Ancestry-specific effects of <i>APOE</i> on Alzheimer Disease Endophenotypes

Abstract Importance APOE *ε4 is the strongest genetic risk factor for Alzheimer’s disease (AD), yet its effect varies across ancestral populations. As blood-based biomarkers increasingly inform AD diagnosis, failure to account for both APOE genotype and ancestry could lead to misinterpretation of biomarker profiles and inaccurate diagnostic classification. Understanding how ancestry modulates APOE effects is crucial for ensuring accurate biomarker-based assessments and AD diagnosis. Objective To determine whether genetic ancestry modulates APOE association with cognitive function, brain morphometry, and plasma biomarkers. Design, Setting, Participants Cross-sectional analysis of community-dwelling older adults from the Health and Aging Brain Study–Health Disparities (HABS-HD) cohort (N = 2733). Participants spanning the cognitive spectrum underwent cognitive assessment, neuroimaging, plasma biomarker collection, and genome-wide genotyping from 2018 to 2023. Main Outcomes and Measures Cognitive performance (global cognition, memory, executive function, verbal ability), brain morphometry (cortical thickness, hippocampal volume), and plasma biomarkers (Aβ 42 /Aβ 40 , pTau 181 , pTau 217 , total tau, NfL). Results In the full cohort, APOE ε4+ was associated with worse cognitive performance across all domains, reduced cortical thickness and hippocampal volume, lower Aβ 42 /Aβ 40 , and elevated pTau 181 and pTau 217 . APOE ε2+ was associated with lower pTau 217 . Ancestry-stratified analyses revealed attenuated ε4+ effects on pTau 217 and pTau 181 in African compared with European participants (∼2.5-fold for both), with the pTau 217 difference surviving FDR correction. Compositional analysis confirmed that ε4+ effects on pTau 181 and pTau 217 strengthened with increasing European ancestry proportion. Local ancestry analysis showed ε4+ effects on pTau 217 were significantly attenuated in individuals with African local ancestry at the APOE locus. In contrast, ε4+ effects on Aβ 42 /Aβ 40 , cognition, and neuroimaging were largely consistent across ancestry groups. Meta-analysis with an independent multi-ancestry cohort replicated the attenuated pTau 181 findings. Conclusions and Relevance Genetic ancestry modifies the effect of APOE on AD endophenotypes. In particular, African ancestry attenuates the association between APOE ε4+ and pTau 181 and pTau 217. Accurate AD diagnosis requires consideration of both APOE genotype and ancestry to avoid misclassification in biomarker-based evaluations.