Integrating Polygenic Risk and Environmental Exposures to Uncover Biological Mechanisms Underlying Dementia in a Diverse Cohort

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PROJECT SUMMARY Alzheimer’s disease (AD) is a leading cause of death in developed countries. Over 50 genetic loci have been associated with late-onset AD risk, yet we still do not fully understand the disease pathogenesis and have failed to find successful solutions for prevention or treatment of dementia or cognitive decline. AD is influenced by genetic and environmental (social, built, and physical) factors. Understanding the interplay between these genetic and non-genetic factors is crucial to address the underlying biology of the disease. Many studies have focused on identifying either genetic causes or modifiable risk factors associated with AD, and most gene- environment studies of AD have been restricted to single-gene x single-environmental factor studies (primarily focusing on the gene APOE). Few studies have addressed how upstream factors like socioeconomic status and ambient air pollution interact with risk across many genetic locations (polygenic) to influence gene expression and proteomic changes that lead to AD and related dementias. The specific aims of this study are to 1. (F99 phase) determine social, built, and physical environmental variables associated with dementia risk and/or cognitive decline, independent of and modified by polygenic risk and 2. (K00 phase) identify transcriptomic and proteomic signatures that mediate the effect of environmental exposure on dementia/cognitive decline. During my dissertation phase, I will train in polygenic risk score computation, predictive analysis, mixed-effect modeling, and machine learning to characterize the effects of genetic and environmental determinants on AD and related dementias. I will employ polygenic risk score methods that have been designed to improve predictive accuracy in multi-ethnic populations. As a post-doctoral fellow, I will expand my training to multi-omic data integration and analysis to move our understanding of risk factors for AD and related dementias beyond studies of association to an understanding of causal pathways and the biological mediators of environmental exposures. This research will leverage the Multi-Ethnic Study of Atherosclerosis parent and ancillary studies (MESA Neighborhood and Aging, MESA MIND, and MESA Air), a longitudinal cohort unprecedented in its scope of social determinants of health along with dementia adjudication and multi-omic data. This fellowship application aligns with the NIA Strategic Directions for Research Goal D-1 “to determine how genetic, molecular, cellular, and social/environmental factors interact for brain health and neurodegeneration.” As a result of this work, we will have identified upstream (policy-level) and downstream (biological mechanisms) points of intervention and prevention. In addition, the research and career development provided by this award will help me launch my career as an independent investigator of AD prediction and prevention.