Neurol Genet. 2026 Jul 16;12(4):e200417. doi: 10.1212/NXG.0000000000200417. eCollection 2026 Aug.
ABSTRACT
BACKGROUND AND OBJECTIVES: The apolipoprotein E (APOE) haplotypes are known to be associated with dementia, with the ε4 haplotype associated with higher risk. It has been suggested that the APOE ε2 allele serves as a protective factor for dementia. However, data on the effects of the homozygous APOE ε2/ε2 genotype are limited, likely due to the rarity of the APOE ε2/ε2 genotype. Furthermore, the association between APOE genotypes and dementia may differ across self-reported race. We aim to investigate the association between APOE genotypes and dementia overall and across self-reported race, with a focus on the potential protective effects of the ε2 haplotype and differences across race.
METHODS: Data from 7 large, community-based, prospective cohort studies from the Dementia Risk Prediction Pooling Project: Age, Gene/Environment Susceptibility-Reykjavik Study, Whitehall II study, Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Honolulu-Asia Aging Study, Multi-Ethnic Study of Atherosclerosis, and Framingham Heart Study and its associated cohorts were used. Cox proportional hazard models were used to estimate the cause-specific hazard ratios of dementia by APOE genotypes overall and by self-reported race.
RESULTS: The study consisted of 45,022 participants (10% Asian, 15% Black, 75% White, 52% male) with a mean age of 56 years (SD: 14.5) at baseline. Compared with participants with an APOE ε3/ε3 genotype, those with an ε2/ε3 genotype had a lower risk of dementia (HR: 0.87, 95% CI 0.80-0.96). There was an indication of protective effects of the ε2/ε2 genotype compared with the ε3/ε3 genotype (HR: 0.98, 95% CI 0.71-1.37). These associations were similar among Black and White participants. The detrimental effect of an ε4/ε4 genotype compared with an ε3/ε3 genotype was also seen overall and among Black and White participants. Those with an APOE ε4/ε4 genotype experienced dementia onset approximately 8 years earlier than those with an APOE ε3/ε3 genotype.
DISCUSSION: In this large, pooled cohort, the presence of at least one APOE ε2 allele was associated with lower risk of dementia overall and by self-reported race, suggesting a protective effect. APOE ε4/ε4 was associated with an earlier age of dementia onset with differences across race.
PMID:42519715 | PMC:PMC13382979 | DOI:10.1212/NXG.0000000000200417