Neuroimaging-derived biological brain age and its associations with glial reactivity and synaptic dysfunction cerebrospinal fluid biomarkers

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  • dc.contributor.author Cumplido-Mayoral, Irene
  • dc.contributor.author Sánchez Benavides, Gonzalo
  • dc.contributor.author Vilor Tejedor, Natàlia, 1988-
  • dc.contributor.author López Martos, David
  • dc.contributor.author Brugulat Serrat, Anna, 1986-
  • dc.contributor.author Milà Alomà, Marta
  • dc.contributor.author Falcón, Carles
  • dc.contributor.author Cacciaglia, Raffaele
  • dc.contributor.author Minguillón, Carolina
  • dc.contributor.author Fauria, Karine
  • dc.contributor.author Kollmorgen, Gwendlyn
  • dc.contributor.author Quijano Rubio, Clara
  • dc.contributor.author Molinuevo, José Luis
  • dc.contributor.author Grau-Rivera, Oriol
  • dc.contributor.author Suárez-Calvet, Marc
  • dc.contributor.author Vilaplana, Verónica
  • dc.contributor.author Gispert López, Juan Domingo
  • dc.contributor.author ALFA Study
  • dc.contributor.author ADNI
  • dc.contributor.other Cumplido-Mayoral, Irene; Sánchez Benavides, Gonzalo; Vilor Tejedor, Natàlia, 1988-; López Martos, David; Brugulat Serrat, Anna, 1986-; Milà Alomà, Marta; Falcón, Carles; Cacciaglia, Raffaele; Minguillón, Carolina; Fauria, Karine; Kollmorgen, Gwendlyn; Quijano Rubio, Clara; Molinuevo, José Luis; Grau-Rivera, Oriol; Suárez-Calvet, Marc; Vilaplana, Verónica; Gispert López, Juan Domingo; ALFA Study; ADNI
  • dc.date.accessioned 2025-09-04T06:38:50Z
  • dc.date.available 2025-09-04T06:38:50Z
  • dc.date.issued 2025
  • dc.description.abstract Magnetic resonance Imaging (MRI)-derived brain-age prediction is a promising biomarker of biological brain aging. Accelerated brain aging has been found in Alzheimer's disease (AD) and other neurodegenerative diseases. However, no previous studies have investigated the relationship between specific pathophysiological pathways in AD and biological brain aging. Here, we studied whether glial reactivity and synaptic dysfunction are associated with biological brain aging in the earliest stages of the Alzheimer's continuum, and if these mechanisms are differently associated with AD-related cortical atrophy. We further evaluated their effects on cognitive decline. We included 380 cognitively unimpaired individuals from the ALFA+ study, for which we computed their brain-age deltas by subtracting chronological age from their brain age predicted by machine learning algorithms. We studied the cross-sectional linear associations between brain-age delta and cerebrospinal fluid (CSF) biomarkers of synaptic dysfunction (neurogranin, GAP43, synaptotagmin-1, SNAP25, and α-synuclein), glial reactivity (sTREM2, YKL-40, GFAP, and S100b) and inflammation (interleukin-6). We also studied the cross-sectional linear associations between AD signature and these CSF biomarkers, We further evaluated the mechanisms linking baseline brain-age delta and longitudinal cognitive decline by performing mediation analyses. To reproduce our findings on an independent cohort, we included 152 cognitively unimpaired and 310 mild cognitive impaired (MCI) individuals from the ADNI study. We found that higher CSF sTREM2 was associated with a younger brain-age after adjusting for AD pathology, both in ALFA+ cognitively unimpaired and in ADNI MCI individuals. Furthermore, we found that CSF sTREM2 fully mediated the link between older brain-age and cognitive decline in ALFA+. In summary, we showed that the protective microglial state reflected by higher CSF sTREM2 has a beneficial impact on biological brain aging that may partly explains the variability in cognitive decline in early AD stages, independently of AD pathology.
  • dc.description.sponsorship The study was approved by the Independent Ethics Committee “Parc de Salut Mar,” Barcelona, and all participants gave written informed consent. The ALFA+ study receives funding from “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/GN17/50300004 and the Alzheimer’s Association and an international anonymous charity foundation through the TriBEKa Imaging Platform project (TriBEKa 17 519007). Additional support has been received from the Universities and Research Secretariat, Ministry of Business and Knowledge of the Catalan Government under the grant no. 2021 SGR 009132017-SGR-892. MS-C receives funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant agreement No. 948677); ERA PerMed (ERAPERMED2021-184); Project “PI19/00155” and “PI22/00456, funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union (FEDER); and from a fellowship from ”la Caixa” Foundation (ID 100010434) and the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 847648 (LCF/BQ/PR21/11840004). DLM is supported by the project PI19/00117, funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union (FEDER). VV has been supported by the project PID2020-116907RB-I00, funded by the Ministry of Science and Innovation - State Research Agency, MCIN/ AEI /10.13039/501100011033. GSB is supported by the Spanish Ministry of Science and Innovation - State Research Agency MCIN/AEI/10.13039/501100011033 through the project PID2020-119556RA-I00 and by the Instituto de Salud Carlos III (ISCIII) through the project CP23/00039 (Miguel Servet contract), co-funded by the European Union (FSE+). OGR receives funding from the Alzheimer’s Association Research Fellowship Program (2019-AARF-644568), from Instituto de Salud Carlos III co-funded by the European Union (FEDER) (PI19/00117) and from Ministry of Science and Innovation - State Research Agency MCIN/ AEI /10.13039/501100011033 co-funded by the the European Union «NextGenerationEU»/PRTR (IJC2020-043417-I). NV-T is supported by the Spanish Ministry of Science and Innovation - State Research Agency MCIN/AEI/10.13039/501100011033, co-funded by the the European Union «NextGenerationEU»/PRTR (IJC2020-043216-I). In addition, NV-T receives funding from the Alzheimer’s Disease Data Initiative (ADDI) through the William H. Gates Sr. Fellowship program, and the PID2022-143106OA-I00 project, funded by MCIN/AEI /10.13039/501100011033 and co-funded by the European Union (FEDER). RC is supported by the Spanish Ministry of Science and Innovation - State Research Agency MCIN/AEI/10.13039/501100011033 through the project PID2021-125433OA-100 (co-funded by the European Union (FEDER)) and a Ramón y Cajal contract (RYC2021-031128-I, co-funded by the European Union «NextGenerationEU»/PRTR).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Cumplido-Mayoral I, Sánchez-Benavides G, Vilor-Tejedor N, López-Martos D, Brugulat-Serrat A, Milà-Alomà M, et al. Neuroimaging-derived biological brain age and its associations with glial reactivity and synaptic dysfunction cerebrospinal fluid biomarkers. Mol Psychiatry. 2025 Aug;30(8):3718-28. DOI: 10.1038/s41380-025-02961-x
  • dc.identifier.doi http://dx.doi.org/10.1038/s41380-025-02961-x
  • dc.identifier.issn 1359-4184
  • dc.identifier.uri http://hdl.handle.net/10230/71102
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Mol Psychiatry. 2025 Aug;30(8):3718-28
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/948677
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/847648
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-116907RB-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-119556RA-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2022-143106OA-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-125433OA-100
  • dc.rights © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
  • dc.subject.keyword Biomarkers
  • dc.subject.keyword Neuroscience
  • dc.title Neuroimaging-derived biological brain age and its associations with glial reactivity and synaptic dysfunction cerebrospinal fluid biomarkers
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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