Social Mechanisms Underlying Sex Differences in Alzheimer’s Disease.

Alzheimer’s disease (AD) is a major public health burden that disproportionately affects women. Women in the U.S. have experienced societal barriers that prevent them from accessing health-enhancing opportunities and resources that may have a negative impact on their AD risk. For Black women, the societal barriers associated with being a woman are further compounded by those associated with being Black. Little has been done to understand the link between these societal barriers and sex differences in AD. Differences between men and women are assumed to be primarily biological (e.g., because of sex-steroid hormones), and socially driven heterogeneity among women has been largely ignored. To move the field forward, researchers interested in sex differences in AD must identify and understand the societal drivers of cognitive health disparities between men and women. This research plan aims to determine whether contextual determinants influence sex differences in AD outcomes. This project examines how multiple experiences of societal barriers overlap and interact to produce disparate cognitive health outcomes among non-Latino Black and White women and men. The K99 phase of this study showed that exposure to higher levels of societal barriers was associated with lower baseline memory performance among both women and men and a more rapid rate of memory decline among women. The goal of the R00 phase is to evaluate whether sex differences in cognitive and brain resilience to AD pathology and neurodegeneration vary across levels of societal barrier exposure (Aim 1). This proposal leverages cognitive trajectory and AD-biomarker data from five cohort and national longitudinal studies: Washington Heights-Inwood Community Aging Project (WHICAP), Offspring study, Minority Aging Research Study (MARS), Health and Retirement Study (HRS), and Reasons for Geographic and Racial Differences in Stroke (REGARDS). State-level indicators of societal barriers will be used. To accomplish these goals, the applicant has built on her strengths in sex differences, neuropsychology, cognitive aging, health disparities, and advanced statistical methods through the training obtained during the K99 phase, which focused on (1) cutting-edge analytic techniques, (2) measuring and modeling contextual determinants of health, (3) sex differences in AD-biomarkers, and (4) causal inference methods. This R00 proposal lays the foundation for an independent research career focused on identifying contextual and biological determinants of sex differences in AD.