Microglia in AD

Objectives:
Alzheimer's disease (AD) is the most common cause of dementia, yet its cellular and molecular mechanisms remain incompletely understood. Microglia are key contributors to AD pathogenesis, and GWAS-identified AD risk variants are enriched in microglial genes. Our preliminary data indicate GPNMB is among the most strongly differentially expressed genes in AD microglia, its expression correlates with cognitive slope and neuropathology score. Whether GPNMB is causal or marks downstream microglial activation is unresolved. We propose to test whether there exists an association between GPNMB genotype and these disease outcomes, which may explain a causal role for GPNMB in the pathogenesis of AD.
Study design:
Retrospective, computational analysis of pre-existing, de-identified data. No participants will be recruited and no new specimens collected. We request whole genome sequencing data from the Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD) cohort deposited in NIAGADS (NG00174): up to 84 postmortem brain donors spanning the full spectrum of AD pathology. We already possess paired quantitative neuropathology, single-nucleus RNA-seq, and clinical metadata.
Analysis plan:
Our aims are to (1) extract GPNMB genotype from SEA-AD variant call files using standard bioinformatics tools; (2) test association of GPNMB variants with clinical variables; and (3) test association with degree of AD neuropathology. Phenotypic characteristics evaluated in association with genetic variants will include age of onset, cognitive status, and dementia diagnosis, together with amyloid burden, tau pathology, and Braak stage. Associations will be tested by linear or logistic regression as appropriate, with age, sex, and ancestry principal components as covariates. Publicly available SEA-AD single-nucleus expression data will be used to relate genotype to microglial transcriptional state.

Alzheimer's disease is the most common cause of dementia and affects millions of Americans, but we still do not fully understand its cause. Immune cells in the brain, microglia, appear to play an important role. We are studying a gene called GPNMB that is active in these cells and may influence the disease.
This study uses information that has already been collected. We will not recruit anyone or collect new samples. Instead, we will analyze de-identified genetic data from brain donors, along with information about their cognitive slopes, their diagnosis, and neuropathology scores. We will look at whether genotypes at the GPNMB gene are linked to the slope of cognitive decline, a diagnosis of dementia, or neuropathology scores.
Donor identities are protected, and all work will be done on secure computers at the University of Pennsylvania.