Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration

The mammalian brain fundamentally relies on precise lipid homeostasis to maintain structural integrity and complex neural signaling. Emerging evidence positions lipid metabolism reprogramming not merely as a secondary pathological byproduct but as a core initiating driver of age-related neurodegenerative diseases. This review systematically evaluates the mechanisms of cerebral lipid dyshomeostasis during brain aging, highlighting glial cells as the central mediators of this pathological cascade. We comprehensively dissect the age-associated “lipid drift”, emphasizing apolipoprotein E (APOE)-induced cholesterol transport defects and lipid raft pathology, the accumulation of lipid droplets that triggers microglial metabolic stress (LDAMs), and ceramide-driven neuronal apoptosis coupled with the exosome-mediated propagation of pathogenic proteins. Furthermore, we map these aberrant lipid networks to specific pathological signatures in Alzheimer’s, Parkinson’s, and demyelinating diseases. Finally, we critically evaluate promising therapeutic interventions, including nutritional strategies, LXR/RXR agonists, and nanotechnology-enabled delivery systems designed to bypass the blood–brain barrier. By integrating high-throughput lipidomics for early diagnostic biomarker discovery, we underscore the translational imperative of restoring cerebral lipid homeostasis as a disease-modifying strategy for neurodegeneration.