Targeting lipid homeostasis for preventive intervention in brain aging and Alzheimer’s disease

Abstract Background Lipids are essential for brain structure and function, contributing to membrane integrity, synaptic activity, signal transduction, and energy metabolism. Converging evidence from human genetics, epidemiology, lipidomics, and neuroimaging indicates that disrupted lipid homeostasis is an early and biologically relevant feature of brain aging and Alzheimer’s disease (AD), rather than a mere downstream consequence of neurodegeneration. In particular, abnormalities in cholesterol transport, sphingolipid metabolism, phospholipid turnover, and apolipoprotein-mediated lipid trafficking have been associated with cognitive decline, structural brain changes, and AD risk. Main body This narrative review synthesizes evidence from selected major human cohort, biomarker, neuroimaging, and clinical intervention studies linking lipid homeostasis to brain aging and AD, with a particular focus on blood, cerebrospinal fluid (CSF), and brain imaging biomarkers, as well as preventive interventions targeting lipid metabolism. Across human cohorts, the most consistent findings include altered ceramide and sphingomyelin metabolism, changes in phosphatidylcholine and membrane phospholipid turnover, and impaired cholesterol transport involving APOE and ATP-binding cassette transporters such as ABCA1 and ABCA7. Although direct evidence for lipid droplets (LDs) involvement in humans remains limited, indirect clinical and translational findings support their emerging relevance in neuron-glia metabolic crosstalk, cellular stress responses, and neuroinflammation. Importantly, many lipid-related pathways appear modifiable. Lifestyle factors such as diet, physical activity, and metabolic health strongly influence lipid homeostasis and overlap with established modifiable dementia risk factors. Clinical studies of lipid-targeted interventions, including omega-3 fatty acids, ketogenic strategies, multinutrient formulations, statins, plasmalogens, and pharmacological approaches targeting cholesterol turnover or ApoE-related pathways, suggest that efficacy is heterogeneous, context-dependent, and most likely to emerge when interventions are implemented early, before advanced neurodegeneration is established. Conclusions Current human evidence highlights lipid homeostasis as a measurable and partly tractable interface between systemic metabolism, brain aging, and AD pathogenesis. Lipid dysregulation may therefore provide clinically relevant biomarkers for early risk stratification and monitoring of disease progression, as well as a mechanistic framework for prevention-oriented interventions. Preserving or restoring lipid balance may represent a promising strategy to promote brain health and reduce dementia risk across aging trajectories.