APOE:RAAS epistasis as a population specific risk factor for cognitive impairment and cardiovascular health

Background The strongest genetic risk factor for development of Alzheimer's disease (AD) and/or AD-related dementias is the ε4 allele in the apolipoprotein E ( APOE ) gene, though the frequency and impact of this variant on cognitive decline can vary across populations. Vascular and metabolic disorders (e.g., hypertension and diabetes) are co-morbidities for AD and are particularly impactful in underrepresented, non-White populations and may play a role in differential AD outcomes. Here we investigate the impact of gene-gene interactions between the vascular regulating renin-angiotensin-aldosterone system (RAAS) and APOE and how they relate to cognitive impairment. Objective Determine if vascular and AD genetic risk factors interact to contribute to differential cognitive impairment outcomes across populations. Methods Stratifying by APOE ε4 status, RAAS:APOE epistasis association testing was completed on self-reported African American (AAs), Mexican Americans (MAs), and non-Hispanic Whites (NHWs) enrolled in the Health & Aging Brain Study-Health Disparities dataset, using PLINK. Results Population-specific epistasis profiles connecting cardiovascular and cognitive impairment were found in APOE ε4- AAs, and APOE ε4+ MAs. Conclusions Population-specific epistasis profiles support epistasis as a potential mechanism for differential AD outcomes in AAs, MAs, and NHWs, considering ε4 positivity. This is the first study linking AD and vascular co-morbidities to cognitive impairment risk in the HABS-HD dataset via epistasis.