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.
