Cumplido-Mayoral, IreneSánchez Benavides, GonzaloVilor Tejedor, Natàlia, 1988-López Martos, DavidBrugulat Serrat, Anna, 1986-Milà Alomà, MartaFalcón, CarlesCacciaglia, RaffaeleMinguillón, CarolinaFauria, KarineKollmorgen, GwendlynQuijano Rubio, ClaraMolinuevo, José LuisGrau-Rivera, OriolSuárez-Calvet, MarcVilaplana, VerónicaGispert López, Juan DomingoALFA StudyADNICumplido-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; ADNI2025-09-042025-09-042025Cumplido-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-x1359-4184http://hdl.handle.net/10230/71102Magnetic 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.application/pdfeng© 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/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41380-025-02961-xBiomarkersNeuroscienceinfo:eu-repo/semantics/openAccess