Show YAML
name: com_Alzheimer_Disease__Cancer
creation_date: "2026-07-03T14:04:34Z"
curation_status: CURATED
notes: >-
The cancer/Alzheimer's-disease "inverse correlation" (or "cancer-AD paradox"):
a history of cancer is associated with a reduced subsequent risk of Alzheimer's
disease, and a diagnosis of Alzheimer's disease is associated with a reduced
subsequent risk of cancer. This is a reciprocal (bidirectional) PROTECTIVE
association, curated here as the flagship inverse comorbidity. Two features
distinguish it from an artifact and from generic neurodegeneration. First, the
major methodological biases (competing risk of death, diagnostic bias,
selective survival) have been evaluated and are judged unlikely to fully
explain the association (Ospina-Romero 2020), and the pattern is corroborated
at the neuropathological level - a prior cancer diagnosis is associated with a
lower burden of Alzheimer's-type neuropathology (Karanth 2022). Second, the
inverse association appears relatively specific to Alzheimer's disease: it is
seen for AD but not for vascular dementia (Roe 2010). Mechanistically this is
framed as an evolutionary trade-off in which shared aging pathways are driven
in opposite directions (cancer = sustained proliferation / growth-suppressor
evasion / immune evasion; AD = excess neuronal death / growth-suppressor
activation / immune activation), with AD-specific effectors such as APP and
amyloid-beta acting as tumour suppressors. The antagonistic-pleiotropy
substrate is captured by the `cellular_senescence` (deleterious arm) and
`senescence_tumor_suppression` (tumour-suppressive arm) mechanism modules; the
aging-associated loss of stemness node of the latter (PMID:39633048) is one
conserved arm by which aging biology suppresses tumour initiation. Curation of
this entry was prompted by the Comment "The cancer Alzheimer's disease paradox"
(Feng, npj Aging 2026;12:93, doi:10.1038/s41514-026-00442-1). Note that the
relationship is NOT uniformly protective across all neurodegeneration: cancer
and Parkinson's disease show a more complex pattern (inverse for most cancers
but a positive association with melanoma), which would be curated separately as
effect_direction: MIXED. Two further nuances are captured in the "Shared
molecular and inherited-genetic architecture" hypothesis: the AD-cancer
relationship is inverse for lung cancer but DIRECT (positive) for glioblastoma
(Sanchez-Valle 2017), and the inherited-genetic inverse signal is
subtype-specific - familial AD carries a strong NEGATIVE (protective) genetic
correlation with lung cancer while the aggregate, subtype-agnostic AD-cancer
genetic correlation is null; late-onset AD does not carry the signal, so
subtype-agnostic estimates dilute it. Familial AD's penetrant amyloid biology
(APP/PSEN1/PSEN2) ties this back to the tumour-suppressive amyloid/APP arm.
disease_a:
slug: Alzheimer_Disease
preferred_term: Alzheimer disease
term:
id: MONDO:0004975
label: Alzheimer disease
disease_b:
slug: Cancer
preferred_term: cancer
term:
id: MONDO:0004992
label: cancer
directionality: BIDIRECTIONAL
effect_direction: PROTECTIVE
literature_evidence:
- reference: PMID:33185677
reference_title: "Association Between Alzheimer Disease and Cancer With Evaluation of Study Biases: A Systematic Review and Meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Observational studies consistently report inverse associations between cancer and Alzheimer disease (AD)."
explanation: >-
Systematic review and meta-analysis (22 studies, 9,630,435 individuals)
establishing the consistently reported inverse (protective) association
between cancer and Alzheimer's disease.
- reference: PMID:33185677
reference_title: "Association Between Alzheimer Disease and Cancer With Evaluation of Study Biases: A Systematic Review and Meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "cancer was associated with decreased AD incidence (cohort studies: random-effects hazard ratio, 0.89; 95% CI, 0.79-1.00; case-control studies: random-effects odds ratio, 0.75; 95% CI, 0.61-0.93)."
explanation: >-
Pooled effect estimates below 1 quantify the protective direction: a prior
cancer diagnosis is associated with lower Alzheimer's disease incidence.
