APOE across ancestry and environmental contexts

Defining how APOE-associated risk varies across ancestry, life stage, biomarkers, and modifiable health factors

APOE is the strongest common genetic risk factor for late-onset Alzheimer’s disease, but its effects are not fixed across people or populations. My work has helped define how APOE-associated risk varies with age, sex, genetic ancestry, Alzheimer’s disease biomarkers, and modifiable health factors. This context is important because a single risk estimate may misrepresent the meaning of APOE genotype for people from different backgrounds.

In the largest multi-population analysis of APOE at the time, we evaluated 68,756 participants and found a stepwise pattern in the association of APOE ε4 with Alzheimer’s disease risk: effects were strongest in East Asian participants, followed by non-Hispanic White, non-Hispanic Black, and Hispanic participants. The protective association of APOE ε2 also varied across groups and was not evident in East Asian or Hispanic participants. We additionally identified an age-specific period in which women carrying one ε4 allele had greater risk than men. These findings demonstrated that APOE risk estimates depend on the population and life stage in which they are measured.

I extended this work beyond clinical diagnosis to Alzheimer’s disease endophenotypes, including plasma amyloid and phosphorylated tau, cognition, and brain structure. In a diverse community-based cohort, APOE ε4 was associated with worse biomarker, cognitive, and neuroimaging profiles. However, its associations with phosphorylated tau were substantially weaker among participants with African genetic ancestry, including those with African local ancestry at the APOE locus, while associations with amyloid, cognition, and brain structure were more consistent across ancestry groups. My earlier and more recent gene-environment studies further showed that hypertension and an unfavorable cardiovascular risk profile can worsen APOE-associated cognitive decline and dementia risk, while an unfavorable risk profile can weaken the protection associated with ε2. Together, this research shows that APOE acts within a broader ancestral and environmental context, supporting risk assessment and biomarker interpretation that account for both genotype and the individual in whom it occurs.

Selected publications

  • Boeriu AI, Gu T, Fulton-Howard B, et al. (2026). “Ancestry-specific effects of APOE on Alzheimer Disease Endophenotypes.” medRxiv. doi:10.64898/2026.03.23.26349095.
  • Belloy ME, Andrews SJ, Le Guen Y, et al. (2023). “APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry.” JAMA Neurology. doi:10.1001/jamaneurol.2023.3599.
  • Andrews SJ, Boeriu AI, Belloy ME, et al. (2024). “Dementia risk scores, apolipoprotein E, and risk of Alzheimer’s disease: One size does not fit all.” Alzheimer’s & Dementia. doi:10.1002/alz.14300.
  • Andrews SJ, Das D, Anstey KJ, Easteal S. (2015). “Interactive Effect of APOE Genotype and Blood Pressure on Cognitive Decline: The PATH Through Life Study.” Journal of Alzheimer’s Disease. doi:10.3233/JAD-140630.