently incurable, fully penetrant nature of the result) — pre- and post-test counseling, psychological support, and consideration of implications for insurance/employment/family planning are essential; documented elevated suicidal-ideation risk in this population underscores the need for structured counseling (PMC10046467). - Chromosomal microarray/karyotyping is relevant specifically to detect APP locus duplication or trisomy 21 as a cause. - Not relevant: mitochondrial DNA testing, repeat-expansion testing (ADAD is not a repeat-expansion disorder).

Omics-based diagnostics: Not yet standard clinical practice for ADAD; used in research contexts (multi-omic endotyping, PMC11699654) but blood p-tau217 is the closest omics-adjacent tool nearing clinical/trial-screening utility.

Clinical criteria: Standard AD clinical diagnostic frameworks (NIA-AA criteria, now biomarker-integrated) apply; DSM-5 criteria for Major/Mild Neurocognitive Disorder due to Alzheimer's Disease apply clinically. Differential diagnosis must consider: frontotemporal dementia (especially when behavioral/language-predominant presentation), other early-onset dementia genes (e.g., MAPT, GRN, C9orf72 for FTD spectrum; prion disease given the amyloid/prion overlap noted in OMIM:605055), and reversible causes of cognitive decline in a young patient (metabolic, autoimmune, structural).

Screening: Cascade genetic testing in at-risk relatives once a family proband variant is identified is the standard screening approach (not population newborn screening, given adult onset). Preimplantation genetic diagnosis (PGD/PGT-M) has been successfully used to select unaffected embryos for at-risk couples (documented case for an APP V717L family resulting in birth of an unaffected child, PMID:11866650).

11. Outcome/Prognosis

Survival/mortality: ADAD is ultimately fatal; life expectancy after symptom onset is broadly comparable to or somewhat shorter than sporadic AD, commonly on the order of 8–10 years from diagnosis to death, though this varies by causal variant and access to supportive care. No disease-modifying therapy has yet been shown to alter mortality.

Morbidity/function: Progressive functional decline through the classic AD trajectory — loss of instrumental then basic activities of daily living, eventual total care dependency. Given the working-age onset, morbidity burden (loss of employment, caregiving strain on a typically younger family unit with dependent children) is proportionally more disruptive than in late-onset sporadic AD.

Quality of life: Progressive decline across cognitive, functional, and psychological domains for both patients and caregivers; documented elevated psychological distress (including suicidal ideation) in unaffected at-risk relatives navigating predictive testing decisions is itself a distinct QoL/mental-health outcome domain specific to this genetically-predictable disease.

Complications: Seizures and myoclonus (notably more frequent than sporadic AD, particularly with PSEN1); intracerebral hemorrhage in CAA-associated APP variants; aspiration pneumonia and other end-stage-dementia complications as the ultimate proximate causes of death, as in sporadic AD.

Prognostic factors: Causal gene and specific variant (via its Aβ-species "biochemical signature") is the single strongest predictor of age at onset and, to a lesser extent, of rate of progression and accompanying neurological features (myoclonus/seizures/spasticity cluster with PSEN1). APOE genotype and, more speculatively, DAOA genotype and educational attainment act as secondary modifiers of onset timing and/or cognitive trajectory. Biomarker trajectory (rate of amyloid accumulation, tau-PET spread) is an active area of prognostic-biomarker research within DIAN and the newer anti-tau trials (e.g., etalanetug/E2814 targeting tau spread).

12. Treatment

Pharmacotherapy (symptomatic, shared with sporadic AD): - Cholinesterase inhibitors (donepezil, rivastigmine, galantamine) — MAXO term: pharmacotherapy generically (NCIT:C15986); symptomatic cognitive treatment, not disease-modifying. - NMDA receptor antagonist (memantine) — symptomatic, moderate-to-severe stages. - Symptomatic management of myoclonus/seizures (anti-seizure medications, e.g., levetiracetam) given their elevated frequency in ADAD.

