Understanding Biological and Lifestyle Contributions to Alzheimer's Disease Pathology and Clinical Profiles in Black Women: Defining Prevention Targets in High Risk Groups

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PROJECT SUMMARY/ABSTRACT Women have higher rate of Alzheimer's disease (AD) and tend to show a more aggressive profile of AD than men, with greater pathological tau burden and steeper cognitive decline. The prevalence of AD also differs by race with higher rates among Black versus White older adults. Yet, very little is known about AD in Black individuals given their historical exclusion in research. Even less is known about the intersection of race and sex in AD. In this proposal, we aim to study how sex- and/or race-disparate biological (inflammation, insulin resistance [IR]) pathways and physical activity potentially contribute to tau accumulation and cognitive decline specifically among older Black women at-risk for AD. We focus on potentially modifiable risk/protective factors given the recent surge in evidence that modification of these factors can be highly effective in delaying or even preventing cognitive decline. Our own preliminary work indicated that women may be more susceptible than men to the adverse effect of inflammation on levels of phosphorylated tau (p-tau) and cognitive function. There is also evidence that certain lifestyle factors, including physical activity, have a greater impact on AD-related outcomes such as tau in women versus men. Given links between physical activity and inflammation, we propose to investigate the interplay between inflammation and physical activity in their contributions to tau and cognitive decline in older Black women at risk for AD. Since IR is a key driver of inflammation, and the rates of prediabetes/diabetes are higher in Black adults, we will examine how IR impacts tau accumulation and cognitive decline. It is critical to examine these relationships in the context of social determinants of health, which are a driving factor in health outcomes such as inflammation and IR particularly in Black women. To achieve this, we propose a prospective study that will assess all variables of interest and their interactive pathways. The proposed study will build upon an ongoing pilot study that will collect these variables in 30 White women by study end (June, 2022), but will represent a more targeted and less invasive study in order to enhance recruitment in the understudied yet higher risk group of older Black women. We propose to recruit Black women at two sites, one leveraging an existing research registry of Black women in Los Angeles, and the other leveraging local community connections and previous research experience to create a new cohort in San Diego. We will use a community-based participatory research approach to recruitment that involves decision making at each level involving a Community Advisory Board. We will measure inflammatory markers in blood, IR, physical activity and the Area Deprivation Index as our primary social determinant of interest in 100 Black women at-risk for AD and relate these measures to changes in cognitive function and accumulation of tau, measured in plasma, over a two-year period. This project will help to close critical gaps in our understanding of risk factors for AD in Black women by examining biomarkers and social determinants of health in this under-researched yet highly- vulnerable group. Furthermore, our findings will inform risk reduction strategies that influence these mechanisms.