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

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. G M3 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 Details

Journal
Molecular Psychiatry
Published
2026-06-16
DOI
https://doi.org/10.1038/s41380-026-03626-z
Primary Topic
Fatty Acid Research and Health
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Colette Blach, R C Green, JB Brewer, Najaf Amin et al.
Molecular Psychiatry
Fatty Acid Research and Health
article

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

Colette Blach, R C Green, JB Brewer, Najaf Amin, Clifford R. Jack, Jun Pyo Kim, Peter J. Meikle, Rhoda Au, Shannon L. Risacher, Nick C. Fox, W Jia, Jan Krumsiek, Rima F Kaddurah-Daouk, Andrew J. Saykin, Rob Knight, Karsten Suhre, Paul Thompson, Bruce S. Kristal, R R Krishnan, Kevin Huynh, Priyanka Baloni, Therese Koal, Paula J. Bice, Arpana Gupta, DINESH BARUPAL, Laurie Ryan, Molchan Se, Gabi Kastenmüller, Ines Thiele, Matthias Arnold, Thomas Hankemeier, Siamak Mahmoudiandehkhordi, Robert A. Koeppe, E Lee, Kwangsik Nho, Kwangsik Nho, Kathleen Welsh-Balmer, Xianlin Han, Robin Vogt, Tatiana Foroud, C van Duijn, David Bennett, Roberta Brinton, E D Mayer, Doraiswamy Pm, J P Newman, Frank Sacks, Gil Rabinovici, Ozioma Okonkwo, Tingting Wang, Leslie Shaw, David Wishart, Monica Rivera-Mindt, Pieter Dorrestein, Alejo Nevado-Holgado, Sarkis Mazmanian, Arfan Ikram, Neil Buckholtz, Laurel Beckett, Nigel J. Cairns, Shannon L. Risacher, Susan Landau, Michael Weiner, Oliver Fiehn, Danielle Harvey, Pierre Baldi, Tatiana M. Foroud, Peter Würtz, Peter Meikle, Ivan Hernandez, Brenda Plassman, John Morris, Ronald Petersen, for the Alzheimer’s Disease Neuroimaging Initiative, Anna Greenwood, Jennifer Labus, Alexandra Kueider-Paisley, Ali Keshavarzian, William Jagust, Lindsay Farrer, Wendy Qiu, Rima Kaddurah-Daouk, Arthur W. Toga, Arthur Moseley, Duygu Tosun, Richard J. Perrin, Leslie M. Shaw, Cory Funk, John K. Hsiao, Rebecca Baillie, Charles DeCarli, Dan Rader, Paul Aisen
article en

Abstract

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. G M3 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.

Molecular Psychiatry
University of Southern California (US), University of Hawaiʻi at Mānoa (US), Leiden University (NL), California Institute of Technology (US), Brigham and Women's Hospital (US), Agricultural Research Service (US), Sage Bionetworks (US), University of Hawaii System (US), University of Wisconsin–Madison (US), Harvard University (US), University of Arizona (US), Baker Heart and Diabetes Institute (AU), University of California, Los Angeles (US), Fordham University (US), The University of Melbourne (AU), The University of Texas at San Antonio Health Science Center (US), Duke University (US), University of California, San Francisco (US), SUNY Downstate Health Sciences University (US), Ollscoil na Gaillimhe – University of Galway (IE), La Trobe University (AU), Washington University in St. Louis (US), Cornell University (US), Purdue University West Lafayette (US), University of Michigan (US), Erasmus MC (NL), Samsung Medical Center (KR), Helmholtz Zentrum München (DE), Institute for Systems Biology (US), University of California San Diego (US), University of Oxford (GB), Clinical Research Institute (US), Rosa (United States) (US), Cancer Center of Hawaii (US), Netherlands Metabolomics Centre (NL), Alzheimer’s Disease Neuroimaging Initiative (US), Mayo Clinic in Arizona (US), National Institute on Aging (US), The Metabolomics Innovation Centre (CA), Biocrates Life Sciences (Austria) (AT), Deutsches Diabetes-Zentrum e.V. (DE), Weill Cornell Medical College in Qatar (QA), Duke University Hospital (US), German Center for Diabetes Research (DE), University of Hawaii Cancer Center, Indiana University School of Medicine, Heinrich Heine University Düsseldorf (DE), University College London (GB), Rush University (US), Indiana University – Purdue University Indianapolis (US), University of Pennsylvania (US), University of California, Davis (US), Erasmus University Rotterdam (NL), University of California, Berkeley (US), Icahn School of Medicine at Mount Sinai (US)
U.S. Department of Defense, Foundation for the National Institutes of Health, Alzheimer's Association, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Biogen, University of Southern California, Meso Scale Diagnostics, Alzheimer's Disease Neuroimaging Initiative, BioClinica, Novartis Pharmaceuticals Corporation, Northern California Institute for Research and Education, Korea Disease Control and Prevention Agency, Eisai, Servier, H. Lundbeck A/S, Baker Heart and Diabetes Institute, IXICO, National Institutes of Health, Genentech, Canadian Institutes of Health Research, Korea National Institute of Health, National Institute on Aging
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