Microglia in Alzheimer’s disease: from pathogenic mechanisms to therapeutic targeting

Abstract

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder driven by β-amyloid (Aβ) deposition, tau hyperphosphorylation, synaptic dysfunction, neuroinflammation, vascular injury, and metabolic dysregulation. Recent advances in single-cell, spatial, and multi-omics transcriptomics have substantially reshaped our understanding of microglia, shifting the field from the classical M1/M2-like polarization dichotomy toward a model of state-dependent functional heterogeneity. Distinct subpopulations-including disease-associated microglia, lipid-associated microglia, interferon-responsive microglia, and senescence-associated microglia are now mechanistically linked to Aβ clearance, tau propagation, complement-mediated synaptic pruning, NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, and immunometabolic reprogramming. Central to this regulatory network are the TREM2-ApoE axis, complement cascades, NLRP3 inflammasome, mitochondrial dysfunction, and aberrant lipid/iron metabolism, which largely contribute to AD progression. In parallel, the clinical deployment of anti-Aβ monoclonal antibodies such as lecanemab has ushered in the era of disease-modifying therapy; however, limited efficacy and the occurrence of amyloid-related imaging abnormalities underscore that Aβ removal alone is insufficient to halt disease evolution completely. In this review, we systematically synthesize the evolving landscape of microglial states and their pathogenic contributions, and we further evaluate current therapeutic avenues, including microglia-targeted strategies, anti-Aβ antibody combination regimens, non-pharmacological interventions, and peripheral immunomodulation. We also compare these microglial mechanisms with those in multiple sclerosis to highlight shared neuroimmune modules and disease-specific features. Our goal is to provide a valuable updated reference for accurate molecular subtyping and multi-target combination therapy in AD.