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.

Grant Number: 1F31AG091981-01A1
NIH Institute/Center: NIH
Principal Investigator: Katrina Bazemore