Advanced/disease-modifying therapeutics (the major current research/clinical frontier, largely trialed specifically in ADAD via DIAN-TU because of presymptomatic identifiability): - Anti-amyloid monoclonal antibodies: - Gantenerumab and solanezumab — tested in the DIAN-TU-001 platform trial (2012–2019 double-blind phase): did not meet the primary endpoint of slowing cognitive decline across combined symptomatic/asymptomatic cohorts, but gantenerumab produced significant, dose-dependent amyloid plaque reduction and reduced CSF tau/synaptic-degeneration/neuroinflammation markers, especially in asymptomatic carriers (Nature Medicine 2021, JAMA Neurology downstream-biomarker analysis). A subsequent open-label extension (2020–2023, up to 10 years cumulative treatment in some asymptomatic carriers) examined whether sustained, high-dose treatment yields clinical benefit (Lancet Neurology 2025); amyloid-related imaging abnormalities-edema (ARIA-E) occurred in 19.2% of gantenerumab-treated participants vs. 2.5% placebo, an important safety signal shared across the anti-amyloid antibody class. - Lecanemab — now the backbone anti-amyloid therapy in the ongoing DIAN-TU Tau NexGen study (initiated January 2022), combined with the investigational anti-tau antibody etalanetug (E2814) to test whether reducing pathological tau spread adds benefit atop amyloid removal — trial evaluates outcomes over 208 weeks; interim baseline-characteristics/6-month safety data were presented in 2025. - Donanemab — approved and studied extensively in sporadic AD (TRAILBLAZER-ALZ program) but not yet reported with ADAD-specific dominantly-inherited-cohort trial data in the current literature search. - Anti-tau therapy: Etalanetug (E2814), an anti-tau monoclonal antibody targeting extracellular tau spread, is being trialed specifically in DIAD mutation carriers as an adjunct to lecanemab (DIAN-TU NexGen) — this represents the field's leading edge in testing combination amyloid+tau disease-modification in a genetically-defined, presymptomatic population. - Gene-directed/other advanced modalities: No approved gene therapy, RNA-based therapy (ASO/siRNA), or cell therapy for ADAD specifically exists as of this report; given the well-defined single-gene cause, ADAD is a plausible future candidate for allele-specific ASO knockdown approaches (as pursued in other dominant neurodegenerative diseases), but no ADAD-specific program has reached the clinical literature reviewed here.

Surgical/interventional: Not applicable as a primary treatment modality for ADAD itself.

Supportive/rehabilitative: Multidisciplinary dementia supportive care (physical/occupational/speech therapy as needed for functional decline), caregiver support programs, and psychiatric/behavioral symptom management (MAXO:0000950 supportive care; MAXO:0000011 physical therapy where applicable).

Experimental/clinical trials (selected, with identifiers where available): - DIAN-TU Platform Trial extensions — NCT06424236 ("Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia") - DIAN Observational Study — NCT00869817 - Colombia-API (Alzheimer's Prevention Initiative) autosomal-dominant AD trial in the PSEN1 E280A kindred (crenezumab, subsequently discontinued as primary endpoint not met, though biomarker signals were reported)

Treatment outcomes/adverse events: ARIA-E/ARIA-H (amyloid-related imaging abnormalities — edema/hemorrhage) is the dominant class-wide safety concern for anti-amyloid antibodies, with meaningfully elevated incidence versus placebo across trials; monitoring via serial MRI is now standard trial (and increasingly clinical) protocol. To date, no anti-amyloid or anti-tau agent has demonstrated a clearly established clinical cognitive benefit specific to the ADAD/DIAD population, despite robust biomarker (amyloid/tau/neurodegeneration marker) modification — a key ongoing translational gap actively being addressed by the tau-directed combination trials.

Treatment strategy/personalized medicine: Presymptomatic/prevention-oriented dosing strategy (treating carriers years before expected onset, leveraging the known ~20-year presymptomatic biomarker window) is the field's central strategic hypothesis, distinguishing ADAD trial design fundamentally from sporadic late-onset AD trials, which necessarily enroll after some degree of established pathology/symptoms.

13. Prevention

Primary prevention: Not currently achievable pharmacologically (no proven method to prevent disease onset in a confirmed mutation carrier), but is the explicit long-term goal of the presymptomatic DIAN-TU/NexGen and historical API trials — administering anti-amyloid (and now anti-tau) therapy during the decades-long presymptomatic biomarker-positive window in the hope of preventing or substantially delaying clinical onset.

