Postmortem Brain Lipidomics in Alzheimer's Disease and Lewy Body Dementias: A Systematic Review of Disease-Specific Signatures and Shared Vulnerabilities

Background: Lipid dysregulation is increasingly recognised as a key feature of neurodegenerative disease, yet systematic comparison of lipid alterations across Alzheimer’s disease (AD) and Lewy body dementias (LBD) remains limited. Methods: We systematically reviewed 52 postmortem human brain lipidomic studies (40 AD-focused, 6 Parkinson’s disease-focused, 6 multi-disease), examining sphingolipids, glycerophospholipids, fatty acids and lipid peroxidation markers. Results: AD, Parkinson’s disease (PD) and LBD show lipid alterations strongly influenced by anatomical region and tissue compartment. In AD, cortical studies report ceramide elevation and sulfatide depletion, including up to 93% sulfatide loss in a very mild AD cortical study. In contrast, PD/LBD basal ganglia studies report ceramide reduction with sulfatide elevation. PD studies largely comprise individuals without dementia (PD-ND), and findings from these cohorts are therefore distinguished from dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). Plasmalogen depletion of 26 to 73% is repeatedly reported in AD prefrontal/frontal cortex, though this range should not be generalised to all AD regions. In PD/LBD, plasmalogen findings are compartment-dependent, with depletion in lipid rafts from PD-ND [1] but bulk-tissue elevation in LBD with co-occurring AD pathology [2]. Docosahexaenoic acid findings are inconsistent in AD but more consistently elevated in synucleinopathy bulk or cytosolic fractions. Both diseases show elevated lipid peroxidation markers, with 4-hydroxynonenal and acrolein detectable from the MCI stage in AD. Spatial lipidomics reveal distinct lipid niches within amyloid plaques, including unsaturated fatty acid depletion and ceramide enrichment. Conclusions: Current postmortem evidence supports disease, region and compartment-associated lipid signatures across AD, PD-ND and LBD, but direct cross-disease comparisons remain limited. The opposing sphingolipid patterns in AD cortex versus PD/LBD basal ganglia should be interpreted as hypothesis-generating rather than definitive evidence of disease specificity. Whether these changes represent primary pathogenic mechanisms or downstream consequences of neurodegeneration remains unresolved and bears on their therapeutic relevance. Early-stage changes, particularly sulfatide depletion and plasmalogen loss, warrant validation using peripheral measures and imaging applicable in living patients, though standard clinical proton MRS resolves only broad metabolite ratios rather than individual lipid species. Methodological standardisation is needed to resolve discrepant findings, particularly for oxidation-prone species.