Amyloidosis

1. Disease Information

Overview

Amyloidosis is a heterogeneous group of diseases characterized by the pathological extracellular deposition of insoluble misfolded protein material called "amyloid" in tissues and organs (poli2023hereditarytransthyretinamyloidosis pages 1-2). These amyloid fibrils are ordered structures of 7–13 nm diameter with cross-β-sheet secondary structure that damage tissue organization and induce progressive organ dysfunction (ajmal2023proteinmisfoldingand pages 4-6). Over 30 types of amyloid fibrils have been identified in humans, but the clinically most important systemic forms are immunoglobulin light-chain (AL) amyloidosis, transthyretin (ATTR) amyloidosis (both hereditary/variant [ATTRv] and wild-type [ATTRwt]), and serum amyloid A (AA) amyloidosis (fontana2025thelastdecade pages 1-3, zanwar2023immunoglobulinlightchain pages 1-2).

Key Identifiers

• MONDO ID: MONDO:0019065 (amyloidosis); MONDO:0018634 (hereditary amyloidosis); MONDO:0019438 (AL amyloidosis) (OpenTargets Search: amyloidosis)
• ICD-10: E85 (Amyloidosis), with subtypes E85.0–E85.9
• OMIM: #105210 (Amyloidosis, hereditary, transthyretin-related); #204900 (Amyloidosis, primary/AL)
• MeSH: D000686
• Orphanet: ORPHA:69 (Amyloidosis); ORPHA:85443 (AL amyloidosis); ORPHA:271861 (ATTR amyloidosis)

Synonyms

Common alternative names include: amyloid disease, systemic amyloidosis, primary amyloidosis (AL), secondary amyloidosis (AA), senile systemic amyloidosis (ATTRwt), familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), and transthyretin-related hereditary amyloidosis.

The following table summarizes the four major systemic amyloidosis types:

Table: This table compares the four major systemic amyloidosis categories across precursor protein, genetics, etiology, organ involvement, onset, epidemiology, and current treatment strategy. It is useful as a compact disease-knowledge-base reference grounded in the gathered evidence.

2. Etiology

Disease Causal Factors

AL Amyloidosis: Caused by a clonal non-proliferative plasma cell disorder in which fragments of immunoglobulin light chains (κ or λ) misfold and deposit as amyloid fibrils in tissues. It often arises from pre-malignant conditions such as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma, and approximately 10% of patients also meet criteria for multiple myeloma (zerdan2023systemicalamyloidosis pages 1-2).

ATTR Amyloidosis (Hereditary): Caused by autosomal dominant mutations in the TTR gene (chromosome 18q11.2–q12.1), which destabilize the transthyretin tetramer, promoting dissociation into monomers that misfold and aggregate into amyloid fibrils (poli2023hereditarytransthyretinamyloidosis pages 2-3, poli2023hereditarytransthyretinamyloidosis pages 1-2).

ATTR Amyloidosis (Wild-type): Results from age-related destabilization of native wild-type TTR protein without pathogenic coding mutations, predominantly causing cardiac deposition in elderly individuals. Autopsy studies revealed myocardial ATTR deposits in approximately 25% of individuals aged ≥85 years (kim2026autotacmediatedtargeteddegradation pages 4-8).

AA Amyloidosis: A complication of chronic inflammatory disorders where sustained overproduction of serum amyloid A (SAA) protein leads to fibril deposition. Common causes include chronic infections, inflammatory arthritis, familial Mediterranean fever (FMF), and primary immunodeficiencies. Approximately 20% of cases are idiopathic (mirioglu2024aaamyloidosisa pages 1-2).

Risk Factors

Genetic risk factors: - TTR gene mutations: Over 150 pathogenic variants identified, predominantly missense. Val30Met (p.Val50Met) is probably the most common worldwide, and Val122Ile (p.Val142Ile) is carried by 3–4% of African Americans (poli2023hereditarytransthyretinamyloidosis pages 2-3, ioannou2023rnatargetingand pages 1-2). - SAA1.1 homozygosity increases risk for AA amyloidosis in European populations (mirioglu2024aaamyloidosisa pages 1-2). - Cytogenetic abnormalities in AL amyloidosis: t(11;14) occurs in 40–60% of patients; 1q21 gain in ~50%; trisomies in up to 30% (zanwar2023immunoglobulinlightchain pages 6-7).

