Lipidomics in Brain Health and Neurodegenerative Diseases: Mechanisms, Biomarkers, and Therapeutic Perspectives

Lipids constitute nearly half of the brain’s dry weight and play a crucial role in maintaining the function of the central nervous system (CNS). Beyond their well-known function as structural components of cellular membranes and energy storage, lipids are now identified as dynamic bioactive mediators that regulate neuronal signaling, synaptic plasticity, membrane integrity and neuroinflammatory responses. Emerging evidence demonstrates that altered lipid homeostasis is associated with the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). In this review, we highlight key pathophysiological mechanisms, including dysregulation of lipid transport by cholesterol and apolipoprotein E4 (ApoE4), which may influence the aggregation of amyloid-β in AD. We discuss sphingolipid dysregulation and impaired glucocerebrosidase activity in modulating α-synuclein pathology in PD. Furthermore, we emphasize the importance of polyunsaturated fatty acids (PUFAs) and their oxidized forms in the regulation of oxidative stress, ferroptosis, and neuronal cell death in ALS and HD. Besides mechanistic information, this review also highlights the recent advancements in modern lipidomic technologies, such as high-resolution mass spectrometry and multi-omics integration, which have facilitated the comprehensive characterization of disease-associated lipid alterations. Emerging lipid signatures, including alterations in ceramide, cholesterol metabolism and lipid droplet biogenesis in glial cells, are being investigated as candidate biomarkers and therapeutic targets. Collectively, we outline a strategy for exploiting the brain lipidome to explore the potential for personalized disease-modifying strategies against neurodegeneration by integrating mechanistic, diagnostic and therapeutic insights.