Lipid metabolism dysregulation in late-life depression: peripheral metabolic disturbance, central lipid alterations, and dietary modulation.

Late-life depression involves neurodegeneration, inflammation, metabolic disruption, and psychosocial stress. Lipid metabolism has drawn increasing attention in this field. This review examines three interconnected aspects: peripheral metabolic disturbance, potential central lipid alterations, and dietary lipid regulation. Peripherally, adverse lipid profiles and lipidomic shifts correlate with depressive symptoms, cognitive decline, and cardiometabolic load. Mechanisms include inflammation, membrane remodeling, mitochondrial dysfunction, and oxidative stress. Centrally, the disorder may involve aberrant membrane phospholipid metabolism, brain region-specific lipid alterations, and apolipoprotein E-mediated transport disruption, affecting myelin integrity, synaptic plasticity, neuroinflammation, and cerebrovascular function. Evidence regarding dietary lipids remains mixed: omega-3 supplementation has not shown a consistent preventive benefit, whereas high-fat, fried, and Western dietary patterns have been associated with depressive outcomes in observational studies. However, much of the current evidence is extrapolated from MDD or general populations, limiting its direct applicability to late-life depression. Future work should combine longitudinal designs, multi-omics, neuroimaging, and intervention studies to establish causality and identify biomarkers and tailored strategies.