Environmental/demographic risk factors: - Advanced age (particularly for ATTRwt and late-onset ATTRv) - Male sex predominates in ATTR-CM and AA amyloidosis (mirioglu2024aaamyloidosisa pages 1-2, delgado2025epidemiologyoftransthyretin pages 2-4) - African ancestry (Val122Ile variant prevalence 3.8% in African-descent populations in UK Biobank) (aung2024prevalencecardiacphenotype pages 11-15) - Sustained chronic inflammation for AA amyloidosis (mirioglu2024aaamyloidosisa pages 1-2)

3. Phenotypes and Clinical Manifestations

Cardiac Involvement

Cardiac amyloidosis is the key determinant of survival across all types. In AL amyloidosis, cardiac involvement occurs in approximately 70% of cases, presenting with heart failure, biventricular hypertrophy, restrictive filling pattern, arrhythmias (atrial fibrillation, ventricular tachycardia), AV conduction delays, low voltage on ECG, and poor R-wave progression (dima2023diagnosticandtreatment pages 1-2). Echocardiographic findings include concentric hypertrophy, small LV cavity, diastolic dysfunction, reduced global longitudinal strain with preserved apical strain, and biatrial dilatation (chompoopong2024amyloidneuropathyfrom pages 7-7, zanwar2023immunoglobulinlightchain pages 2-4). Untreated advanced cardiac AL amyloidosis has a median survival of 6 months (fontana2025thelastdecade pages 1-3).

Suggested HPO terms: HP:0001638 (Cardiomyopathy); HP:0001635 (Congestive heart failure); HP:0004749 (Atrial flutter/fibrillation); HP:0001712 (Left ventricular hypertrophy)

Renal Involvement

The kidney is the major affected organ in AA amyloidosis, manifesting as nephrotic-range proteinuria and progressive renal failure (mirioglu2024aaamyloidosisa pages 1-2). In AL amyloidosis, renal involvement presents as nephrotic syndrome without obvious etiology (zanwar2023immunoglobulinlightchain pages 1-2). In ATTRv, approximately one-third of endemic and 6% of non-endemic cases develop nephrotic syndrome (poli2023hereditarytransthyretinamyloidosis pages 4-6).

Suggested HPO terms: HP:0000100 (Nephrotic syndrome); HP:0000093 (Proteinuria); HP:0003774 (Stage 5 chronic kidney disease)

Neurological Manifestations

Amyloid neuropathy is manifested as a length-dependent sensory-predominant neuropathy associated with generalized autonomic failure (chompoopong2024amyloidneuropathyfrom pages 6-6). Small unmyelinated nerves are involved early in early-onset Val30Met ATTRv, whereas other variants and AL amyloidosis present with large- and small-fiber involvement. Carpal tunnel syndrome occurs in two-thirds of ATTRv patients, sometimes preceding diagnosis by 10 years (poli2023hereditarytransthyretinamyloidosis pages 4-6). Neurogenic orthostatic hypotension occurs in 40–60% of ATTRv patients (chompoopong2024amyloidneuropathyfrom pages 6-6). CNS involvement (leptomeningeal amyloidosis) can cause stroke, hemorrhage, cognitive impairment, ataxia, and epilepsy (poli2023hereditarytransthyretinamyloidosis pages 4-6).

Suggested HPO terms: HP:0009830 (Peripheral neuropathy); HP:0002459 (Dysautonomia); HP:0012185 (Orthostatic hypotension); HP:0012531 (Pain); HP:0001324 (Muscle weakness)

Gastrointestinal and Other Manifestations

GI symptoms include premature satiety, gastric distension, nausea, vomiting, diarrhea from malabsorption, and constipation (poli2023hereditarytransthyretinamyloidosis pages 4-6, zanwar2023immunoglobulinlightchain pages 2-4). Hepatomegaly with elevated alkaline phosphatase is common in AL amyloidosis. Classic pathognomonic findings in AL include macroglossia, periorbital ecchymoses ("raccoon eyes"), and musculoskeletal pathologies (zanwar2023immunoglobulinlightchain pages 2-4). Ocular involvement in ATTRv (10% of patients) includes vitreous opacities, glaucoma, and keratoconjunctivitis sicca (poli2023hereditarytransthyretinamyloidosis pages 4-6).

