ABCA7‐80 moderates vascular stiffness–p‐tau217 association in older African Americans
Miray Budak, Kevin S. Heffernan, Martina Ishaq, Victoria Paruzel, Demiana Abdalla, Soodeh Moallemian, Bernadette A. Fausto, Fanny M. Elahi, Mark A. GluckAbstract
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, η 2 p = 0.064) and higher p‐tau217 levels ( F (1,130) = 30.11, p < 0.001, η 2 p = 0.201). APOE ε4 allele carriers also showed higher p‐tau217 levels ( F (1,131) = 12.96, p < 0.001, η 2 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.