Microglial senescence has emerged as a potentially important aging-related mechanism in Alzheimer's disease (AD), shaped in part by epigenetic reprogramming and closely coupled to immunometabolic dysfunction. While microglia initially mount adaptive responses to amyloid-beta (Aβ), tau, and tissue stress, persistent exposure to chronic neurodegenerative cues may drive subsets of microglia toward senescence-like states characterized by altered chromatin regulation, transcriptional remodeling, stable cell-cycle arrest, and a sustained senescence-associated secretory phenotype (SASP). These changes are accompanied by impaired phagocytosis, lysosomal and autophagic dysfunction, mitochondrial stress, and disrupted lipid handling, collectively weakening homeostatic surveillance and promoting a neurotoxic microenvironment. In turn, senescence-associated microglial dysfunction may contribute to amyloid and tau pathology, synaptic injury, neurovascular unit impairment, and chronic neuroinflammation across the AD continuum. In this review, we synthesize current evidence on the phenotypic and molecular features of senescent microglia, with particular emphasis on epigenetic and transcriptional reprogramming as an organizing framework linking aging, immune dysregulation, and metabolic vulnerability. We further discuss how senescent microglia relate to other disease-associated microglial states, and we highlight unresolved questions regarding causality, biomarker specificity, and the distinction between chronic activation and true senescence in human AD. Finally, we evaluate emerging therapeutic approaches—including senolytic strategies, microglial depletion–repopulation paradigms, and metabolic or epigenetic interventions—and discuss their opportunities, limitations, and translational challenges. Together, this perspective positions microglial senescence not as an isolated driver, but as a biologically relevant and potentially targetable component of the aging neuroimmune landscape in AD. • Epigenetic reprogramming helps shape microglial senescence in AD. • Senescent microglia show impaired clearance, lysosomal stress, and SASP. • Microglial senescence overlaps with DAM, IRM, and LDAM under stress. • Senescence-targeting strategies in AD remain promising but preclinical.
Ma et al. (Fri,) studied this question.