Suggested HPO terms: HP:0002240 (Hepatomegaly); HP:0000158 (Macroglossia); HP:0002014 (Diarrhea); HP:0001824 (Weight loss)

4. Genetic/Molecular Information

Causal Genes

TTR (Transthyretin): HGNC:12405; ENSG00000118271; chromosome 18q12.1. The TTR gene encodes a 127-amino acid protein that functions as a transporter of thyroxine and retinol-binding protein, primarily synthesized in the liver, choroid plexus, and retinal pigment epithelium (poli2023hereditarytransthyretinamyloidosis pages 1-2). Over 140–150 pathogenic variants have been identified, predominantly single-nucleotide substitutions producing missense mutations (poli2023hereditarytransthyretinamyloidosis pages 2-3, kim2026autotacmediatedtargeteddegradation pages 1-4, bhatt2024hereditarytransthyretinamyloidosis pages 1-2).

Key Pathogenic Variants: - p.Val50Met (Val30Met): Probably the most common disease-causing variant worldwide; associated with familial amyloid polyneuropathy. Can manifest as early-onset (age <50) with predominant polyneuropathy or late-onset with mixed phenotype. Higher penetrance in Portuguese families versus French and Swedish families (chompoopong2024amyloidneuropathyfrom pages 6-6, ioannou2023rnatargetingand pages 1-2). - p.Val142Ile (Val122Ile): Carried by 3–4% of African Americans and associated with predominant cardiomyopathy. In UK Biobank, prevalence was 4.3% in participants with African ancestry, associated with HR 2.68 for heart failure (ioannou2023rnatargetingand pages 1-2, aung2024prevalencecardiacphenotype pages 11-15). - p.Thr80Ala: Cardiac-predominant or mixed phenotype with earlier onset (~10 years earlier than Val142Ile) (aung2024prevalencecardiacphenotype pages 11-15).

Inheritance: Autosomal dominant with incomplete and variable penetrance. Genetic anticipation has been reported in Val30Met families, with shorter disease intervals in mother-to-son transmission (chompoopong2024amyloidneuropathyfrom pages 6-6). Maternal inheritance of Val30Met shows earlier disease onset in offspring, suggesting parental imprinting and possible mitochondrial genome involvement (poli2023hereditarytransthyretinamyloidosis pages 2-3).

Other Amyloidogenic Genes (from OpenTargets): - APP (amyloid beta precursor protein; score 0.86) - GSN (gelsolin; score 0.85) — causes Finnish-type amyloidosis - ITM2B (integral membrane protein 2B; score 0.84) - FGA (fibrinogen alpha chain; score 0.79) — causes hereditary renal amyloidosis - APOA1 (apolipoprotein A1; score 0.78) — causes hereditary systemic amyloidosis - CST3 (cystatin C; score 0.73) — causes Icelandic-type cerebral amyloid angiopathy - LYZ (lysozyme; score 0.72) — causes hereditary systemic amyloidosis - B2M (beta-2-microglobulin; score 0.67) — causes dialysis-related amyloidosis - SAA1 (serum amyloid A1) — precursor protein in AA amyloidosis (OpenTargets Search: amyloidosis)

5. Mechanism / Pathophysiology

Protein Misfolding and Amyloid Formation

The fundamental pathological process in all amyloidoses involves protein misfolding and aggregation. Under normal conditions, molecular chaperones guide proteins through energy landscapes to facilitate productive folding and prevent aggregation (louros2023mechanismsandpathology pages 1-4). In amyloidosis, precursor proteins become trapped in local energy minima with non-native structures, exposing hydrophobic patches that promote self-assembly into oligomers, protofibrils, and ultimately insoluble amyloid fibrils (ajmal2023proteinmisfoldingand pages 4-6).

Specific Mechanisms by Subtype

In ATTR amyloidosis, TTR tetramer destabilization (caused by mutations in ATTRv or aging in ATTRwt) leads to dissociation into monomers that misfold, aggregate abnormally, and deposit in extracellular locations, leading to progressive multiorgan damage (poli2023hereditarytransthyretinamyloidosis pages 2-3). Current therapies include tetramer stabilizers and RNA interference agents, but they do not eliminate pre-existing aggregates, underscoring the need for disease-modifying therapeutics capable of removing pathogenic TTR species (kim2026autotacmediatedtargeteddegradation pages 4-8).

Toxicity Mechanisms

Toxicity is attributed to both small soluble oligomeric species and fibrillar aggregates. Soluble oligomers cause permeabilization of cellular membranes, impairment of degradation pathways, disruption of synaptic signaling, and mitochondrial dysfunction. Fibrillar toxicity results from mechanical perturbations, sequestration of cellular factors, and inflammatory responses (louros2023mechanismsandpathology pages 16-19). Amyloid fibrils deposit in the endoneurium of peripheral nerves, extensively in dorsal root ganglia and sympathetic ganglia, leading to Schwann cell atrophy and blood–nerve barrier disruption (chompoopong2024amyloidneuropathyfrom pages 6-6).

