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and astroglia, is disrupted throughout aging and early on in neurodegenerative diseases. Our aim was to study the relationship between TREM2-dependent microglial reactivity, astroglial response and synaptic dysfunction in two longitudinal cohorts of cognitively healthy volunteers and determine whether this relationship is influenced by AD core biomarkers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed cross-sectional and longitudinal associations between cerebrospinal fluid levels of soluble TREM2 (sTREM2), astroglial markers (GFAP, S100B), and synaptic markers (neurogranin, \u03b1-synuclein) in cognitively unimpaired participants from the Wisconsin Registry for Alzheimer\u2019s Prevention (WRAP) and the Alzheimer\u2019s and Families (ALFA+) cohort. Biomarkers were quantified using validated immunoassays (NeuroToolKit, Roche), with sTREM2 measured using an in-house MSD-based assay in the WRAP cohort. Linear regression and linear mixed-effects models were used, both unadjusted and adjusted for A\u03b242 and p-tau. Subgroup analyses were performed based on AT classification,\n                      <jats:italic>APOE<\/jats:italic>\n                      -\u03b54 status, and median splits of A\u03b242\/A\u03b240 ratio and p-tau, to capture profiles suggestive of early AD-related neuropathogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found significant cross-sectional associations between sTREM2 and \u03b1-synuclein, as well as between sTREM2 and S100B, in subgroups exhibiting AD-related biomarker profiles. Longitudinally, lower baseline neurogranin and \u03b1-synuclein and higher S100B predicted greater increases in sTREM2 over time independently of AD-related markers in the WRAP cohort (\u03b2 = \u22120.02,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.006; \u03b2 = \u22120.02,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.01; \u03b2\u2009=\u20090.02,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.03, respectively). In ALFA+, lower baseline \u03b1-synuclein also predicted a greater subsequent longitudinal increase in sTREM2, but only among individuals with A\u03b242\/A\u03b240 ratio above the median (\u03b2 = -0.01,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.05). Notably, higher baseline sTREM2 was associated with a smaller longitudinal increase in neurogranin in both cohorts (\u03b2 = -0.01,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.03 for WRAP, \u03b2 = -0.01,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.04 in ALFA+).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Synaptic dysfunction markers at baseline influence the longitudinal dynamics of CSF sTREM2 independently of AD-pathology related biomarkers throughout aging and earliest stages of neurodegeneration. In turn, higher baseline sTREM2 is associated with more stable neurogranin levels over time. These results suggest an independent interaction between synaptic dysfunction and TREM2-dependent microglial activation throughout aging and early neurodegeneration beyond AD pathology.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13024-025-00901-5","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T23:01:44Z","timestamp":1760655704000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Synaptic dysfunction and glial activation markers throughout aging and early neurodegeneration: a longitudinal CSF biomarker-based study"],"prefix":"10.1186","volume":"20","author":[{"given":"Mariana I.","family":"Mu\u00f1oz-Garc\u00eda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuetiva","family":"Deming","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferran","family":"Lugo-Hern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sterling","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Asthana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwendlyn","family":"Kollmorgen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Quijano-Rubio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Carlsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ozioma C.","family":"Okonkwo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"P\u00e9rez-Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Villarejo-Galende","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Su\u00e1rez-Calvet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara B.","family":"Bendlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estrella","family":"Morenas-Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"901_CR1","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.cell.2022.12.032","volume":"186","author":"DM Wilson III","year":"2023","unstructured":"Wilson DM III, Cookson MR, Van L, Bosch D, Zetterberg H, Holtzman DM, et al. 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The ALFA study protocol was approved by the Independent Ethics committee\n                      Parc de Salut Mar\n                      and registered at clinicaltrials.gov (identifier: NCT01835717). It was conducted in accordance with the directives of the Spanish Law 14\/2007, of 3rd of July, on Biomedical Research. All participants in the ALFA study accepted the study procedures by signing an informed consent form and had a close relative volunteering to participate in the functional assessment procedure of the participant, who also granted his or her consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"M.I.M.-G has received in the past 36mo speaker fees by Almirall. E.M.-R. has given lectures and symposia sponsored by KRKA Farmaceutica SL and Laboratorios Esteve SA. M.S.-C. has received in the past 36mo consultancy\/speaker fees (paid to the institution) from by Almirall, Eli Lilly, Quanterix, Novo Nordisk, and Roche Diagnostics. He has received consultancy fees or served on advisory boards (paid to the institution) of Eli Lilly, Grifols, Novo Nordisk, and Roche Diagnostics. He was granted a project and is a site investigator of a clinical trial (funded to the institution) by Roche Diagnostics. In-kind support for research (to the institution) was received from ADx Neurosciences, Alamar Biosciences, ALZPath, Avid Radiopharmaceuticals, Eli Lilly, Fujirebio, Janssen Research & Development, Meso Scale Discovery, and Roche Diagnostics; MS-C did not receive any personal compensation from these organizations or any other for-profit organization.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 MicThera (outside submitted work).S.C.-J. serves as a consultant to Eli Lilly, Merck, AlzPath and Enigma Biomedical.G.K. is a full-time employee of Roche Diagnostics GmbH, Penzberg, Germany. CQ-R is a full-time employee of Roche Diagnostics International Ltd, Rotkreuz, Switzerland.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"109"}}