| Gene Symbol | ADPD2026PRECISIONMEDICINEGENETICSTRATIFICATION |
| Function | APOE4 fragment accumulation disrupts mitochondrial function and synaptic homeostasis |
| Penetrance | Nearly 100% of APOE4/4 homozygotes develop AD pathology by age 85, approaching monogenic disease penetrance |
| Pathological mechanisms | Distinct from amyloid-driven AD, with APOE4/4 showing accelerated tau pathology independent of amyloid burden |
| Treatment response | Differential response to anti-amyloid therapies (lower lecanemab efficacy, higher ARIA risk in APOE4/4) |
| Biomarker trajectory | Accelerated amyloid accumulation, earlier tau PET positivity, more rapid neurodegeneration |
| Diagnostic utility | Supports AD probability assessment in symptomatic patients |
| Risk communication | Enables discussion of lifetime risk, though requires careful counseling |
| Treatment selection | Critical for anti-amyloid therapy decision-making (ARIA risk stratification) |
| Clinical trial stratification | Essential for trial design, particularly for prevention studies |
| Lecanemab | APOE4/4 carriers show 30-40% less amyloid reduction vs. non-carriers |
| ARIA risk | APOE4/4 increases ARIA-E incidence 3-4 fold, ARIA-H 2-fold compared to E3/E3 |
| Dosing considerations | Some protocols recommend reduced dosing for E4 homozygotes |
| Monitoring | More frequent MRI monitoring warranted in E4/4 patients |
| GWAS variants | 100-500+ variants from large-scale AD GWAS (predominantly European-ancestry) |
| Effect size weighting | Each variant weighted by its association strength (beta coefficient) |
| Databases | GeneCardsUniProtNCBI GeneHPASTRING |
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