{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T05:48:13Z","timestamp":1782193693624,"version":"3.54.5"},"reference-count":132,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immuno-metabolic dysregulation contributes to Alzheimer\u2019s disease (AD) pathogenesis, yet the peripheral metabolic landscape and its interplay with neuroinflammation remain poorly characterized in treatment-na\u00efve, late-stage patients. This study aimed to delineate plasma metabolic alterations and immuno-metabolic interactions in Chinese first-time outpatients with late-onset AD (CFTO-LOAD).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Untargeted metabolomics and ELISA were applied to plasma from 35 CFTO-LOAD patients and 35 sex-matched cognitively healthy controls (CHCs) to quantify metabolites, cytokines (TNF-\u03b1, IL-17, IL-9), and soluble A\u03b2\/Tau markers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 875 differentially abundant metabolites (DAMs) were identified in CFTO-LOAD, comprising 227 upregulated and 648 downregulated species (\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05), predominantly lipids, fatty acids (e.g., dodecanoic acid, arachidonic acid), and amino acids (e.g., L-arginine, L-leucine). KEGG analysis revealed enrichment in fatty acid and amino acid metabolism, GABAergic synapse, and intestinal immune network pathways. CFTO-LOAD patients exhibited elevated pro-inflammatory cytokines TNF-\u03b1 and IL-17 (\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic>adj<\/jats:italic>\n                      <\/jats:sub>\n                      &amp;lt; 0.05), reduced IL-9 (\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic>adj<\/jats:italic>\n                      <\/jats:sub>\n                      &amp;lt; 0.001), increased soluble p-Tau, p-Tau181, and p-Tau217 (\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic>adj<\/jats:italic>\n                      <\/jats:sub>\n                      &amp;lt; 0.01), and decreased A\u03b242\/A\u03b240 ratio (\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic>adj<\/jats:italic>\n                      <\/jats:sub>\n                      &amp;lt; 0.001). Linear regression identified significant correlations between differential metabolites and immune\/pathological markers, including positive associations of dodecanoic acid with TNF-\u03b1 (\n                      <jats:italic>r<\/jats:italic>\n                      = 0.34,\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic>adj<\/jats:italic>\n                      <\/jats:sub>\n                      &amp;lt; 0.05) and arachidonic acid with A\u03b242\/A\u03b240 ratio (\n                      <jats:italic>r<\/jats:italic>\n                      = 0.30,\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic>adj<\/jats:italic>\n                      <\/jats:sub>\n                      &amp;lt; 0.05), and negative associations of arachidonic acid with p-Tau217 (\n                      <jats:italic>r<\/jats:italic>\n                      = \u22120.43,\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic>adj<\/jats:italic>\n                      <\/jats:sub>\n                      &amp;lt; 0.01) and sphinganine 1-phosphate with TNF-\u03b1 (\n                      <jats:italic>r<\/jats:italic>\n                      = \u22120.28,\n                      <jats:italic>P<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic>adj<\/jats:italic>\n                      <\/jats:sub>\n                      &amp;lt; 0.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings characterize the peripheral immuno-metabolic landscape in treatment-na\u00efve late-onset AD, identifying metabolic mediators that may mechanistically link neuroinflammation to A\u03b2 and Tau pathology. This provides a foundation for biomarker development and therapeutic targeting in late-stage disease, pending independent validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2026.1858299","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T05:27:09Z","timestamp":1782192429000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Peripheral metabolomic profiling reveals lipid and amino acid alterations associated with immuno-inflammatory responses in treatment-na\u00efve late-onset Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"18","author":[{"given":"Pei-Juan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Nantong Fourth People\u2019s Hospital","place":["Nantong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Yu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Nantong Fourth People\u2019s Hospital","place":["Nantong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Nantong Fourth People\u2019s Hospital","place":["Nantong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Jia","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Nantong Fourth People\u2019s Hospital","place":["Nantong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-Ming","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Nantong Fourth People\u2019s Hospital","place":["Nantong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Sun","sequence":"additional","affiliation":[{"name":"Lishui Key Laboratory of Brain Health and Severe Brain Disorders, Lishui Second People\u2019s Hospital, Wenzhou Medical University","place":["Lishui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He-Xu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, China"]},{"name":"Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Nantong Fourth People\u2019s Hospital","place":["Nantong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Yang","sequence":"additional","affiliation":[{"name":"Lishui Key Laboratory of Brain Health and Severe Brain Disorders, Lishui Second People\u2019s Hospital, Wenzhou Medical University","place":["Lishui, China"]},{"name":"Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"32548","DOI":"10.1039\/d0ra05326k","article-title":"Metabolic characterisation of Magnetospirillum gryphiswaldense MSR-1 using LC-MS-based metabolite profiling.","volume":"10","author":"Abdelrazig","year":"2020","journal-title":"RSC Adv."},{"key":"B2","doi-asserted-by":"publisher","first-page":"102331","DOI":"10.1016\/j.pneurobio.2022.102331","article-title":"Astrocyte energy and neurotransmitter metabolism in Alzheimer\u2019s disease: Integration of the glutamate\/GABA-glutamine cycle.","volume":"217","author":"Andersen","year":"2022","journal-title":"Prog. 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