The AD odyssey 2023: Tales of single cell

Deciphering cellular changes in Alzheimer’s disease (AD) using large cohorts with defined clinical stages is essential for understanding the diverse trajectories of AD progression. In this issue of Cell, five studies harnessed the power of single-nuclei RNA sequencing (snRNA-seq) and single-nuclei ATAC sequencing (snATAC-seq) at unprecedented scale and revealed exciting insights into cell-type-specific mechanisms underlying the progression of AD pathogenesis. Deciphering cellular changes in Alzheimer’s disease (AD) using large cohorts with defined clinical stages is essential for understanding the diverse trajectories of AD progression. In this issue of Cell, five studies harnessed the power of single-nuclei RNA sequencing (snRNA-seq) and single-nuclei ATAC sequencing (snATAC-seq) at unprecedented scale and revealed exciting insights into cell-type-specific mechanisms underlying the progression of AD pathogenesis. Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer’s disease pathologyMathys et al.CellSeptember 28, 2023In BriefA 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. Full-Text PDF Open AccessEarly Alzheimer’s disease pathology in human cortex involves transient cell statesGazestani et al.CellSeptember 28, 2023In BriefGenerating single-nucleus atlas from cortical biopsies of living individuals at early stage of Alzheimer’s disease, cell states of neurons, microglia, and oligodendrocytes associated with AD pathology are identified. Full-Text PDF Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegenerationDileep et al.CellSeptember 28, 2023In BriefDisruption of genome stability and 3D genome organization by DNA double-strand breaks in neurons are pathological steps in the progression of neurodegeneration. Full-Text PDF Open AccessHuman microglial state dynamics in Alzheimer’s disease progressionSun et al.CellSeptember 28, 2023In BriefMicroglia 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. Full-Text PDF Open AccessEpigenomic dissection of Alzheimer’s disease pinpoints causal variants and reveals epigenome erosionXiong et al.CellSeptember 28, 2023In BriefA large-scale single-cell transcriptomic and epigenomic atlas of Alzheimer’s disease (AD) dissects regulatory programs during AD progression. This study highlights key genetic risk loci and ATAC-QTLs and also reveals epigenomic erosion and cell identity loss during late-stage AD. Full-Text PDF Open Access