Microglial response to amyloid-β pathology is modulated by X chromosome dosage

Alzheimer’s disease (AD) exhibits sex-specific prevalence rates, yet the biological basis of this disparity remains unclear. Microglia, the brain’s resident macrophages, play a central role in neuroinflammation and AD pathogenesis, displaying sex-dependent functional differences. However, whether sex chromosome complement directly affects their immune response is unknown. Here we use isogenic human iPSC derived microglia with XX, XY, and single X (XO) sex chromosome complements transplanted into an AD mouse model (AppNL-G-F) to demonstrate that X-chromosome dosage regulates microglia responses to amyloid-β pathology. Single-cell transcriptomes reveal an X-dosage driven immune response and metabolic alterations, co-expressed with multiple X-chromosome inactivation (XCI) escape genes and independent of genetic background or hormonal exposure. Notably, these X-linked metabolic modules are conserved across both xenograft and post-mortem datasets, linking X dosage to conserved microglial responses in amyloid-β pathology. Our findings demonstrate that X-chromosome dosage acts as a cell intrinsic regulator of microglial immune states, uncovering a potential genetic mechanism contributing to female-biased AD vulnerability.