Abstract Body

Alzheimer’s disease (AD) is the most common cause of dementia worldwide, but the molecular and cellular mechanisms underlying cognitive impairment remain poorly understood. Altered microglial states affect neuroinflammation, neurodegeneration, and disease, but remain poorly understood. We have generated single cell transcriptomic atlas of the aged human prefrontal cortex covering 2.3 million cells from post-mortem human brain samples of 427 individuals with varying degrees of AD pathology and cognitive impairment. We uncovered genes and pathways associated with high cognitive function, dementia, and resilience to AD pathology. Moreover, we analyzed 194,000 single-nucleus microglial transcriptomes and epigenomes across 443 human subjects, and diverse Alzheimer’s disease (AD) pathological phenotypes. We annotate 12 microglial transcriptional states, including AD-dysregulated homeostatic, inflammatory, and lipid-processing states. We identify 1,699 AD-differentially-expressed genes, including both microglia-state-specific and disease-stage-specific alterations. By integrating epigenomic, transcriptomic, and motif information, we infer upstream regulators of microglial cell states, gene-regulatory networks, enhancer-gene links, and transcription factor-driven microglial state transitions. We demonstrate that ectopic expression of our predicted homeostatic-state activators induces homeostatic features in human iPSC-derived microglia-like cells, while inhibiting activators of inflammation can block inflammatory progression. Overall, we provide new insights underlying microglial states, including state-specific and AD-stage-specific microglial alterations at unprecedented resolution.