biostudies-literatureFancy NNUK Dementia Research InstituteMedical Research CouncilAlzheimer’s Research UK78https://www.ebi.ac.uk/biostudies/studies/S-EPMC11065703biostudies-literatureUnknown147(1)Aging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in postmortem brains from non-diseased controls (NDC) and donors with Alzheimer's disease (AD) using imaging mass cytometry (IMC) and single nuclear RNA (snRNA) sequencing (> 200,000 nuclei). We found increases in numbers of glia immunostaining for galactosidase beta (> fourfold) and p16^INK4A (up to twofold) with AD relative to NDC. Increased glial expression of genes related to senescence was associated with greater β-amyloid load. Prematurely senescent microglia downregulated phagocytic pathways suggesting reduced capacity for β-amyloid clearance. Gene set enrichment and pseudo-time trajectories described extensive DNA double-strand breaks (DSBs), mitochondrActa neuropathologicaCharacterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics.PMC11065703MR/P024572/1Smith AMDavey KTsartsalis SBoulger SPapageorgopoulou MJenkyns MHMcGarry AAdair EKhozoie CChau VThomas MWillumsen NGomez-Nicola DCaramello AJackson JSFancy NNMuirhead RCJSchneegans EMatthews PMCheung TKDfalseCharacterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics.Aging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in postmortem brains from non-diseased controls (NDC) and donors with Alzheimer's disease (AD) using imaging mass cytometry (IMC) and single nuclear RNA (snRNA) sequencing (> 200,000 nuclei). We found increases in numbers of glia immunostaining for galactosidase beta (> fourfold) and p16^INK4A (up to twofold) with AD relative to NDC. Increased glial expression of genes related to senescence was associated with greater β-amyloid load. Prematurely senescent microglia downregulated phagocytic pathways suggesting reduced capacity for β-amyloid clearance. Gene set enrichment and pseudo-time trajectories described extensive DNA double-strand breaks (DSBs), mitochondr2024-01-01T00:00:00Z2024 May2026-07-15T01:54:37.118Z2026-06-27T03:18:38.29ZS-EPMC110657033869595210.1007/s00401-024-02727-9