An exhausted-like microglial population accumulates in aged and APOE4 genotype Alzheimer’s brains 2593

Abstract Description The dominant risk factors for Alzheimer’s disease (AD) are advanced age and the APOE4 genetic variant. However, while AD is tightly linked to neuroinflammation, the impacts of these two factors on brain immune function are poorly understood. To address this question, we generated an integrative, longitudinal single-cell atlas of brain immune cells in AD model mice bearing knock-in of the three common human APOE alleles (APOE2, APOE3, and APOE4). Transcriptomic and chromatin accessibility analyses identified a reactive microglial population defined by the concomitant expression of inflammatory signals and cell-intrinsic stress markers whose frequency drastically increased with age and APOE4 burden. An equivalent cell state was detectable in the cortical tissue of human AD patients by multiplexed spatial transcriptomics. This population, which we name terminally inflammatory microglia (TIM), exhibited defects in amyloid-β clearance and acted as a key orchestrator of the recruitment of adaptive immune populations from the meninges during aducanumab therapy. Our findings cast TIM as a functionally impaired state induced by chronic neuroinflammation, suggestive of an exhausted-like microglial phenotype analogous to T cell exhaustion in the tumor microenvironment. As TIM accumulation in the AD milieu is most pronounced in APOE4 carriers and the elderly, this microglial population may be implicated in AD risk and pathology and thus presents a potential therapeutic target for AD. Funding Sources Supported by NIH R35CA274446; T32GM132083; Reem Kayden Award. Topic Categories Computational and Systems Immunology (COMP)