Microglial Therapeutic Potential in Alzheimer's Disease: From Phenotypic Diversity to Targeted Interventions

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, tau pathology and cognitive decline. Increasing evidence from genetic, transcriptomic, experimental and clinical studies has identified microglia as key regulators of AD pathogenesis. Under physiological conditions, microglia maintain central nervous system homeostasis through immune surveillance, phagocytosis and neurotrophic support. However, persistent exposure to pathological stimuli promotes a shift toward dysfunctional inflammatory states that contribute to neuroinflammation, synaptic impairment, tau propagation and neurodegeneration. Recent advances have revealed substantial microglial heterogeneity, highlighting the existence of dynamic and disease stage-dependent activation states rather than fixed phenotypes. In early disease stages, microglia can promote Aβ clearance and tissue repair, whereas chronic activation may exacerbate pathological processes. These findings have driven the development of microglia-targeted therapeutic strategies aimed at enhancing protective functions while limiting maladaptive inflammatory responses. This review summarizes current knowledge regarding microglial involvement in AD and discusses emerging therapeutic approaches, ranging from immunomodulation and metabolic reprogramming to gene-based and nanotechnology-driven interventions, with a focus on their translational potential.