{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T00:31:48Z","timestamp":1792369908354,"version":"4.4.0"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Lipidomics offers potential for the early detection of Alzheimer\u2019s disease (AD) and for elucidating the molecular mechanisms driving the progression from mild cognitive impairment (MCI) to AD. In this study, we investigated and validated the association between 139 cerebrospinal fluid (CSF) lipids and MCI-to-AD conversion. We included 400 MCI participants from the Ace Alzheimer Center Barcelona (ACE) cohort, all free of type 2 diabetes, comprising both ATN+ and ATN\u2212 individuals. After a median follow-up of 2.1\u00a0years, 142 participants progressed to AD dementia. We identified a multi-lipid signature of 11 lipids (including phosphatidylcholines, lysophosphatidylcholines, triglycerides, phosphatidylethanolamines, lysophosphatidylethanolamines and phosphatidylinositols) in CSF, which was associated with increased AD progression (HR\u2009=\u20091.85, 95% CI: 1.53\u20132.27). This signature was validated in paired plasma samples, a less invasive biofluid (HR\u2009=\u20091.26, 95% CI: 1.04\u20131.52) and in plasma samples from an external cohort of 189 participants (149 with subjective cognitive decline, 40 with MCI; \u03b2\u2009=\u20090.261, 95% CI: 0.022\u20130.500), demonstrating moderate-to-high predictive accuracy for MCI-to-AD progression. Counterfactual-based mediation analysis revealed that plasma phosphorylated tau-181 mediated up to 47% of the association between the lipid signature and AD dementia, highlighting glycerophospholipid metabolism as a key pathway. Exploratory Mendelian randomisation analyses suggested a potential causal association of lipid signature and AD, with two instrumental single-nucleotide polymorphisms mapped to loci implicated in neurodevelopmental and metabolic regulation (RBFOX1 and CDKAL1). In conclusion, our findings support the growing evidence of lipid metabolism dysregulation as an early marker of AD and identify plasma lipids reflecting CSF profiles that may be promising prognostic markers for AD dementia.<\/jats:p>","DOI":"10.1093\/ageing\/afaf363","type":"journal-article","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T12:54:35Z","timestamp":1765284875000},"source":"Crossref","is-referenced-by-count":4,"title":["Plasma lipid dysregulation reflecting cerebrospinal fluid profile predicts Alzheimer\u2019s disease progression"],"prefix":"10.1093","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7229-7540","authenticated-orcid":false,"given":"Nil","family":"Novau-Ferr\u00e9","sequence":"first","affiliation":[{"name":"Nutrition and Metabolic Health Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili (URV) , Reus ,","place":["Spain"]},{"name":"Institut d\u2019Investigaci\u00f3 Sanit\u00e0ria Pere Virgili 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,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0125-5403","authenticated-orcid":false,"given":"Pablo","family":"Garc\u00eda-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya , Barcelona ,","place":["Spain"]},{"name":"CIBER of Neurodegenerative Diseases (CIBERNED), Carlos III Health Institute , Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1628-0118","authenticated-orcid":false,"given":"Javier","family":"Mateu-Fabregat","sequence":"additional","affiliation":[{"name":"Nutrition and Metabolic Health Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili (URV) , Reus ,","place":["Spain"]},{"name":"Institut d\u2019Investigaci\u00f3 Sanit\u00e0ria Pere Virgili (IISPV) , Reus ,","place":["Spain"]},{"name":"Center of Environmental, Food and Toxicological Technology (TecnATox), Universitat Rovira i Virgili (URV) , Reus ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2628-7076","authenticated-orcid":false,"given":"Jose L","family":"Cantero","sequence":"additional","affiliation":[{"name":"CIBER of Neurodegenerative Diseases (CIBERNED), Carlos III Health Institute , Madrid ,","place":["Spain"]},{"name":"Laboratory of Functional Neuroscience, Pablo de Olavide University (UPO) , Seville ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6760-1252","authenticated-orcid":false,"given":"Mercedes","family":"Atienza","sequence":"additional","affiliation":[{"name":"CIBER of Neurodegenerative Diseases (CIBERNED), Carlos III Health Institute , Madrid ,","place":["Spain"]},{"name":"Laboratory of Functional Neuroscience, Pablo de Olavide University (UPO) , Seville ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2617-3009","authenticated-orcid":false,"given":"Merc\u00e8","family":"Boada","sequence":"additional","affiliation":[{"name":"ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya , Barcelona ,","place":["Spain"]},{"name":"CIBER of Neurodegenerative Diseases (CIBERNED), Carlos III Health Institute , Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2633-2495","authenticated-orcid":false,"given":"Agust\u00edn","family":"Ruiz","sequence":"additional","affiliation":[{"name":"ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya , Barcelona ,","place":["Spain"]},{"name":"CIBER of Neurodegenerative Diseases (CIBERNED), Carlos III Health Institute , Madrid ,","place":["Spain"]},{"name":"Glenn Biggs Institute for Alzheimer\u2019s and Neurodegenerative Diseases , University of Texas Health Science Center, San Antonio, TX ,","place":["USA"]},{"name":"Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center , San Antonio, TX ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0218-7046","authenticated-orcid":false,"given":"M\u00f2nica","family":"Bull\u00f3","sequence":"additional","affiliation":[{"name":"Nutrition and Metabolic Health Research Group, Department of Biochemistry and Biotechnology, Universitat Rovira i Virgili (URV) , Reus ,","place":["Spain"]},{"name":"Institut d\u2019Investigaci\u00f3 Sanit\u00e0ria Pere Virgili (IISPV) , Reus ,","place":["Spain"]},{"name":"Center of Environmental, Food and Toxicological Technology (TecnATox), Universitat Rovira i Virgili (URV) , Reus ,","place":["Spain"]},{"name":"CIBER Physiology of Obesity and Nutrition (CIBEROBN), Carlos III Health Institute , Madrid 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