APOE genotype (ε2/ε3/ε4)

Apolipoprotein E (APOE) is a lipid-transport protein encoded by the APOE gene, which segregates into three alleles — ε2, ε3, and ε4 — producing six possible genotypes. The ε4 allele is the strongest common genetic risk factor for late-onset Alzheimer's disease, conferring roughly 3-fold higher risk per allele in heterozygous carriers, while homozygous ε4/ε4 carriers face approximately 10–15-fold elevated risk; a 2024 study (Fortea et al., Nature Medicine) proposed reclassifying this genotype as a near-deterministic genetic form of late-onset Alzheimer's, though this remains under debate. Conversely, ε2 appears modestly protective against Alzheimer's and is associated with lower LDL levels. Because APOE genotype is fixed at birth and has large, well-replicated effect sizes, it is uniquely informative for stratifying lifetime dementia and cardiovascular risk, though penetrance is incomplete and lifestyle factors can modify the trajectory.