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Alzheimer's disease (AD) is the most common cause of dementia worldwide, but the molecular and cellular mechanisms underlying cognitive impairment remain poorly understood. To address this, we generated a single-cell transcriptomic atlas of the aged human prefrontal cortex covering 2.3 million cells from postmortem human brain samples of 427 individuals with varying degrees of AD pathology and cognitive impairment. Our analyses identified AD-pathology-associated alterations shared between excitatory neuron subtypes, revealed a coordinated increase of the cohesin complex and DNA damage response factors in excitatory neurons and in oligodendrocytes, and uncovered genes and pathways associated with high cognitive function, dementia, and resilience to AD pathology. Furthermore, we identified selectively vulnerable somatostatin inhibitory neuron subtypes depleted in AD, discovered two distinct groups of inhibitory neurons that were more abundant in individuals with preserved high cognitive function late in life, and uncovered a link between inhibitory neurons and resilience to AD pathology. [Display omitted] • Single-cell atlas of the aged human prefrontal cortex across 427 individuals • Coordinated increase of the cohesin complex and DNA damage response factors in AD • Selectively vulnerable somatostatin inhibitory neuron subtypes are depleted in AD • Subsets of inhibitory neurons are linked with preserved cognitive function in old age A single-cell atlas of the aged human prefrontal cortex across 2.3 million nuclei isolated from 427 ROSMAP study participants reveals cellular and molecular correlates of high cognitive function, dementia, and resilience to Alzheimer's disease pathology. [ABSTRACT FROM AUTHOR]

Altered microglial states affect neuroinflammation, neurodegeneration, and disease but remain poorly understood. Here, we report 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 1,542 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. Lastly, we pinpoint the expression of AD-risk genes in microglial states and differential expression of AD-risk genes and their regulators during AD progression. Overall, we provide insights underlying microglial states, including state-specific and AD-stage-specific microglial alterations at unprecedented resolution. [Display omitted] • Single-nucleus transcriptomes and epigenomes of human microglia • Microglia state-specific and disease-stage-specific profile in Alzheimer's disease • Chromatin accessibility poorly captured microglia transcriptional state diversity • Transcription factor networks regulate microglial states and their transitions Microglia states showing Alzheimer's disease (AD)-risk-gene expression and AD-progression-associated expression differences were identified from the microglial transcriptome and epigenomes from the 443 human subjects spanning brain regions and diverse clinical and pathological states. Computational framework and functional studies using iPSC-derived microglia defined the diversity of microglial states across disease, the disease-stage changes of gene expression, and the regulatory network that governs microglial state transitions during the progression of AD. [ABSTRACT FROM AUTHOR]