Microglia energy metabolism: A new perspective on Alzheimer's disease treatment

Alzheimer's disease (AD) is a progressive age-associated neurodegenerative disorder characterized by systemic cerebral metabolic disturbances. Neuroimaging and biochemical analyses reveal three hallmark features: decreased glucose utilization, mitochondrial bioenergetic deficits, and impaired energy homeostasis within hippocampal circuits. Emerging evidence highlights the pivotal role of microglia, the brain's specialized immune guardians, whose metabolic plasticity forms a self-reinforcing pathological cycle with AD progression. During early disease stages, oxidative phosphorylation (OXPHOS)-dependent M2 microglia mediate neuroprotective functions through efficient β-amyloid (Aβ) phagocytosis. However, progressive metabolic reprogramming drives a pathological shift toward glycolysis-dominant M1, characterized by heightened proinflammatory cytokine secretion and compromised clearance capacity. Notably, AD-associated pathological aggregates disrupt microglial metabolic adaptation, suppress mitophagy processes, and perpetuate sustained neuroinflammatory responses. The metabolic flexibility of microglia allows them to adapt to different energy demands. This study reviews the roles of major metabolic pathways and metabolic regulators of microglia in AD and the link between AD pathology and microglia energy metabolism, and describes the potential of relevant drugs and non-drug approaches in AD treatment, revealing metabolic regulation as a new target for AD therapy.