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Blood-based biomarkers such as phosphorylated tau at threonine 181 (p-tau181), glial fibrillary acidic protein (GFAP), and amyloid\u2013tau ratios have improved diagnostic performance; however, their integration with systemic metabolic markers remains insufficiently investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To characterize metabolic\u2013neuroglial plasma signatures across the cognitive continuum and identify biomarkers capable of discriminating mild cognitive impairment (MCI) from mild AD and cognitively unimpaired (CU) individuals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Seventy adults classified as CU, MCI, or mild AD underwent plasma quantification of A\u03b2\n                      <jats:sub>40<\/jats:sub>\n                      , A\u03b2\n                      <jats:sub>42<\/jats:sub>\n                      , p-tau181, and GFAP alongside metabolic markers, including glycated hemoglobin, calcium, vitamin D, homocysteine, thyroid-stimulating hormone, C-reactive protein, and platelet count. Group comparisons were conducted using non-parametric tests. Multivariate approaches, principal component analysis, partial least squares discriminant analysis, and Random Forest (RF), were applied to detect discriminative biomarker patterns, incorporating automatically generated ratios.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MCI participants showed higher plasma homocysteine and A\u03b2\n                      <jats:sub>40<\/jats:sub>\n                      than CU. Mild AD was characterized by elevated p-tau181 and GFAP and a reduced amyloid\u2013tau balance captured by A\u03b2\n                      <jats:sub>40<\/jats:sub>\n                      -based ratios. CU was distinguishable from both clinical groups using univariate markers and ratios, whereas separation between MCI and mild AD required multivariate integration. A six-biomarker RF signature robustly discriminated MCI from mild AD (AUC = 0.854; permutation p\u2009=\u20090.0044).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Integrated plasma panels combining neurodegenerative and metabolic markers improve staging across the AD continuum and may support clinical decision-making where advanced diagnostics are limited.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877261441581","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T14:37:35Z","timestamp":1776955055000},"page":"1139-1155","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["A metabolic\u2013glial plasma signature defines early Alzheimer's disease: Insights from an understudied cohort"],"prefix":"10.1177","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6739-8258","authenticated-orcid":false,"given":"Lucas Tadeu Rocha","family":"Santos","sequence":"first","affiliation":[{"name":"Neuropsychopharmacology and Translational Psychiatry Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Cear\u00e1, Fortaleza, Cear\u00e1, Brazil"},{"name":"Postgraduate Program in Translational Medicine, Faculty of Medicine, Federal University of Cear\u00e1, Fortaleza, Cear\u00e1, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7606-1287","authenticated-orcid":false,"given":"Fernanda Leit\u00e3o","family":"Costa","sequence":"additional","affiliation":[{"name":"Neuropsychopharmacology and Translational Psychiatry Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Cear\u00e1, Fortaleza, Cear\u00e1, Brazil"},{"name":"Postgraduate Program in Translational Medicine, Faculty of Medicine, Federal University of Cear\u00e1, Fortaleza, Cear\u00e1, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3889-7906","authenticated-orcid":false,"given":"Isabele Dantas","family":"Rosa","sequence":"additional","affiliation":[{"name":"Neuropsychopharmacology and Translational Psychiatry Laboratory, Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Cear\u00e1, Fortaleza, Cear\u00e1, Brazil"},{"name":"Postgraduate Program in Translational Medicine, Faculty of Medicine, Federal University of Cear\u00e1, Fortaleza, Cear\u00e1, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4550-0266","authenticated-orcid":false,"given":"Annyta 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