Lipid Metabolism in Alzheimer's Disease Pathogenesis and Neurodegeneration

Alzheimer’s disease (AD) is increasingly recognised as a disorder in which disturbances of lipid homeostasis contribute to amyloid accumulation, tau pathology, neuroinflammation and synaptic loss. In the healthy brain, tightly regulated lipid synthesis, transport and degradation maintain membrane integrity, support myelination, regulate signal transduction and ensure efficient energy metabolism. Dysregulation of these processes can perturb the processing of amyloid precursor protein (APP), promote tau hyperphosphorylation and fuel chronic inflammatory responses. Genetic risk factors such as APOE ε4 modulate lipid transport and apolipoprotein E (apoE) lipidation, while enzymes controlling sphingolipid and ceramide production influence membrane microdomains, extracellular vesicle formation and the spread of pathogenic tau species. Moreover, the activity of lipid transporters like ABCA1 and regulators such as microRNA-33 shape the lipid environment of glia, affecting amyloid clearance and glial activation. Recent advances in lipidomics and mechanistic studies have begun to map the temporal and spatial alterations in specific lipid classes across disease stages, highlighting opportunities to target lipid pathways for diagnostic and therapeutic intervention.

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Lipid Metabolism in Alzheimer's Disease Pathogenesis and Neurodegeneration publication trend

The graph below shows the total number of articles in lipid metabolism in alzheimer's disease pathogenesis and neurodegeneration across all publications each year (not limited to Nature Index journals).

Technical terms

Lipidome: The complete profile of lipid species within a cell or tissue, reflecting changes in membrane composition and metabolic state.

Ceramides: Sphingolipid intermediates that regulate membrane microdomains and can trigger inflammatory and apoptotic signalling.

Sphingolipids: A class of lipids containing a sphingoid base, essential for membrane structure and cell signalling.

Neutral sphingomyelinase 2 (nSMase2): An enzyme that hydrolyses sphingomyelin to generate ceramide, influencing extracellular vesicle biogenesis.

Extracellular vesicles (EVs): Membrane-bound particles released by cells that can transport proteins, lipids and nucleic acids between cells.

miR-33: A microRNA that downregulates the ABCA1–APOE pathway, affecting cholesterol efflux and apoE lipidation.

ABCA1–APOE pathway: A lipid transport mechanism in glia by which ABCA1 transfers cholesterol and phospholipids onto apoE, crucial for lipid clearance and neuronal support.

Lipidation: The process of attaching lipid molecules to proteins or lipoproteins, which influences their solubility, receptor interactions and clearance.

References

1. Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies. Frontiers in Physiology (2020).
2. Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer’s disease mouse model. Translational Neurodegeneration (2023).
3. Changes in lipid metabolism track with the progression of neurofibrillary pathology in tauopathies. Journal of Neuroinflammation (2024).
4. Deletion of miR‐33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice. Alzheimer's & Dementia (2024).