Secondary prevention: Early biomarker detection (CSF/plasma p-tau217, amyloid-PET) in known mutation carriers enables early trial enrollment and monitoring, functioning as the operational "secondary prevention" framework in this genetically-predictable disease, though it does not yet translate into a proven clinical intervention.

Reproductive/genetic prevention: - Preimplantation genetic diagnosis (PGD/PGT-M) — successfully used for ADAD-causing APP variants to select unaffected embryos, resulting in births of unaffected children (PMID:11866650). - Prenatal testing is possible for known-carrier pregnancies (analogous framework to other dominant, adult-onset, fully penetrant disorders such as Huntington disease), though ethically and psychologically complex given adult onset. - Cascade/predictive genetic testing in at-risk relatives, paired with formal genetic counseling, is the standard risk-stratification and family-planning-guidance approach (NSGC/ACMG-informed protocols, modeled closely on Huntington disease predictive-testing guidelines given comparable ethical weight).

Behavioral/lifestyle interventions: General brain-health/cardiovascular-risk-reduction measures (as recommended for sporadic AD risk reduction) are reasonable adjuncts but are not established to meaningfully alter the essentially deterministic course in confirmed mutation carriers.

Public health/environmental interventions: Not a primary prevention lever for this monogenic disorder; population-level public-health prevention strategies relevant to sporadic AD (cardiovascular risk factor control, education, physical activity) do not have established ADAD-specific efficacy data.

Prophylaxis: The presymptomatic anti-amyloid/anti-tau trial paradigm described above is, in effect, the field's prophylaxis research program, though no agent is yet validated/approved for this indication.

14. Other Species / Natural Disease

Taxonomy: No naturally occurring, spontaneous orthologous disease with an equivalent PSEN1/PSEN2/APP-driven fully penetrant dominant Alzheimer-like dementia has been well documented in non-human species under natural conditions. Aged dogs (Canis lupus familiaris, NCBITaxon:9615) and aged non-human primates can develop age-related, sporadic-AD-like cognitive dysfunction syndrome with some amyloid pathology, but this is an aging-associated phenomenon, not a monogenic dominant disease analogous to human ADAD.

Orthologous genes: App, Psen1, Psen2 are conserved across mammals (mouse orthologs: App MGI:88059, Psen1 MGI:104779, Psen2 MGI:108086); rodents do not naturally develop human-like amyloid pathology even when carrying these orthologs unmodified, which is precisely why transgenic/knock-in humanized models were developed (see Section 15).

Veterinary relevance: Canine cognitive dysfunction syndrome (CCDS) is studied as a naturally occurring, sporadic aging model with some amyloid deposition, of comparative interest but not a direct ADAD model (OMIA does not list a canonical monogenic canine ADAD ortholog disease).

Comparative biology: The core γ-secretase/APP processing pathway is deeply evolutionarily conserved, which is precisely why humanized knock-in and transgenic rodent models (below) can be constructed to express human pathogenic variants and partially recapitulate amyloid pathology, despite the absence of natural disease in these species.

Zoonotic potential: Not applicable — ADAD is a purely genetic, non-transmissible disease.

15. Model Organisms

Rodent transgenic overexpression models: Classic APP/PS1 double-transgenic mice (overexpressing mutant human APP and PSEN1 from non-physiological promoters) robustly and reproducibly develop amyloid plaque pathology and are the most widely used preclinical AD model, but suffer from significant limitations: APP overexpression from an early age (unlike the gradual human increase), non-physiological accumulation of APP fragments (CTFs, AICD) not seen in human AD brain that may independently cause artifactual endosomal/transcriptional abnormalities, and — most importantly for translational validity — frequent failure to fully recapitulate human-comparable tau pathology, neurodegeneration, and behavioral/cognitive decline patterns at physiologically relevant timescales.

Knock-in models (designed to address overexpression artifacts): App^NL-G-F^ and related humanized App knock-in lines (Saito/Saido-style knock-ins) express mutant human Aβ sequence at physiological levels under the endogenous promoter, better modeling the gradual human amyloid accumulation trajectory and revealing profound microglial metabolic dysregulation (Molecular Neurodegeneration, PMC9188195); however, recent work (bioRxiv 2024) reports that App-KI mice do not display the hallmark age-dependent cognitive decline seen in overexpression models or in human disease, and PSEN1 knock-in alone (without an accompanying APP mutation) is generally insufficient to induce Aβ pathology at all, indicating that a combined, humanized APP+PSEN1(or PSEN2) knock-in approach is needed to approach physiological relevance, and even then, cognitive-behavioral phenotype fidelity to human ADAD remains incompletely validated (an appropriate candidate for a HUMAN_MODEL_MISMATCH framing in mechanistic curation, per this project's conventions).

