Senescent microglia: the hidden mechanism driving Alzheimer's and cognitive decline

Senescent microglia emerge as a central mechanism in Alzheimer's progression, transforming brain immune cells that should protect neural tissue into chronic inflammation drivers. With age, these microglia—analogous to systemic macrophages—undergo epigenetic reprogramming where phagocytic capacity deteriorates, mitochondria experience stress, and lipid handling fails, weakening the brain's homeostatic surveillance. Chronic exposure to amyloid-beta and tau proteins pushes them into senescence marked by stable cell-cycle arrest and sustained secretion of neurotoxic factors that amplify amyloid pathology, synaptic injury, and neurovascular dysfunction. Notably, validated methods already exist to selectively eliminate senescent microglia or clear the entire population to allow reconstitution over weeks—an intervention that could interrupt the Alzheimer's continuum. Yet clinical translation of these senolytic and depletion-repopulation strategies proceeds slowly, leaving a critical gap between what biology enables and what medicine can deliver today.