Microglia-specific polygenic risk stratification reveals distinct pathological subtypes in Alzheimer's disease

INTRODUCTION: Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder in which numerous common variants collectively influence risk. Polygenic risk scores (PRSs) quantify this genetic predisposition, but conventional PRS approaches aggregate biologically diverse variants, potentially masking cell type-specific contributions. METHODS: We developed PRSs for major brain cell types and evaluated their performance in two genomic datasets (n = 4,678 and n = 76). AD cases were stratified by microglia-specific PRS, followed by bulk-brain RNA-seq (n = 16), single-nucleus RNA-seq (n = 15), and spatial transcriptomics of postmortem brains. RESULTS: The microglia-specific PRS most robustly captured AD genetic risk. High-microglia PRS cases exhibited dystrophic microglia with elevated ribosomal gene expression, whereas low-microglia PRS cases exhibited lipid-associated microglia. DISCUSSION: Microglia-focused PRS resolves molecular heterogeneity in AD and provides a framework for the use of cell type-specific genetic models in precision medicine.