Pathway-based Polygenic Risk Score Analysis of Brain Glial Indicates Cell-type-specific Roles in Alzheimer's Disease

Background: Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline and extensive brain pathology, including amyloid plaques, neurofibrillary tangles, and neuroinflammation. This study aims to identify any glial cell type-specific pathways associated with AD. Methods: We first investigated the correlation between AD and the genetic risk of glia-specific pathways using pathway-based polygenic risk score (PRS) with PRSet software in the discovery data (ADc1234ADA) adjusted by the top two principal components (PC1, PC2) (Model 1), followed by additional adjustment with sex, age, and APOE ε4 count in Model 2. Further PRSet analyses were replicated in independent data (ADNI) if a nominal association (p < 0.05) was found in the discovery data. Tentative associations were determined via meta-analyses of both discovery and replication datasets with Bonferroni correction. Finally, a competitive p-value test was used to determine the significance of each pathway within each glial cell type. Results: In model 1, we identified six pathways significantly associated with astrocytes with the immune system on the top, six pathways associated with microglia with antigen processing on the top, and five pathways associated with oligodendrocytes with transport & trafficking on the top. In model 2, five pathways in astrocytes and four pathways in oligodendrocytes were found to be significant. However, none of the pathways in microglia remained significant. Conclusion: Our findings demonstrate a glia-specific polygenic contribution to AD risk, especially in the immune system, highlighting the significance of PRSet analysis in uncovering cell-type specific and pathway-specific biological mechanisms for diseases.