{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T06:27:11Z","timestamp":1787120831450,"version":"build-2736575974"},"reference-count":102,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100032554","name":"Peking University Shenzhen Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100032554","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Alzheimer\u2019s disease (AD) is the leading cause of dementia, with early diagnosis remaining constrained by the invasiveness and limited accessibility of current biomarkers. The gut\u2013brain axis has emerged as a critical communication network linking intestinal homeostasis with central nervous system function, yet the diagnostic utility of gut-microbiota-associated circulating metabolites in AD remains largely unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this case-control study, 85 participants (37 AD patients and 48 cognitively normal controls) were enrolled. Targeted plasma metabolomics using four complementary UPLC-MS\/MS assays covering 375 endogenous metabolites was integrated with fecal metagenomic sequencing in 72 participants with paired samples. Differential metabolites were screened using the Mann\u2013Whitney U test, orthogonal partial least squares discriminant analysis, and fold-change thresholds. Gut-microbiota-associated plasma metabolites were defined through Spearman correlation with linear discriminant analysis effect size-identified differential bacterial species. A diagnostic panel was constructed using least absolute shrinkage and selection operator logistic regression with stability selection, and its performance was evaluated by support vector machine with repeated cross-validation, with age and sex evaluated as covariates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We identified 27 differential plasma metabolites enriched in tricarboxylic acid cycle and amino acid metabolic pathways. Correlation analysis identified 10 gut-microbiota-associated plasma metabolites significantly associated with gut microbial alterations. A three-metabolite panel (citric acid, 3-hydroxyoctanoic acid, and glyoxylic acid) achieved a cross-validated area under the curve of 0.865, with a modest sensitivity of 62.2% and specificity of 100.0%, positioning it as a confirmatory auxiliary tool rather than a broad screening instrument. The panel score correlated negatively with Mini-Mental State Examination scores (r = \u22120.544, P &amp;lt; 0.001), and integration with clinical cognitive assessment yielded an area under the curve of 0.978.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings potentially advance the translational understanding of the gut\u2013brain metabolic axis in neurodegeneration and support the exploratory clinical utility of microbiota-linked peripheral metabolic signatures as non-invasive auxiliary diagnostic tools for AD, awaiting external validation in larger, multi-center cohorts.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1933454","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T05:44:25Z","timestamp":1787118265000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics integration identifies a gut-microbiota-associated plasma metabolite signature for alzheimer disease diagnosis and metabolic pathway targeting"],"prefix":"10.3389","volume":"17","author":[{"given":"Jiao","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Neurology, Peking University Shenzhen Hospital","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuhui","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Peking University Shenzhen Hospital","place":["Shenzhen, China"]},{"name":"Department of Neurology, Peking University First Hospital","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Peking University Shenzhen Hospital","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Shenzhen Second People\u2019s Hospital","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhigang","family":"Liu","sequence":"additional","affiliation":[{"name":"Huadong Hospital, Medicine-Agriculture Interdisciplinary Center, Institute of Nutrition, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Peking University Shenzhen Hospital","place":["Shenzhen, China"]},{"name":"Shenzhen Key Laboratory for Neuronal Structural Biology, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e38544","DOI":"10.7759\/cureus.38544","article-title":"Neuroimaging in alzheimer's disease for early diagnosis: a comprehensive review","volume":"15","author":"Aramadaka","year":"2023","journal-title":"Cureus"},{"key":"B2","doi-asserted-by":"publisher","first-page":"149242","DOI":"10.1016\/j.brainres.2024.149242","article-title":"Linking gut microbiota dysbiosis to molecular pathways in alzheimer's disease","volume":"1845","author":"Asadifard","year":"2024","journal-title":"Brain Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1001\/jamaneurol.2023.5319","article-title":"Diagnostic accuracy of a plasma phosphorylated tau 217 immunoassay for alzheimer disease pathology","volume":"81","author":"Ashton","year":"2024","journal-title":"JAMA Neurol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1038\/s41588-022-01024-z","article-title":"New insights into the genetic etiology of alzheimer's disease and related dementias","volume":"54","author":"Bellenguez","year":"2022","journal-title":"Nat. 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