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Kim, J.P.* ; Nho, K.* ; Wang, T.* ; Huynh, K.* ; Arnold, M. ; Risacher, S.L.* ; Bice, P.J.* ; Han, X.* ; Kristal, B.S.* ; Blach, C.* ; Baillie, R.* ; Kastenmüller, G. ; Meikle, P.J.* ; Saykin, A.J.* ; Kaddurah‐Daouk, R.*

Circulating lipids are related to longitudinal changes of ATN biomarkers for Alzheimer’s disease.

Mol. Psychiatry, DOI: 10.1038/s41380-026-03626-z (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Investigating the relationship of circulating lipidome profiles with cross-sectional and longitudinal changes of central Alzheimer’s disease (AD) biomarkers, including amyloid/tau/neurodegeneration (A/T/N), can provide a holistic view between the lipidome and AD pathophysiology. In this study, we quantified a total of 749 plasma lipid species at baseline using liquid chromatography–mass spectrometry and performed cross-sectional and longitudinal association analysis of plasma lipidome profiles with longitudinal A/T/N biomarkers for AD in the Alzheimer’s Disease Neuroimaging Initiative cohort (N = 1395). We identified several lipid species, classes, and network modules of correlated lipids that were significantly associated with cross-sectional and longitudinal changes of A/T/N biomarkers. Notably, we identified lysoalkylphosphatidylcholine (LPC(O)) as associated with cross-sectional “A/N” biomarkers at the lipid species, class, and module levels. Also, Phosphatidylethanolamine (PE) ethers were associated with A/T/N biomarkers in the species level and with “N” biomarkers in the class and module levels. GM3 ganglioside showed association with cross-sectional and longitudinal changes of “N” biomarkers at the species and class levels. Furthermore, 20 lipid species, out of all 57 species identified as associated with “less severe” AD biomarkers, contained docosahexaenoic acid (DHA), indicating that the previously reported beneficial effects of DHA on AD were significant at the central biomarker level. In conclusion, our approach linking peripheral metabolic changes with brain metabolic, structural, and functional states strengthens evidence from previous studies that were performed using only clinical AD diagnosis. Importantly, our study also enabled identification of novel lipids that play potential roles in progression of AD pathophysiology, suggesting dysregulation of lipid metabolic pathways as precursors to AD development and progression.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Lipidome ; Lipidomics ; Biomarker ; Disease ; Lipid Metabolism ; Metabolome ; Docosahexaenoic Acid ; Phosphatidylethanolamine
ISSN (print) / ISBN 1359-4184
e-ISSN 1476-5578
Journal Molecular Psychiatry
Publisher Springer
Reviewing status Peer reviewed
Institute(s) Institute of Computational Biology (ICB)
Grants Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)
U.S. Department of Health & Human Services | National Institutes of Health (NIH)