Polygenic risk for Alzheimer’s disease shapes microglial inflammatory and antigen-presentation programs in vivo

How polygenic risk translates into cellular dysfunction remains largely unknown in Alzheimer’s disease and related disorders. Here, we selected 31 donors broadly spanning the Caucasian-based polygenic risk distribution for AD and show that human polygenic architecture modulates microglial immune responses to amyloid pathology in vivo. We developed a “microglia village” model by xenotransplanting pooled iPSC-derived microglia from these genetically diverse donors into amyloid-bearing (AppNLGF) and control (AppHu) mouse brains, allowing the effect of genetic background to be separated from shared environmental influences. Marked inter-donor transcriptomic differences were observed in hMG derived from homeostatic, non-amyloid brain environments, demonstrating divergent baseline states across individuals. Amyloid exposure induced highly varied expression of MHC class II genes across donor, which correlated with individual’s AD polygenic risk scores. These findings demonstrate that polygenic risk can be decoded into functional immune phenotypes in human microglia and establish a scalable in vivo platform to dissect the genetic regulation of cellular responses in complex brain disorders.