- reference: PMID:33185677
reference_title: "Association Between Alzheimer Disease and Cancer With Evaluation of Study Biases: A Systematic Review and Meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Studies with insufficient or inappropriate confounder control or greater likelihood of AD diagnostic bias had mean hazard ratios closer to the null value, indicating that these biases could not explain the observed inverse association."
explanation: >-
Bias-adjusted metaregression argues the inverse association is not merely an
artifact of confounding or diagnostic bias, supporting a genuine protective
relationship.
- reference: PMID:22411920
reference_title: "Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cancer survivors had a lower risk of Alzheimer's disease than those without cancer, and patients with Alzheimer's disease had a lower risk of incident cancer."
explanation: >-
Framingham Heart Study prospective cohort plus nested case-control analysis
demonstrating the reciprocal (bidirectional) protective association in both
directions.
- reference: PMID:20032288
reference_title: "Cancer linked to Alzheimer disease but not vascular dementia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD"
explanation: >-
Cardiovascular Health Study cohort independently confirming the reciprocal
protective association between Alzheimer's disease and cancer.
- reference: PMID:20032288
reference_title: "Cancer linked to Alzheimer disease but not vascular dementia."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "No significant association was found between cancer and subsequent development of VaD."
explanation: >-
Specificity evidence: the inverse association holds for Alzheimer's disease
but not for vascular dementia, arguing the effect is AD-specific rather than
a generic dementia/neurodegeneration phenomenon.
- reference: PMID:35094057
reference_title: "Cancer diagnosis is associated with a lower burden of dementia and less Alzheimer's-type neuropathology."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cancer diagnosis was associated with a lower burden of Alzheimer's disease pathology and less cognitive impairment. These findings from a community-based cohort with neuropathological confirmation of substrates support the hypothesis that there is an inverse relationship between cancer and Alzheimer's disease."
explanation: >-
Autopsy cohort (University of Kentucky ADRC linked to the Kentucky Cancer
Registry) providing neuropathological corroboration: prior cancer is
associated with a lower burden of Alzheimer's-type pathology and cognitive
impairment.
hypotheses:
- description: >-
Tumour-suppressive amyloid/APP arm. Beyond the epidemiology, Alzheimer's
disease-specific effectors provide a candidate mechanism for the protective
direction: amyloid-beta (Abeta) and its precursor APP have tumour-suppressive
and anti-angiogenic activity. Amyloid-beta oligomers inhibit the proliferation
of human cancer cell lines in vitro, and transgenic mouse models of AD that
overproduce Abeta show impaired growth and vascularization of implanted
tumours - i.e., the AD-like, Abeta-rich brain environment is hostile to
tumour growth. This is the AD-specific complement to the conserved
aging/senescence tumour-suppressive barrier captured by the
`senescence_tumor_suppression` module, and together they frame the cancer-AD
inverse correlation as an antagonistic-pleiotropy trade-off in shared aging
pathways rather than two independent phenomena.
evidence:
- reference: PMID:31509551
reference_title: "Amyloid β oligomers inhibit growth of human cancer cells."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "The effect of the cell growth inhibition, which was stronger in the case of HFIP Aβ oligomers, was observed for all cell lines."
explanation: >-
In vitro evidence that amyloid-beta oligomers inhibit growth across
multiple human cancer cell lines (leukemia, lung, breast), supporting a
direct tumour-suppressive activity of an AD-defining molecule.
- reference: PMID:20739545
reference_title: "Impaired orthotopic glioma growth and vascularization in transgenic mouse models of Alzheimer's disease."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Our data reveal that intracranial tumor growth and angiogenesis is significantly reduced in Tg APPsw and Tg PS1/APPsw mice compared with their wild-type littermates."
explanation: >-
In vivo model-organism evidence that an Abeta-overproducing, AD-like brain
environment suppresses orthotopic glioma growth and angiogenesis,
supporting the protective direction at the tissue level. Model-organism
evidence is kept distinct from the human epidemiological evidence above.
