Lipid Metabolism in Neurodegenerative Diseases

Lipid metabolism underpins the structure and function of the central nervous system and is emerging as a critical factor in the onset and progression of neurodegenerative disorders. In healthy brain tissue, diverse lipid classes—including glycerophospholipids, sphingolipids, sterols and fatty acids—contribute to membrane integrity, myelin formation, synaptic signalling and energy homeostasis. Neuronal and glial lipid homeostasis is tightly regulated by biosynthetic and catabolic pathways; disruption of these processes can compromise membrane fluidity, impair vesicular trafficking, and promote oxidative damage. In Alzheimer’s and Parkinson’s diseases, aberrant lipid profiles accompany the accumulation of misfolded proteins, intensify neuroinflammation and exacerbate mitochondrial dysfunction. Genetic variants affecting enzymes such as glucocerebrosidase (GBA) and phospholipase A₂ (PLA₂G6) further link lipid dysregulation to vulnerability for disease. Advances in lipidomic technologies have revealed region-specific alterations in lipid composition, underscoring the interdependence of lipid pathways, protein aggregation and cellular stress responses. Understanding how lipid metabolism intersects with amyloid, tau and α-synuclein pathology offers new avenues for biomarker discovery and targeted intervention.

Research from Nature Portfolio

Recent studies have delivered a comprehensive atlas of the adult human brain lipidome, quantifying over 400 molecular species across 75 distinct regions. This work demonstrates that lipid distributions vary in relation to myelin density, neuronal cell type and functional connectivity, with particular classes of phospholipids and fatty acids distinguishing cortical layers and subcortical nuclei. Integration of lipidomic profiles with gene expression data illuminates how regional metabolic signatures correlate with information-processing hierarchies. Parallel analyses in non-human primates and murine neurons validate core findings, confirming the conserved nature of lipid organization and its relevance to neural circuit function. Such a detailed map now provides a reference framework for detecting disease-associated lipid perturbations and for interpreting how local lipid environments may influence vulnerability to protein aggregation and neurodegeneration.

Lipid Metabolism in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in lipid metabolism in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Lipidome: The complete set of lipids within a cell, tissue or organism, reflecting its metabolic state.

Glycerophospholipid: A class of phospholipids containing a glycerol backbone, fatty acid chains and a phosphate-containing head group, essential for membrane structure.

Sphingolipid: A lipid family based on a sphingoid base backbone, involved in membrane microdomains and cell signalling.

Plasmalogen: A vinyl-ether phospholipid abundant in neural tissue, implicated in antioxidative protection and membrane dynamics.

Lipid raft: Microdomains within cell membranes enriched in cholesterol and sphingolipids, serving as platforms for signalling and protein sorting.

α-Synuclein: A neuronal protein whose pathological aggregation into Lewy bodies is a hallmark of Parkinson’s disease and related synucleinopathies.

References

1. Lipidome atlas of the adult human brain. Nature Communications (2024).
2. More than meets the eye in Parkinson’s disease and other synucleinopathies: from proteinopathy to lipidopathy. Acta Neuropathologica (2023).
3. Spatial lipidomics reveals brain region-specific changes of sulfatides in an experimental MPTP Parkinson’s disease primate model. npj Parkinson's Disease (2023).
4. Lipid and Transcriptional Regulation in a Parkinson's Disease Mouse Model by Intranasal Vesicular and Hexosomal Plasmalogen‐Based Nanomedicines. Advanced Healthcare Materials (2024).