Cellular Quality Control

Cells employ the ubiquitin-proteasome system (UPS) as the first-line mechanism for degrading soluble misfolded proteins, while autophagy-lysosome pathways clear insoluble aggregates (ajmal2023proteinmisfoldingand pages 9-11, ajmal2023proteinmisfoldingand pages 8-9, kim2026autotacmediatedtargeteddegradation pages 4-8). When these quality control systems are overwhelmed, accumulation of protein aggregates causes proteotoxicity and cell death (ajmal2023proteinmisfoldingand pages 9-11).

Suggested GO terms: GO:0006986 (Response to unfolded protein); GO:0006914 (Autophagy); GO:0030163 (Protein catabolic process); GO:0051082 (Unfolded protein binding); GO:0070841 (Inclusion body assembly)

6. Anatomical Structures Affected

Organ Level

• Heart (UBERON:0000948): Primary organ in ATTR-CM and frequently in AL. Amyloid fibril deposition in the myocardium causes restrictive cardiomyopathy. Cardiac involvement is the single most important prognostic marker in AL amyloidosis (zanwar2023immunoglobulinlightchain pages 1-2, fontana2025thelastdecade pages 1-3).
• Kidney (UBERON:0002113): Major target organ in AA amyloidosis and frequently in AL. Manifests as nephrotic syndrome and progressive renal failure (mirioglu2024aaamyloidosisa pages 1-2, zanwar2023immunoglobulinlightchain pages 1-2).
• Peripheral nervous system (UBERON:0000010): Predominantly in ATTRv and AL. Length-dependent sensorimotor polyneuropathy and autonomic neuropathy (poli2023hereditarytransthyretinamyloidosis pages 4-6, chompoopong2024amyloidneuropathyfrom pages 6-6).
• Liver (UBERON:0002107): Hepatomegaly in AL amyloidosis; primary source of TTR and SAA synthesis (zanwar2023immunoglobulinlightchain pages 2-4).
• Gastrointestinal tract (UBERON:0001555): Motility disorders, malabsorption (poli2023hereditarytransthyretinamyloidosis pages 4-6).
• Eye (UBERON:0000970): Vitreous opacities, glaucoma in ATTRv (poli2023hereditarytransthyretinamyloidosis pages 4-6).

Cell Types Involved

• Cardiomyocytes (CL:0000746): Direct fibril toxicity causes sarcomere disruption and electromechanical uncoupling
• Plasma cells (CL:0000786): Clonal source of amyloidogenic light chains in AL
• Hepatocytes (CL:0000182): Primary site of TTR and SAA synthesis
• Schwann cells (CL:0002573): Atrophy in proximity to amyloid fibrils in nerves
• Macrophages (CL:0000235): Inflammatory response to amyloid deposits

7. Epidemiology and Population

Prevalence and Incidence

• AL amyloidosis: Incidence approximately 1 per 100,000 person-years (3,500–4,500 new cases annually in the US), also reported as ~10 per million/year (zanwar2023immunoglobulinlightchain pages 1-2, zerdan2023systemicalamyloidosis pages 1-2).
• ATTR amyloidosis: Prevalence varies dramatically by geography: 6.1 per million in the US to 232 per million in Portugal (delgado2025epidemiologyoftransthyretin pages 1-2). In endemic sub-regions, prevalence reaches up to 1,631 per million (poli2023hereditarytransthyretinamyloidosis pages 2-3). ATTRwt estimated to affect ~500,000 individuals worldwide (ishida2026crispr–cas3basededitingfor pages 1-2). In the US, 2018 incidence was 3.9 per million person-years overall, rising to 36.6 PMPY in elderly individuals (delgado2025epidemiologyoftransthyretin pages 4-6).
• AA amyloidosis: Incidence 1–2 cases per million person-years in developed countries; now represents only ~2.9% of all amyloidosis cases (mirioglu2024aaamyloidosisa pages 1-2).

Population Demographics

• ATTRwt predominantly affects older males (>70–80 years) (fontana2025thelastdecade pages 1-3, delgado2025epidemiologyoftransthyretin pages 2-4).
• ATTRv Val122Ile: 4.3% prevalence in UK Biobank participants with African ancestry; represents the fourth most common cause of heart failure (11%) in Afro-Caribbeans (aung2024prevalencecardiacphenotype pages 11-15).
• Study populations are predominantly male (56–94%), with mean ages ranging from 52.3 to 83 years (delgado2025epidemiologyoftransthyretin pages 2-4).
• Endemic ATTRv clusters exist in Portugal, Sweden, Brazil, and Japan (poli2023hereditarytransthyretinamyloidosis pages 2-3).

