The Role of Lipids in Alzheimer's Disease and Related Dementias among Black Americans: Examining Lifecouse Mechanisms

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PROJECT SUMMARY/ABSTRACT Black Americans experience a disproportionate burden of cardiovascular disease (CVD) risk factors and Alzheimer's disease and related dementias (ADRD). Studies have identified midlife (~ ages 45-65) dyslipidemia as a risk factor for ADRD. Black Americans have more favorable lipid profiles compared to Whites or Latinos, but their incidence of dyslipidemia in midlife is higher. This seemingly paradoxical relationship between favorable midlife lipid profiles yet high incidence of midlife dyslipidemia and high risk of ADRD among Black Americans has been severely understudied. Lipids play a vital role in neurodegenerative disease, and epidemiologic and metabolomic studies have identified commonly tested lipids (total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides) as well as sphingolipids (ceramides) as predictors of cognitive aging. Prior work has largely overlooked the contributions of lipids to ADRD risk in Black Americans and few studies have examined the relationship of ceramides with cognitive aging and ADRD in this high-risk group. This project will leverage over 40 years of longitudinal data from two NIH/NIA funded cohort studies, the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) Study and the Study of Health Aging in African Americans (STAR), to better understand the role of lipids in cognitive aging and ADRD among Black Americans. The scientific objective of this research plan is to characterize the relationship of early adulthood (~ age 30) total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides as well as the novel lipid biomarker, ceramides, with late life cognitive decline, ADRD, and MRI markers of neurodegeneration and vascular brain injury in an all-Black cohort of older adults. The proposed research seeks to: 1) define the role of early adulthood lipids in cognitive aging and ADRD; 2) examine genetic (APOE) and psychosocial (racism) factors as potential effect modifiers; and 3) determine whether the relationship of early adulthood lipid levels with late life cognitive decline and ADRD is partially mediated by midlife (~ ages 45-65) cardiometabolic disease (hypertension, diabetes, obesity, and dyslipidemia). For aging Black Americans with high prevalence of CVD risk factors and at disproportionate risk of dementia, prevention of ADRD has enormous health and economic consequences. This research will be complimented by a detailed training plan based at the University of California, Davis, with guidance from an exceptional mentorship team of nationally and internationally recognized ADRD, lipids, dementia, and cognitive aging researchers. The training will build upon the applicant's background in CVD and dementia epidemiology by incorporating specialized training in lifecourse theory and modern causal inference methods, biology of lipids, psychometric testing, and measurement and modeling of neuroimaging biomarkers. The combined research and training will prepare the applicant to successfully transition to an independent researcher of disparities in vascular contributions to ADRD.