Lipid metabolic regulation of neuroinflammation in Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid deposition, tau pathology, and sustained neuroinflammation. Increasing evidence indicates that dysregulated lipid metabolism is not merely a metabolic disturbance but a critical modulator of inflammatory responses driving AD pathogenesis. The brain, one of the most lipid-enriched organs, relies on tightly controlled lipid homeostasis to maintain neuronal function and synaptic integrity. Alterations in fatty acid composition, apolipoprotein E (ApoE) isoforms, lipoprotein lipase activity, and lipid-derived signaling mediators profoundly reshape microglial activation states and inflammatory cascades. Obesity, insulin resistance, and gut microbiota dysbiosis further exacerbate systemic and central lipid imbalance, amplifying neuroinflammatory signaling through cytokine networks and blood-brain barrier disruption. Notably, polyunsaturated fatty acids and lipid mediators exert dual immunomodulatory effects, influencing β-amyloid aggregation, oxidative stress, and microglial polarization. This review synthesizes recent advances in understanding how lipid metabolism modulates neuroinflammation and microglia-neuron crosstalk in AD, highlighting emerging therapeutic strategies targeting lipid-inflammation axes as promising avenues for disease modification.