Mortality

• Two-year mortality risk: 10–30% for wild-type ATTR-CM; 10–50% for variant ATTR-CM (delgado2025epidemiologyoftransthyretin pages 1-2).
• Median survival times across ATTR studies: 12–80 months (delgado2025epidemiologyoftransthyretin pages 4-6).
• AL amyloidosis: Median OS 48.8 months in the European EMN23 study; early mortality 13.4%; stage IIIb patients had median OS of only 4.5–5.0 months (zanwar2023immunoglobulinlightchain pages 6-7).
• Untreated advanced cardiac AL: median survival 6 months (fontana2025thelastdecade pages 1-3).

8. Diagnostics

Histopathological Diagnosis

Congo red staining with characteristic apple-green birefringence under polarized light microscopy is the primary diagnostic method. Alternative stains include thioflavin T and sulfated alcian blue (zerdan2023systemicalamyloidosis pages 1-2, zanwar2023immunoglobulinlightchain pages 2-4, mirioglu2024aaamyloidosisa pages 4-6). Electron microscopy reveals rigid, unbranched fibrils of 8–12 nm diameter (mirioglu2024aaamyloidosisa pages 4-6).

Tissue Sources and Sensitivity

Bone marrow biopsy (56–70% sensitivity) and fat pad aspiration (70–80% sensitivity) performed concurrently achieve 80–90% sensitivity for AL amyloidosis diagnosis (zanwar2023immunoglobulinlightchain pages 2-4). Salivary gland biopsy and periumbilical fat aspiration with Congo red staining show 77–89% sensitivity for AA amyloidosis (mirioglu2024aaamyloidosisa pages 4-6).

Amyloid Typing

Mass spectrometry-based proteomic assay (laser microdissection/mass spectrometry) is the gold standard for amyloid typing, offering high sensitivity and specificity (zanwar2023immunoglobulinlightchain pages 2-4).

Cardiac Imaging

• Bone scintigraphy: Technetium-99m pyrophosphate (99mTc-PYP) SPECT demonstrates excellent sensitivity (85–97%) and specificity (97–100%) for diagnosing TTR cardiac amyloidosis non-invasively (zanwar2023immunoglobulinlightchain pages 2-4, fontana2025thelastdecade pages 4-6).
• Cardiac MRI: Provides tissue characterization with late gadolinium enhancement, native T1 mapping, and extracellular volume (ECV) measurement serving as a surrogate for interstitial amyloid burden (fontana2025thelastdecade pages 4-6).
• Echocardiography: Cornerstone first-line imaging showing concentric hypertrophy, restrictive filling, and apical sparing of longitudinal strain (chompoopong2024amyloidneuropathyfrom pages 7-7).

Staging Systems

The Mayo/Boston staging system for AL amyloidosis uses cardiac biomarkers: troponin I (>0.1 ng/mL) and BNP (>81 pg/mL), with further substratification of stage III based on BNP >700 pg/mL (stage IIIb) (dima2023diagnosticandtreatment pages 2-3, chompoopong2024amyloidneuropathyfrom pages 8-9).

Genetic Testing

TTR gene sequencing (single-gene or multigene panel) identifies missense, nonsense, and splice-site variants. Testing is recommended for all patients with suspected ATTR amyloidosis and for family members of known carriers (chompoopong2024amyloidneuropathyfrom pages 6-6).

9. Treatment

AL Amyloidosis Treatment

First-line therapy: Daratumumab (anti-CD38 monoclonal antibody) combined with bortezomib, cyclophosphamide, and dexamethasone (D-VCd) is now standard based on the landmark ANDROMEDA trial. In Asian patients, overall hematologic complete response rate was 58.6% vs. 9.7% with VCd alone (chompoopong2024amyloidneuropathyfrom pages 11-11). Daratumumab achieved clinical remission in 59% of patients, with cardiac improvement in 57% and renal improvement in 57% (chompoopong2024amyloidneuropathyfrom pages 11-11). Real-world UK data with daratumumab-bortezomib-thalidomide-dexamethasone showed 97% overall hematologic response rate and 65% complete response.

Autologous stem cell transplantation (ASCT): Effective strategy after high-dose melphalan, improving survival to 48 months in up to 77% of eligible patients, though only ~20% meet eligibility criteria due to frailty, old age, or multiorgan involvement (chompoopong2024amyloidneuropathyfrom pages 10-11).

