Investigating a molecular basis for AD subtypes using multiomic data integration and machine-learning Despite intense investigation into preclinical Alzheimer?s Disease (AD) disease models, all potential disease- modifying drugs have failed in clinical trials. Numerous genetic studies have proposed a number of biological mechanisms, however there has been no consensus on the genetic etiology of AD. This is likely because the prevailing view of AD as a singular disease is oversimplified and does not consider heterogeneous pathogenic variation in AD genetic architecture. High-throughput studies indicate that AD is a result of complex, nonlinear interactions within and between the genome, transcriptome, epigenome, and proteome. While genome-wide association studies have successfully revealed genes associated with AD, these genes explain disease in a small proportion of the patient population, and the question of ?missing heritability? remains. Thus, in Aim 1, I propose using linear and nonlinear methods in an integrated multiomics framework with machine learning to identify pathways significant in AD. While almost all AD patients present the hallmark b-amyloid and neurofibrillary tangle pathology, they also present significant variability in cognitive symptoms, behaviors, and neurophysiology. Given this, I hypothesize that inter-individual variation in AD-associated and immune pathways drives different disease etiologies across the patient population culminating in a common pathophysiology. One source of heterogeneity may be in immune pathways differentially regulating neuroinflammatory response during AD.
In Aim 2, I propose using an unsupervised classification approach to determine subtypes of AD based on patient similarity in pathway variation across omic levels, imaging data, and phenotypic data. Specifically, I hypothesize that pathogenic variation within innate immunity pathways plays a critical role in driving different disease etiologies between patients.
In aim 3, I propose characterizing each omic subtype by generating protein interaction networks for drug target prioritization. Knowledge from these aims will inform a shift in the current AD drug development paradigm by informing a precision medicine approach to target specific omic subtypes of AD instead of a ?one size fits all? approach that has failed to date. Investigating genomic heterogeneity in AD through these aims has the potential to impact detection of pre-symptomatic AD individuals as well as reveal more insights into the complex genetic architecture of AD.

Public Health Relevance

Alzheimer?s disease is a complex multifactorial disease affecting nearly 40 million individuals worldwide, and yet there are no approved therapies given our limited understanding of underlying genetic risk factors. Tremendous genetic heterogeneity in AD has made it challenging to use genetic data alone to determine prognostic genes that could be predictive of disease in the patient population. This proposal determines AD subtypes, or distinct molecular profiles of patients that are similar, based on integrated multiomic, imaging, and endophenotype data, as well as identifies potential therapeutic gene targets for each different subtype.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31AG069441-01
Application #
10067860
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Luo, Yuan
Project Start
2021-03-01
Project End
Budget Start
2021-03-01
Budget End
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104