This study characterizes premature cell senescence in Alzheimer's disease (AD) using single nuclear transcriptomics and imaging mass cytometry (IMC). Researchers analyzed postmortem brain tissue from non-diseased controls (NDC) and AD donors, identifying increased numbers of senescent glial cells in AD brains. They found higher expression of senescence markers such as GLB1 and p16 in microglia, oligodendrocytes, and astrocytes in AD compared to NDC. These senescent cells were associated with increased β-amyloid load and reduced phagocytic capacity, suggesting a role in disease progression. Gene set enrichment and pseudotime trajectories revealed extensive DNA double-strand breaks, mitochondrial dysfunction, and ER stress linked to premature senescence in microglia. The study replicated these findings using independent datasets, showing that senescent glia contribute significantly to AD pathology. The results support the hypothesis that microglia are a primary target for senolytic treatments in AD. The study also identified cell-specific triggers for premature senescence, including β-amyloid-induced pathways, and highlighted the role of microglial activation in AD progression. The findings suggest that targeting microglial senescence could be a promising therapeutic approach for AD.This study characterizes premature cell senescence in Alzheimer's disease (AD) using single nuclear transcriptomics and imaging mass cytometry (IMC). Researchers analyzed postmortem brain tissue from non-diseased controls (NDC) and AD donors, identifying increased numbers of senescent glial cells in AD brains. They found higher expression of senescence markers such as GLB1 and p16 in microglia, oligodendrocytes, and astrocytes in AD compared to NDC. These senescent cells were associated with increased β-amyloid load and reduced phagocytic capacity, suggesting a role in disease progression. Gene set enrichment and pseudotime trajectories revealed extensive DNA double-strand breaks, mitochondrial dysfunction, and ER stress linked to premature senescence in microglia. The study replicated these findings using independent datasets, showing that senescent glia contribute significantly to AD pathology. The results support the hypothesis that microglia are a primary target for senolytic treatments in AD. The study also identified cell-specific triggers for premature senescence, including β-amyloid-induced pathways, and highlighted the role of microglial activation in AD progression. The findings suggest that targeting microglial senescence could be a promising therapeutic approach for AD.