Emerging therapies in clinical trials: - Teclistamab (bispecific antibody): Phase 2 trials for relapsed/refractory AL (NCT06649695, NCT06935162, NCT07079423) - Elranatamab: Phase 1/2 trial (NCT06569147) - CAR-T cell therapy targeting CD19 and BCMA: Phase 1b/2 (NCT07081646) - Belantamab mafodotin: Phase 1/2 (NCT05145816) - Dara-VCd plus ASCT vs. Dara-VCd alone: Phase 3 (NCT06022939)

Suggested MAXO terms: MAXO:0001001 (Chemotherapy); MAXO:0000068 (Transplantation)

ATTR Amyloidosis Treatment

TTR Stabilizers: - Tafamidis: First FDA-approved disease-modifying therapy for ATTR-CM; demonstrated significant reductions in all-cause mortality and cardiovascular hospitalizations in the ATTR-ACT trial (anan2025advancesinthe pages 4-5). - Acoramidis: FDA-approved TTR stabilizer for ATTR-CM; outperformed placebo in clinical trials (ang2025emergingnovelgenemodulating pages 10-10, dave2024rnainterferencetherapeutics pages 4-5).

Gene Silencers (RNA-based therapies): - Patisiran (siRNA): Licensed for ATTR polyneuropathy; early data suggest cardiac benefit (ioannou2023rnatargetingand pages 1-2). - Vutrisiran (siRNA): Licensed for ATTR polyneuropathy (ioannou2023rnatargetingand pages 1-2). - Inotersen (ASO): Significant improvements in neurological function (mNIS+7 difference −19.7, P<0.001) and quality of life; sustained benefits over 5.2 years (dave2024rnainterferencetherapeutics pages 4-5, chompoopong2024amyloidneuropathyfrom pages 11-11). - Eplontersen (ASO): Well-tolerated with significant TTR reduction; improved LVEF by 4.3% in cardiomyopathy subgroup (dave2024rnainterferencetherapeutics pages 4-5).

Gene Editing: - NTLA-2001 (CRISPR-Cas9): In Phase 3 clinical trials; has demonstrated durable reductions in serum TTR, with up to 90% sustained plasma TTR reduction over 24 months (ishida2026crispr–cas3basededitingfor pages 1-2). - ART001 (CRISPR-Cas9): A single injection achieved >80% TTR knock-down at doses >0.5 mg/kg, lasting at least 72 weeks without serious adverse events. - CRISPR-Cas3: A mechanistically distinct approach generating long-range deletions; achieved 48.7% hepatic editing and 80.1% serum TTR reduction in mice (ishida2026crispr–cas3basededitingfor pages 1-2).

Emerging approaches: - AUTOTAC-mediated targeted degradation of TTR aggregates (ATC201): Novel bifunctional degrader that reduces intracellular TTR aggregates and improves neuromuscular function in hATTR mouse models (kim2026autotacmediatedtargeteddegradation pages 4-8). - Anti-amyloid monoclonal antibodies (PRX004, NI006): In Phase 1 trials, designed to clear existing amyloid deposits (anan2025advancesinthe pages 4-5, dave2024rnainterferencetherapeutics pages 7-8).

AA Amyloidosis Treatment

Management primarily aims to reduce SAA levels by controlling underlying inflammation. Anti-inflammatory biologics including tocilizumab (IL-6 inhibitor) and anakinra (IL-1 receptor antagonist) have dramatically expanded the therapeutic armamentarium (mirioglu2024aaamyloidosisa pages 1-2). Long-term tocilizumab treatment has been associated with disappearance of amyloid deposits from tissues. Kidney transplantation is preferred in patients with kidney failure, with recurrence in allografts becoming rare due to new anti-inflammatory agents (mirioglu2024aaamyloidosisa pages 1-2).

10. Prognosis and Outcomes

Prognostic Factors

• Cardiac involvement is the single most important prognostic marker in AL amyloidosis (zanwar2023immunoglobulinlightchain pages 1-2).
• Cardiac biomarkers (NT-proBNP, troponin) drive staging systems (dima2023diagnosticandtreatment pages 2-3, chompoopong2024amyloidneuropathyfrom pages 8-9).
• Cytogenetic abnormalities: t(11;14) associated with poor bortezomib response; 1q21 gain associated with shorter OS (zanwar2023immunoglobulinlightchain pages 6-7).
• Hematologic response: Complete response (negative immunofixation, normal FLC ratio) achieved in 65–80% with first-line therapy is associated with superior outcomes (zanwar2023immunoglobulinlightchain pages 6-7).
• Age >65–70, poor performance status (ECOG >2), and autonomic involvement are adverse prognostic factors (zanwar2023immunoglobulinlightchain pages 6-7).

