APOE and TREM2 regulate amyloid-responsive microglia in Alzheimer's disease

Beta-amyloid deposition is a defining feature of Alzheimer's disease (AD). How genetic risk factors, likeAPOEandTREM2, intersect with cellular responses to beta-amyloid in human tissues is not fully understood. Using single-nucleus RNA sequencing of postmortem human brain with variedAPOEandTREM2genotypes and neuropathology, we identified distinct microglia subpopulations, including a subpopulation of CD163-positive amyloid-responsive microglia (ARM) that are depleted in cases withAPOEandTREM2risk variants. We validated our single-nucleus RNA sequencing findings in an expanded cohort of AD cases, demonstrating thatAPOEandTREM2risk variants are associated with a significant reduction in CD163-positive amyloid-responsive microglia. Our results showcase the diverse microglial response in AD and underscore how genetic risk factors influence cellular responses to underlying pathologies.