Immunodeficient humanized models: Combined APP/PSEN1 knock-in immunodeficient mice have been reported to exhibit intraneuronal Aβ pathology, microgliosis, and extensive neuronal loss (PMC11975631) — an attempt to better model the human innate-immune/microglial contribution by permitting engraftment of human microglia or other human cellular elements.

Other model systems: - Drosophila melanogaster presenilin models (used to dissect γ-secretase-independent presenilin toxicity mechanisms, e.g., ALZFORUM-reported "protease or not" eye-phenotype screens). - Human iPSC-derived neuronal and astrocyte models carrying patient-specific PSEN1/PSEN2/APP variants — increasingly central for mechanistic study (e.g., iPSC-astrocyte models showing PSEN1-variant-driven inflammatory predisposition via disrupted regulated intramembrane proteolysis, PMC12181884) and for modeling human-specific cellular contexts not well captured by rodents. - Organoid models — cerebral/brain organoids from ADAD patient iPSCs are an emerging platform for studying 3D tissue-context amyloid/tau pathology, though standardization and long-term maturation remain limitations.

Applications: Mouse and iPSC models are used to dissect the amyloid-generation mechanism, test candidate anti-amyloid/anti-tau therapeutics preclinically (informing the DIAN-TU trial pipeline), and study microglial/neuroinflammatory contributions; they are less reliable for modeling the full human cognitive-behavioral phenotype or the neurological accompaniments (myoclonus, seizures, spastic paraparesis) seen in human PSEN1 carriers.

Model limitations (summary): The recurring, well-documented gap across essentially all current models is a mismatch between robust amyloid (and sometimes neuroinflammatory) pathology on one hand, and inconsistent or absent age-dependent cognitive/behavioral decline and incomplete tau pathology/neurodegeneration on the other — meaning translational claims from rodent efficacy data to expected human clinical benefit should be treated cautiously, consistent with the repeated failure of preclinically-promising anti-amyloid agents to show unambiguous cognitive benefit in DIAN-TU human trials despite clear target engagement.

Resources: MGI (Mouse Genome Informatics) for App/Psen1/Psen2 alleles; Alzforum "Research Models" database (the field-standard curated registry of AD mouse/model lines, including full genotype/phenotype-recapitulation summaries); JAX (Jackson Laboratory) repository for physical strain distribution.

Summary Table: Key Ontology Term Suggestions

Category	Term	ID
Disease	Early-onset autosomal dominant Alzheimer disease	MONDO:0015140 / ORPHA:1020
Gene	PSEN1	HGNC:9508
Gene	PSEN2	HGNC:9509
Gene	APP	HGNC:620
Phenotype	Dementia	HP:0000726
Phenotype	Memory impairment	HP:0002354
Phenotype	Myoclonus	HP:0001336
Phenotype	Seizures	HP:0001250
Phenotype	Progressive spastic paraparesis	HP:0007256
Phenotype	Extrapyramidal sign	HP:0002548
Phenotype	Intracerebral hemorrhage	HP:0001342
Inheritance	Autosomal dominant inheritance	HP:0000006
GO (BP)	Amyloid-beta formation	GO:0034205
GO (BP)	Regulation of amyloid-beta formation	GO:1902430
GO (CC)	Gamma-secretase complex	GO:0070765
CL	Glutamatergic neuron	CL:0000679
CL	Microglial cell	CL:0000129
CL	Astrocyte	CL:0000127
UBERON	Hippocampus	UBERON:0002421
UBERON	Cerebral cortex	UBERON:0000956
MAXO	Pharmacotherapy	NCIT:C15986
Drug class	Monoclonal antibody	NCIT:C20401

Early-Onset Autosomal Dominant Alzheimer Disease

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Early-Onset Autosomal Dominant Alzheimer Disease (ADAD/EOFAD): Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary Table: Key Ontology Term Suggestions

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