Spatiotemporal heterogeneity and dynamic evolution of microglial glucose metabolic reprogramming in Alzheimer's disease

Abstract

Abstract Alzheimer's disease (AD) is accompanied by persistent disturbances in brain energy metabolism, and microglial glucose metabolic reprogramming constitutes an important link among pathological protein deposition, neuroinflammation, and impaired clearance. This review examines these metabolic changes across disease stages, brain regions, and plaque‐associated microenvironments and proposes a dynamic state‐composition model. In this model, microglia in different metabolic states coexist, and their relative proportions and spatial distribution change as AD progresses. In early disease or during active phagocytosis, some microglia show enhanced glycolytic and oxidative phosphorylation (OXPHOS) programs. Under persistent pathological stress, increased glucose uptake may not translate into effective energy production and can coexist with inflammation and impaired lipid metabolism. In late disease, microglia with reduced metabolic capacity and impaired phagocytosis become more prevalent. However, higher expression of OXPHOS‐related genes in some microglial states associated with tau pathology does not necessarily indicate improved mitochondrial respiration. These population‐level patterns do not imply that individual microglia follow a fixed sequence of metabolic changes. Longitudinal cell tracking and microglia‐specific metabolic flux measurements are needed to test this model and inform interventions tailored to disease stage and microglial state.