Distinct glial functions are associated with Alzheimer's disease based on cell-type- and pathway-specific polygenic risk score analysis

BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, amyloid plaques, neurofibrillary tangles, and neuroinflammation. Glial cells-astrocytes, microglia, and oligodendrocytes-play essential roles in AD progression, but their pathway-specific genetic contributions remain unclear.ObjectiveTo identify glial cell type-specific biological pathways associated with AD using pathway-based polygenic risk score (PRS) analysis.MethodsWe applied PRSet to evaluate associations between glial-specific pathways and AD in a discovery dataset (ADc1234ADA), adjusting for the top two principal components (Model 1), and additionally for sex, age, and <i>APOE</i> ε4 status (Model 2). Pathways with nominal significance (<i>p </i>< 0.05) were further tested in an independent replication dataset (ADNI). Results from both datasets were meta-analyzed and assessed for statistical significance using Bonferroni correction. Competitive <i>p</i>-values were used to determine the relative contribution of each pathway within glial types. Genes from significant pathways were used in a follow-up gene-based PRS analysis, following the same modeling and validation steps.ResultsIn Model 1, we identified four significant astrocytic, six microglial, and one oligodendrocyte pathways. In Model 2, five astrocytic and three oligodendrocytic pathways remained significant; no microglial pathways met significance. The top pathways were the immune system in astrocytes, antigen processing in microglia, and transport and trafficking in oligodendrocytes. At the gene level, <i>BCL3</i> and <i>BIN1</i> were significant in Model 1, while only <i>BIN1</i> remained in Model 2.ConclusionsThese findings highlight distinct glia-specific genetic contributions to AD, particularly involving immune-related pathways, and demonstrate the value of cell-type-specific PRS approaches in AD research.