Alzheimer's Disease
ICD-11: 8A20
Disease Overview
Alzheimer's disease (AD) is the leading cause of dementia, characterized by progressive neurodegeneration, amyloid-beta plaques, and neurofibrillary tau tangles. Pathophysiology involves amyloid cascade, tau pathology, neuroinflammation, synaptic loss, and eventual neuronal death. Onset is typically late life; early-onset familial AD (5–10%) is caused by rare mutations in APP, PSEN1, and PSEN2. Genetic susceptibility in late-onset AD: heritability is ~60–80%; SNP-based h² is ~0.07. APOE ε4 is the strongest common genetic risk factor (3–15-fold depending on copy number). Over 40 susceptibility loci have been identified. Vascular, metabolic, and lifestyle factors modify risk. Disease begins decades before clinical symptoms; preventive interventions may be most effective in mid-life and earlier.
AD pathology accumulates over decades; adolescence is distant from clinical onset but brain development and cognitive reserve may be shaped during this period. Education, cognitive stimulation, and physical activity in youth may build reserve. Traumatic brain injury in adolescence increases later AD risk. APOE genotype affects brain development and response to injury. Psychosocial stress during development may affect brain structure. Early identification of high genetic risk could enable future prevention trials; current clinical utility in adolescents is nil.
Genetic Architecture Summary
| Gene | Variant | GWAS p | Evidence | Strength |
|---|---|---|---|---|
| APOE | rs429358 | 1.0e-200 | Lipoprotein receptor; ε4 allele increases amyloid deposition and risk; ε2 protective; strongest common AD locus | 0.98 |
| APP | — | — | Amyloid precursor protein; familial AD mutations increase amyloid production | 0.95 |
| PSEN1 | — | — | Presenilin 1; gamma-secretase component; familial AD; alters amyloid processing | 0.95 |
| PSEN2 | — | — | Presenilin 2; gamma-secretase component; familial AD | 0.9 |
Heritability
h² SNP: 0.07; h² narrow-sense: 0.7 — IGAP and twin studies (2019)
PRS notes: AD PRS show moderate predictive ability (AUC ~0.60–0.75); APOE alone contributes substantially. Transferability is limited: European discovery; APOE effects vary by ancestry (ε4 prevalence differs). PRS may stratify risk for prevention trials and research; clinical utility for asymptomatic individuals is limited. G×E (education, vascular factors, head injury) not yet integrated.
Exposure Modifier Panel
| Exposure | Direction | Strength | Confidence | Mechanism hypothesis |
|---|---|---|---|---|
| air-pollution | amplify | 0.65 | MEDIUM | PM2.5 and ultrafine particles may enter brain via olfactory or circulatory routes; oxidative stress and neuroinflammation; epidemiologic associations emerging |
| psychosocial-stress | amplify | 0.55 | MEDIUM | Chronic stress and depression may accelerate cognitive decline; cortisol effects on hippocampus; bidirectional with dementia |
| diet-quality | buffer | 0.6 | MEDIUM | Mediterranean-style diet; antioxidants, omega-3s; may reduce inflammation and support brain health |
| obesity-exposure | amplify | 0.6 | MEDIUM | Mid-life obesity increases AD risk; vascular and metabolic pathways; late-life weight loss may reflect prodromal disease |
Population Equity Notes
GWAS ancestry breakdown: AD GWAS are predominantly European (~90%); multi-ancestry efforts are expanding
Transferability notes: APOE effects vary by ancestry: ε4 prevalence is lower in some populations; risk estimates differ. Other loci may not transfer. PRS performance in non-European populations is reduced. Under-representation of diverse groups limits generalizability.
Data gaps: Under-representation of African, Hispanic, and Asian populations; G×E across ancestries; early-life determinants; biomarker validation in diverse populations.
Tissue Context
Visualizations
Risk Shift by Exposure Stratum
Population-level data only — does not predict individual risk
Tissue Relevance
References
- 1.Kunkle BW, et al. (2019). Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci. Nature Genetics. doi:10.1038/s41588-019-0358-2
- 2.Corder EH, et al. (1994). APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Molecular Psychiatry. doi:10.1038/sj.mp.4000473
- 3.Shi L, et al. (2020). Association of air pollution with dementia. JAMA Neurology. doi:10.1001/jamaneurol.2020.3962
- 4.Anstey KJ, et al. (2011). Midlife obesity and dementia: meta-analysis. Obesity Reviews. doi:10.1111/j.1467-789X.2010.00775.x
- 5.Lourida I, et al. (2013). Mediterranean diet and cognitive decline. Epidemiology. doi:10.1097/EDE.0b013e3182944410