Survival

• AL amyloidosis median OS: 48.8 months overall; stage IIIb median OS only 4.5–5.0 months with no improvement despite newer therapies (zanwar2023immunoglobulinlightchain pages 6-7).
• Early mortality in AL: 13.4% and did not improve over time; remained >39% for stage IIIb patients.
• ATTR-CM: 2-year mortality 10–30% (wild-type) and 10–50% (variant) (delgado2025epidemiologyoftransthyretin pages 1-2).
• TTR LP/P variant carriers: HR 2.68 for heart failure; HR 1.98 for all-cause mortality with non-Val142Ile variants (aung2024prevalencecardiacphenotype pages 11-15).

11. Prevention

Primary Prevention

For AA amyloidosis, primary prevention involves effective control of underlying inflammatory conditions using biological therapies to suppress SAA production (mirioglu2024aaamyloidosisa pages 1-2).

Secondary Prevention / Screening

• Cascade genetic screening of family members of ATTRv patients is recommended, given autosomal dominant inheritance and availability of effective therapies (chompoopong2024amyloidneuropathyfrom pages 6-6, poli2023hereditarytransthyretinamyloidosis pages 1-2).
• Screening for ATTR-CM in patients with HFpEF and left ventricular wall thickness ≥12 mm using 99mTc-PYP scintigraphy has been evaluated but faces cost-effectiveness challenges primarily due to high treatment costs (zanwar2023immunoglobulinlightchain pages 2-4).
• Carpal tunnel syndrome tissue screening for amyloid has been proposed as an early detection strategy.

Genetic Counseling

Genetic counseling is essential for ATTRv families, addressing risk assessment, reproductive planning, and presymptomatic testing. The hATTR Compass Genetic Testing Program identified pathogenic TTR variants in 6.6% of 22,886 referred patients, with only 32% reporting known family history (bhatt2024hereditarytransthyretinamyloidosis pages 1-2).

12. Animal Models

Transgenic Mouse Models

• HM30 transgenic mice: Mouse TTR knocked out with ectopic overexpression of human TTR V30M; used for studying hereditary ATTR amyloidosis pathogenesis and therapeutic interventions (kim2026autotacmediatedtargeteddegradation pages 4-8).
• TTR exon-humanized mice: Used for evaluating CRISPR-Cas3 gene editing approaches; a single LNP-based treatment achieved 48.7% hepatic editing and 80.1% serum TTR reduction (ishida2026crispr–cas3basededitingfor pages 1-2).
• Mouse models carrying human TTR transgenes: Used for evaluation of highly modified sgRNA for CRISPR-based TTR knockdown.

In Vitro Models

• Human iPSC-derived cardiomyocytes, endothelial cells, and fibroblasts seeded on TTR fibrils (WT, V122I, V30M) provide cell-type-specific disease phenotypes including sarcomere disruption, altered calcium handling, and reduced cell viability.
• Choroid plexus organoids model amyloid uptake at the blood-CSF barrier.

13. Disease-Target Associations (OpenTargets)

OpenTargets analysis identified 12 primary targets associated with amyloidosis (MONDO:0019065), with the highest association scores for: 1. TTR (transthyretin) — score 0.90; approved therapies targeting this gene 2. APP (amyloid beta precursor protein) — score 0.87 3. GSN (gelsolin) — score 0.85 4. ITM2B (integral membrane protein 2B) — score 0.84 5. FGA (fibrinogen alpha chain) — score 0.79 6. APOA1 (apolipoprotein A1) — score 0.78 7. CST3 (cystatin C) — score 0.73 8. LYZ (lysozyme) — score 0.72 9. B2M (beta-2-microglobulin) — score 0.67 10. APOE (apolipoprotein E) — score 0.62

For AL amyloidosis specifically, additional associated targets include CCND1 (cyclin D1), CALCA, INS, NPPA, and SAA1 (OpenTargets Search: amyloidosis).

