Is APOE ε2 always a protective allele? Deviations in Hardy-Weinberg equilibrium in admixed Brazilian elderly individuals

The APOE gene is a critical determinant of human healthspan and longevity, with the rare{varepsilon} 2 allele traditionally viewed as a universal protective factor against Alzheimer s disease (AD) and a driver of exceptional lifespan. However, this protective paradigm is predominantly derived from European-centric cohorts, leaving the evolutionary and clinical impacts of{varepsilon} 2 across diverse, highly admixed populations largely unknown due to a lack of local ancestry (LA) resolution. To investigate how local genomic backgrounds modulate APOE survival dynamics we analyzed two Brazilian sample collection of older adults from Sao Paulo city: the Biobank for Aging Studies (BAS, n = 716), a post-mortem autopsy study of naturally deceased individuals; and the Health, Well-being and Aging Study (SABE, n = 952), a census-based elderly sample collection. We evaluated deviations from Hardy-Weinberg equilibrium (HWE) using robust permutation-based models to capture ongoing selective and mortality pressures at the APOE locus. While global APOE frequencies adhered to HWE, integrating LA unveiled striking, mirrored ancestral deviations. Our findings reveal that APOE {varepsilon}2 homozygotes with African ancestry significantly contribute to deviations from HWE in the BAS, with an excess of {varepsilon}2AFR/{varepsilon}2AFR homozygotes observed (p = 0.0196). These distinct HWE deviations demonstrate that an African LA background acts as a genetic buffer, attenuating the phenotypic extreme effects of APOE alleles. Furthermore, we observed an excess of the{varepsilon} 4 European haplotypes in the BAS, which is consistent with a mortality pressure allelic effect in the European LA context. Conversely, the{varepsilon} 4AFR/{varepsilon}4AFR combination was overrepresented in the SABE. While this buffering mechanism mitigates{varepsilon} 4 toxicity, it simultaneously dampens the exceptional longevity advantage typically conferred by the{varepsilon} 2 allele, leading to its neutral accumulation in the post-mortem cohort. Our study challenges the "one-size-fits-all" assumption of APOE biomarkers, demonstrating that{varepsilon} 2 protective mechanisms are context-dependent and modulated by local genomic backgrounds in admixed populations.