- description: >-
Shared molecular and inherited-genetic architecture. Independent of the
AD-specific amyloid/APP arm, the inverse comorbidity has a candidate substrate
in programs that are regulated in opposite directions between the AD and
cancer states. Transcriptomic meta-analyses find many genes with inverse
expression patterns in Alzheimer's disease versus lung cancer (and concordant
patterns in Alzheimer's disease versus glioblastoma, a DIRECT comorbidity),
with mitochondrial metabolism/oxidative phosphorylation a recurrent
oppositely-regulated axis and the immune system a recurrent link. At the
inherited level the signal is subtype-resolved rather than aggregate:
genome-wide, Alzheimer's disease shows NO significant genetic correlation with
cancer in the main (subtype-agnostic) datasets - reflecting little SHARED
inherited risk rather than a negative correlation - and the inverse (negative)
genetic signal emerges only on subtype resolution. Familial Alzheimer's
disease shows strong NEGATIVE genetic correlations with lung cancer, and
meta-analysis finds negative correlations with breast cancer, whereas
late-onset Alzheimer's disease does not carry this negative signal - which is
why subtype-agnostic estimates dilute the relationship. Mechanistically this
converges on the amyloid arm of this entry: familial AD is precisely the
subtype dominated by penetrant amyloid-processing biology (APP, PSEN1, PSEN2),
the same effectors invoked in the tumour-suppressive amyloid/APP hypothesis
above. The genetic-correlation evidence is from a non-peer-reviewed preprint
(PPR:PPR1277612) and is recorded here as an emerging lead complementing the
peer-reviewed transcriptomic and epidemiological evidence, not as sole support.
evidence:
- reference: PMID:28667284
reference_title: "A molecular hypothesis to explain direct and inverse co-morbidities between Alzheimer's Disease, Glioblastoma and Lung cancer."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "Transcriptomic meta-analyses reveal significant numbers of genes with inverse patterns of expression in Alzheimer's disease and lung cancer, and with similar patterns of expression in Alzheimer's disease and glioblastoma."
explanation: >-
Peer-reviewed transcriptomic meta-analysis providing a molecular basis for
the inverse (AD-lung cancer) and direct (AD-glioblastoma) comorbidities via
oppositely- and concordantly-regulated gene sets.
- reference: PMID:28667284
reference_title: "A molecular hypothesis to explain direct and inverse co-morbidities between Alzheimer's Disease, Glioblastoma and Lung cancer."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "Mitochondrial metabolism is regulated oppositely in Alzheimer's disease and lung cancer, indicating that it may be involved in the inverse co-morbidity between these diseases."
explanation: >-
Identifies oppositely-regulated mitochondrial metabolism as a candidate
molecular axis of the inverse comorbidity.
- reference: PPR:PPR1277612
reference_title: "A Genetic Atlas of Direct and Inverse Neuropsychiatric-Cancer Comorbidity"
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "No significant associations with cancer were detected for Alzheimer’s disease in the main-dataset analyses"
explanation: >-
At the aggregate (subtype-agnostic) level the AD-cancer genetic correlation
is null - little shared inherited risk, NOT a negative correlation - which is
why the authors turned to subtype-resolved and meta-analytic approaches.
Corrects any reading of low genetic affinity as itself an inverse signal.
Non-peer-reviewed preprint; emerging lead.
- reference: PPR:PPR1277612
reference_title: "A Genetic Atlas of Direct and Inverse Neuropsychiatric-Cancer Comorbidity"
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "Familial Alzheimer’s disease showed strong negative correlations with lung cancer"
explanation: >-
The subtype-resolved inverse genetic signal that actually supports this
entry: familial AD is negatively genetically correlated with lung cancer
(LDSC/HDL), whereas late-onset AD is not. Non-peer-reviewed preprint;
emerging lead complementing the peer-reviewed evidence above.
- reference: PPR:PPR1277612
reference_title: "A Genetic Atlas of Direct and Inverse Neuropsychiatric-Cancer Comorbidity"
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "meta-analysis identified negative correlations with breast cancer in both methods"
explanation: >-
Meta-analytic AD-cancer negative genetic correlation (breast cancer),
concordant with the protective/inverse direction of this comorbidity.
Non-peer-reviewed preprint; emerging lead, not sole support.
- reference: PPR:PPR1277612
reference_title: "A Genetic Atlas of Direct and Inverse Neuropsychiatric-Cancer Comorbidity"
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "familial Alzheimer’s disease is dominated by penetrant amyloid-processing biology involving APP , PSEN1 and PSEN2"
explanation: >-
Mechanistic convergence with the "Tumour-suppressive amyloid/APP arm"
hypothesis: the AD subtype carrying the negative (protective) genetic signal
is the one driven by penetrant APP/PSEN amyloid biology, tying the inherited
signal back to amyloid-beta/APP tumour suppression. Non-peer-reviewed
preprint; emerging lead.