Dynamic remodeling of microglial responses in Alzheimer’s disease: heterogeneous states, spatiotemporal progression, and immunometabolic dysregulation

Abstract

Alzheimer’s disease (AD) is characterized by progressive neuroinflammation involving microglia whose functional responses extend far beyond the classical M1/M2 framework and form a dynamically heterogeneous continuum. Here, we review recurrent disease-associated microglia (DAM) states and transcriptional programs, including DAM-associated, interferon-responsive, cytokine-responsive, proliferative, antigen-presentation-associated, and lipid-associated features, emphasizing that these labels do not necessarily represent fixed or mutually exclusive cellular subtypes. Across AD progression, the relative engagement and functional consequences of these programs vary according to Aβ and tau burden, local microenvironment, genetic background, metabolic status, and disease stage. DAM-associated programs may support phagocytosis and plaque containment in some contexts, whereas persistent inflammatory and metabolic stress can increase lipid dysregulation, mitochondrial dysfunction, impaired phagocytic competence, and inflammatory signaling in subsets of microglia. Microglia also exert bidirectional effects on tau pathology. Core AD risk pathways, including TREM2 and APOE, together with immunometabolic remodeling, shape microglial plasticity in a context-dependent manner. We discuss the implications of this dynamic framework for stage- and state-aware therapeutic strategies and highlight the need to integrate single-cell, spatial, and multi-omic approaches to resolve microglial trajectories and functional states in human AD.