Genetic Architecture of Alzheimer’s Disease Neuropathology and Clinical Severity Using NACC Phenotypes and Admixture-Informed Genome-wide association studies

Genome-wide association studies (GWAS) have identified over 80 loci influencing Alzheimer’s disease (AD) risk, yet their impact on quantitative neuropathological traits—such as neuritic and diffuse plaque density, Braak staging of neurofibrillary degeneration, cerebrovascular pathology, and synaptic integrity—remains poorly defined. Similarly, the extent to which these variants contribute to clinical heterogeneity, including dementia severity, cognitive trajectory, and resilience, is not fully understood. Genetic ancestry and population structure further complicate interpretation, as most GWAS have been conducted in European-ancestry cohorts, potentially masking ancestry-specific effects or inflating signals due to unmodeled admixture. We hypothesize that: 1) Established AD risk loci exert pleiotropic effects on specific neuropathological features, independent of overall disease risk; 2) Genetic ancestry and local admixture modulate the effect size and penetrance of these variants on both pathology and clinical outcomes; and 3) Integrating fine-scale genetic structure with quantitative trait GWAS will enhance power, reduce bias, and reveal population-specific mechanisms.

Aim 1: Conduct ancestry-aware GWAS of neuropathological traits using NACC postmortem data harmonized with ADSP genetic data
Aim 2: Investigate local genetic admixture and its interaction with AD risk loci
Aim 3: Integrate genetic, pathological, and clinical data to model disease heterogeneity

We anticipate the following: 1) Novel locus-trait associations linking AD risk variants to specific neuropathological outcomes; 2) Evidence of ancestry-dependent genetic regulation of AD pathology, informing inclusive trial design; and 3) A framework for dissecting clinical heterogeneity through genetically informed pathological subtypes. These findings will refine mechanistic models of AD progression, prioritize therapeutic targets with pathology-specific efficacy, and improve risk prediction across diverse populations.

This project aims to better understand how genes linked to Alzheimer’s disease relate to the specific brain changes seen in the condition and why people with the same genetic risk can experience different symptoms or rates of decline. Using clinical and neuropathological data from the National Alzheimer’s Coordinating Center and genetic information from the Alzheimer’s Disease Sequencing Project, we will examine whether known Alzheimer’s‑related genetic variants are associated with measurable neuropathological features such as plaque and tangle burden, blood vessel changes, and markers of synaptic health. We will also study whether these genetic effects differ across individuals with different ancestries or mixed genetic backgrounds. By combining genetic, clinical, and brain‑based information, our goal is to clarify how genetic factors contribute to disease heterogeneity and to improve understanding across diverse populations.