Genetic and Environmental Sources of Heterogeneity in Alzheimer's Disease: A Pathway Specific Approach

PROJECT SUMMARY Alzheimer’s Disease (AD) affects an estimated 6 million people in the US and prevalence is expected to nearly double within the next 30 years increasing the existing economic, healthcare, and quality of life burdens. Though clearly a condition of immense public health significance, there are few treatments to effectively modify disease progression. Elucidating the genetic basis of AD will inform therapeutic development. Thus far, investigations have revealed substantial heterogeneity in genetic effects across populations and environmental contexts, indicative of varying etiologic importance of disease mechanisms. Current analyses have been limited by the lack of methods to quantify individual-level pathway-specific genetic susceptibility. Gene- environment interactions (GxE) likely also contribute to this heterogeneity. Targeting genetic mechanisms in synergy with environmental context can be expected to have a greater impact on AD prevention or progression than genetic mechanisms not influenced by environment. Furthermore, assessing GxE can identify the most influential environmental risk factors to modify in public health interventions to reduce health disparities in AD. Current evidence for GxE in AD comes from applications of general polygenic risk scores (PRS) or targeted explorations of interactions with high-risk variants in the APOE gene. Though such models have improved power to detect interactions, they are less precise in that they do not allow for exploration of specific biological mechanisms involved in AD pathology, and may consider individuals with vastly different genetic risk profiles to have similar genetic susceptibility to AD. The goal of this project is to leverage novel PRS construction methods to explore genetic and environmental sources of heterogeneity in AD. In Aim 1, we will explore approaches for constructing pathway-specific PRS that integrate regulatory genomics and multi-ancestry data. In comparing predictive performance of these PRS, we will identify approaches that best capture pathway- specific genetic susceptibility. In Aim 2, we will use data from a diverse longitudinal cohort study to assess heterogeneity of pathway-specific genetic effects across levels of fine particulate matter exposure ascertained across mid- and late-life. These studies represent crucial steps towards improved understanding of the biological mechanisms of AD to aid in identification of druggable targets and groups at highest risk of AD. This work will further establish a novel framework for the exploration of GxE in other complex diseases.