Ancestry-specific effects of APOE on Alzheimer Disease Endophenotypes

Abstract INTRODUCTION APOE *ε4 is the strongest genetic risk factor for Alzheimer’s disease (AD), yet its effect varies across ancestral populations. As plasma biomarkers increasingly inform AD diagnosis, failure to account for both APOE genotype and genetic ancestry could lead to diagnostic misclassification. METHODS In 2,733 participants from the Health and Aging Brain Study–Health Disparities (HABS-HD), we evaluated whether genetically-inferred ancestry modifies APOE associations with AD endophenotypes. Regression models were applied across three frameworks: ancestry-stratified analyses, compositional modeling of global ancestry, and local ancestry analyses at the APOE locus. RESULTS APOE ε4+ was associated with higher pTau 217 and pTau 181 , lower Aβ 42 /Aβ 40 , and worse global cognition (CDR-SB), significant within ancestry groups after FDR correction. The ε4+ effect on pTau 217 was ∼2.5-fold larger in EUR-like than AFR-like participants. DISCUSSION African ancestry attenuates APOE *ε4+ associations with pTau 217 , highlighting the need to consider both APOE genotype and ancestry in biomarker-based AD evaluations.