Vila-Castelar, ClaraAkinci, MugePalpatzis, EleniAguilar Dominguez, PabloOperto, GrégoryKollmorgen, GwendlynQuijano Rubio, ClaraBlennow, KajZetterberg, HenrikFalcón, CarlesFauria, KarineGispert López, Juan DomingoGrau-Rivera, OriolSuárez-Calvet, MarcArenaza Urquijo, Eider M.ALFA Study2024-11-282024-11-282024Vila-Castelar C, Akinci M, Palpatzis E, Aguilar-Dominguez P, Operto G, Kollmorgen G, et al. Sex/gender effects of glial reactivity on preclinical Alzheimer's disease pathology. Mol Psychiatry. 2024 Oct 9. DOI: 10.1038/s41380-024-02753-91359-4184http://hdl.handle.net/10230/68846Data de publicació electrònica: 09-10-2024Glial reactivity may contribute to sex/gender differences in Alzheimer's disease (AD) pathophysiology. Here, we investigated the differential effect of cerebrospinal fluid (CSF) glial markers on AD pathology and neurodegeneration by sex/gender among cognitively unimpaired older adults at increased risk of developing AD. We included 397 participants from the ALFA+ cohort with CSF Aβ42/40, p-tau181, sTREM2, YKL40, and GFAP, magnetic resonance imaging-based hippocampal volume (n = 299), and amyloid burden (centiloids) measured with [18F] flutemetamol positron emission tomography (n = 341). We ran multiple linear regression models to assess the association between glial markers, AD pathology and hippocampal volumes and their interaction with sex/gender, using False Discovery Rate to correct for multiple comparisons. Glial markers significantly contributed to explain amyloid burden, tau pathology, and hippocampal volumes, beyond age and/or primary AD pathology in a sex/gender-specific manner. Compared to men, women showed increased amyloid burden (centiloids) and CSF p-tau181 with increasing levels of sTREM2 and YKL40, and YKL40 and GFAP, respectively. Compared to women, men with greater tau burden showed lower hippocampal volumes as CSF YKL40 levels increased. Overall, our findings suggest that glial reactivity may contribute to sex/gender differences in AD progression, mostly, downstream amyloid. Further research identifying sex/gender-specific temporal dynamics in AD development is warranted to inform clinical trials.application/pdfeng© The Author(s) 2024. 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/s41380-024-02753-9Diagnostic markersDiseasesinfo:eu-repo/semantics/openAccess