14. Summary and Future Directions

Amyloidosis has undergone a dramatic transformation in the past decade, from an underdiagnosed and universally fatal condition to one with expanding diagnostic and therapeutic options. Key advances include non-invasive cardiac scintigraphy for ATTR diagnosis, daratumumab-based regimens revolutionizing AL amyloidosis treatment, and RNA-based gene silencing and CRISPR gene editing therapies fundamentally altering the ATTR treatment landscape (ioannou2023rnatargetingand pages 1-2, ishida2026crispr–cas3basededitingfor pages 1-2). Despite these advances, critical unmet needs remain: early mortality in advanced cardiac AL amyloidosis has not improved (zanwar2023immunoglobulinlightchain pages 6-7), comprehensive epidemiological data from Africa and South America are lacking (delgado2025epidemiologyoftransthyretin pages 8-8), and therapies capable of clearing pre-existing amyloid deposits are still investigational (kim2026autotacmediatedtargeteddegradation pages 4-8). Novel approaches including AUTOTAC-mediated targeted protein degradation, anti-amyloid monoclonal antibodies, bispecific antibodies, and CAR-T cell therapy represent the next frontier in amyloidosis management.

References

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18. (kim2026autotacmediatedtargeteddegradation pages 4-8): Hee Yeon Kim, Daniel Youngjae Park, Eun Hye Cho, Yeon Sung Son, Sung Hyun Kim, Ki Woon Sung, Helena Sofia Martins, Maria João Saraiva, Maria Rosário Almeida, Chang Hoon Ji, and Yong Tae Kwon. Autotac-mediated targeted degradation of transthyretin aggregates ameliorates hereditary transthyretin amyloidosis. bioRxiv, Feb 2026. URL: https://doi.org/10.64898/2026.02.23.707350, doi:10.64898/2026.02.23.707350. This article has 0 citations.

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33. (ajmal2023proteinmisfoldingand pages 9-11): Mohammad Rehan Ajmal. Protein misfolding and aggregation in proteinopathies: causes, mechanism and cellular response. Diseases, 11:30, Feb 2023. URL: https://doi.org/10.3390/diseases11010030, doi:10.3390/diseases11010030. This article has 135 citations.

34. (ajmal2023proteinmisfoldingand pages 8-9): Mohammad Rehan Ajmal. Protein misfolding and aggregation in proteinopathies: causes, mechanism and cellular response. Diseases, 11:30, Feb 2023. URL: https://doi.org/10.3390/diseases11010030, doi:10.3390/diseases11010030. This article has 135 citations.

35. (fontana2025thelastdecade pages 4-6): Marianna Fontana, Adam Ioannou, Sarah Cuddy, Sharmila Dorbala, Ahmad Masri, James C. Moon, Vasvi Singh, Olivier Clerc, Mazen Hanna, Fredrick Ruberg, Martha Grogan, Michele Emdin, and Julian Gillmore. The last decade in cardiac amyloidosis. JACC. Cardiovascular imaging, 18:478-499, Jan 2025. URL: https://doi.org/10.1016/j.jcmg.2024.10.011, doi:10.1016/j.jcmg.2024.10.011. This article has 79 citations.

36. (chompoopong2024amyloidneuropathyfrom pages 8-9): Pitcha Chompoopong, Michelle L. Mauermann, Hasan Siddiqi, and Amanda Peltier. Amyloid neuropathy: from pathophysiology to treatment in light‐chain amyloidosis and hereditary transthyretin amyloidosis. Annals of Neurology, 96:423-440, Jun 2024. URL: https://doi.org/10.1002/ana.26965, doi:10.1002/ana.26965. This article has 44 citations and is from a highest quality peer-reviewed journal.

37. (dave2024rnainterferencetherapeutics pages 7-8): Prashil Dave, Puneet Anand, Azra Kothawala, Prakhyath Srikaram, Dipsa Shastri, Anwar Uddin, Jill Bhavsar, and Andrew Winer. Rna interference therapeutics for hereditary amyloidosis: a narrative review of clinical trial outcomes and future directions. Cureus, Jun 2024. URL: https://doi.org/10.7759/cureus.62981, doi:10.7759/cureus.62981. This article has 11 citations.

38. (delgado2025epidemiologyoftransthyretin pages 8-8): Diego Delgado, Firas Dabbous, Nitin Shivappa, Faizan Mazhar, Eric Wittbrodt, Divya Shridharmurthy, and Krister Järbrink. Epidemiology of transthyretin (attr) amyloidosis: a systematic literature review. Orphanet Journal of Rare Diseases, Jan 2025. URL: https://doi.org/10.1186/s13023-025-03547-0, doi:10.1186/s13023-025-03547-0. This article has 46 citations and is from a peer-reviewed journal.

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