Microglia in Alzheimer’s Disease: From Homeostatic Guardians to Multifaceted Drivers of Neuropathology

Background: Alzheimer’s disease (AD) affects >55 million people worldwide and lacks disease-modifying therapies. Microglia, the CNS resident immune cells, dynamically transition between protective and pathological states during AD progression. Recent advances in single-cell sequencing and metabolomics reveal that microglial roles extend beyond simple M1/M2 polarization. This review synthesizes these advances into a framework integrating microglial plasticity, metabolic reprogramming, and intercellular communication in AD. Methods: We reviewed recent (2020–2026) studies on microglial biology in AD, focusing on DAM (disease-associated microglia) ontogeny, metabolic reprogramming, immune checkpoints, and glial crosstalk. Results: Microglia exhibit spatiotemporal heterogeneity, shifting from protective phagocytic phenotypes (M2, DAM1/2) in early AD to pro-inflammatory and exhausted states (M1, terminal inflammatory microglia [TIM], lipid droplet-accumulating microglia [LDAM]) as pathology advances. Key pathways—TREM2/SYK phagocytosis, Piezo1 mechanotransduction, TAM (Tyro3, Axl, Mer) receptor signaling, and metabolic regulators (HK2, iron, APOE4-driven lipid metabolism)—orchestrate these transitions. Microglia also interact with astrocytes, T cells, and peripheral immune cells via IL-3, complement C3, MHC-I and MHC-II, forming glial-immune networks that modulate Aβ clearance, tau propagation, and synaptic integrity. Conclusions: Precisely targeting microglial functional states, rather than broad immunosuppression, is a promising disease-modifying strategy for AD. Future therapies should integrate metabolic reprogramming, glial network regulation, and immune checkpoint modulation to preserve protective microglial phenotypes in early AD while suppressing pathological activation and exhaustion in advanced disease.