This study investigates premature cell senescence in Alzheimer's disease (AD) using single-nucleus RNA sequencing (snRNA-seq) and imaging mass cytometry (IMC). The researchers found increased numbers of senescent glial cells, particularly microglia, in AD brains compared to non-diseased controls. Senescent microglia showed reduced phagocytic pathways, suggesting decreased ability to clear β-amyloid. Gene set enrichment and pseudo-time trajectories revealed extensive DNA double-strand breaks, mitochondrial dysfunction, and ER stress associated with increased β-amyloid, leading to premature senescence in microglia. The findings support the hypothesis that microglia are a primary target for senolytic treatments in AD, as they could potentially reduce senescent microglia and enhance β-amyloid clearance. The study also highlights the importance of β-amyloid in driving senescence in microglia and provides insights into the mechanisms underlying premature senescence in AD.This study investigates premature cell senescence in Alzheimer's disease (AD) using single-nucleus RNA sequencing (snRNA-seq) and imaging mass cytometry (IMC). The researchers found increased numbers of senescent glial cells, particularly microglia, in AD brains compared to non-diseased controls. Senescent microglia showed reduced phagocytic pathways, suggesting decreased ability to clear β-amyloid. Gene set enrichment and pseudo-time trajectories revealed extensive DNA double-strand breaks, mitochondrial dysfunction, and ER stress associated with increased β-amyloid, leading to premature senescence in microglia. The findings support the hypothesis that microglia are a primary target for senolytic treatments in AD, as they could potentially reduce senescent microglia and enhance β-amyloid clearance. The study also highlights the importance of β-amyloid in driving senescence in microglia and provides insights into the mechanisms underlying premature senescence in AD.