ABCA7-80 moderates vascular stiffness–p-tau217 association in older African Americans

Introduction: Compromised vascular health is increasingly linked to Alzheimer's disease (AD) risk. Estimated pulse wave velocity (ePWV), derived from age and blood pressure, and provides a practical, non-invasive index of vascular stiffness and overall vascular health. Older African Americans experience a disproportionate burden of vascular disease and AD. Genetic risk factors such as APOE ε4 and ABCA7-80 (rs115550680) further increase AD susceptibility. However, whether these genetic risks influence vascular stiffness and how that may interact with AD pathology remains unknown, especially in African Americans. Methods: A total of 143 older African Americans (mean age = 71.10 ± 6.83 years; 109 women) were included. We examined the effects of both ABCA7-80 and APOE ε4 genotypes on ePWV and plasma phosphorylated tau 217 (p-tau217). All regression models controlled for sex, education, pulse pressure, waist-to-hip ratio, global cognitive status, hypertension status, and APOE genotype (APOE genotype only used for ABCA7-80 regression models). Results: ABCA7-80 risk allele carriers exhibited higher ePWV (F_(1,130) = 8.16, p = 0.005, η²_p = 0.064) and higher p-tau217 levels (F_(1,130) = 30.11, p < 0.001, η²_p = 0.201). APOE ε4 allele carriers also showed higher p-tau217 levels (F_(1,131) = 12.96, p < 0.001, η²_p = 0.092). ABCA7-80 significantly moderated the relationship between ePWV and p-tau217 (F_(1,130) = 6.58, p < 0.001), such that higher ePWV was associated with higher p-tau217 among ABCA7-80 risk carriers (β = 0.52, t₍₁₃₀₎ = 2.69, p = 0.008). Discussion: ABCA7-80 risk, but not APOE ε4, heightens susceptibility to the tau-related effects of compromised vascular health among older African Americans. These findings identify a genetically vulnerable subgroup in which vascular stiffness may disproportionately accelerate AD-related tau pathology and highlight vascular health as a modifiable target for reducing AD risk in African Americans.