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This cross-sectional study aimed to investigate plasma metabolites obtained through targeted profiling using the Biocrates AbsoluteIDQ\u00ae p400 HR kit. The study cohort comprises 100 cognitively unimpaired (CU) older adults, stratified into CU A\u03b2\u2212\u2009(negative positron emission tomography [PET]-amyloid-beta [A\u03b2]) and CU A\u03b2+\u2009(positive PET-A\u03b2) groups. Significantly altered metabolites were further analysed for associations across amyloid plaque deposition, cognitive performance and plasma tau phosphorylated at threonine 181 (P-tau181) levels and for their ability to differentiate cortical PET-A\u03b2 status in CU older adults. Significant between-group differences were observed in eighteen metabolites from phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and ceramide (Cer) classes, wherein significantly lower levels of PC species and higher levels of LPC(17:1) and Cer(43:1) were detected in CU A\u03b2+\u2009individuals compared to CU A\u03b2\u2212. Notably, the differences became more pronounced when PC-to-LPC ratios were analysed. Across the spectrum, lower PC-to-LPC ratios were associated with greater cortical amyloid deposition, poorer cognitive performance and higher plasma P-tau181 levels. Elevated Cer(43:1) levels were also associated with higher cortical amyloid deposition. Upon receiver operating characteristic (ROC) analyses, these metabolite panels significantly distinguished CU A\u03b2\u2009\u2009individuals from CU A\u03b2\u2212, demonstrating good to excellent diagnostic performance. Given their association with membrane damage, synaptic dysfunction, oxidative stress, neuroinflammation and apoptosis, these metabolites may represent potential biomarkers reflecting early AD-related biochemical changes in CU older adults.<\/jats:p>","DOI":"10.1007\/s12035-026-06184-1","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T01:36:34Z","timestamp":1789349794000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Circulating Metabolite Signatures Associated With Amyloid Positivity, Cognitive Performance and Plasma P-tau181 Levels in Cognitively Unimpaired Older Adults"],"prefix":"10.1007","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5496-0670","authenticated-orcid":false,"given":"Tahmida","family":"Sharmin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2863-0293","authenticated-orcid":false,"given":"James D.","family":"Doecke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4877-1958","authenticated-orcid":false,"given":"Pratishtha","family":"Chatterjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8017-8682","authenticated-orcid":false,"given":"Hamid R.","family":"Sohrabi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3930-4354","authenticated-orcid":false,"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6353-9316","authenticated-orcid":false,"given":"Nicholas J.","family":"Ashton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0514-0865","authenticated-orcid":false,"given":"Manohar L.","family":"Garg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1890-4193","authenticated-orcid":false,"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4828-9363","authenticated-orcid":false,"given":"Ralph N.","family":"Martins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"6184_CR1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0333-5","volume":"14","author":"MA DeTure","year":"2019","unstructured":"DeTure MA, Dickson DW (2019) The neuropathological diagnosis of Alzheimer\u2019s disease. 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H.Z. has served at scientific advisory boards and\/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merck Sharp & Dohme, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, ScandiBio Therapeutics AB, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, LabCorp, Lilly, Novo Nordisk, Oy Medix Biochemica AB, Roche, and WebMD, is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, and is a shareholder of CERimmune Therapeutics (outside submitted work). N.J.A. has served as a consultant for Quanterix and has given lectures in symposia sponsored by Lilly, Quanterix and Biogen. K.B. has served as a consultant, at advisory boards, or at data monitoring committees for Acumen, Abcam, ALZpath, AriBio, Axon, BioArctic, Biogen, Eisai, JOMDD\/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside the work presented in this paper).","order":1,"name":"Ethics","label":"Conflict of Interest","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"892"}}