Sex/gender effects of glial reactivity on preclinical Alzheimer's disease pathology

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• dc.contributor.author Vila-Castelar, Clara
• dc.contributor.author Akinci, Muge
• dc.contributor.author Palpatzis, Eleni
• dc.contributor.author Aguilar Dominguez, Pablo
• dc.contributor.author Operto, Grégory
• dc.contributor.author Kollmorgen, Gwendlyn
• dc.contributor.author Quijano Rubio, Clara
• dc.contributor.author Blennow, Kaj
• dc.contributor.author Zetterberg, Henrik
• dc.contributor.author Falcón, Carles
• dc.contributor.author Fauria, Karine
• dc.contributor.author Gispert López, Juan Domingo
• dc.contributor.author Grau-Rivera, Oriol
• dc.contributor.author Suárez-Calvet, Marc
• dc.contributor.author Arenaza Urquijo, Eider M.
• dc.contributor.author ALFA Study
• dc.date.accessioned 2024-11-28T08:27:07Z
• dc.date.available 2024-11-28T08:27:07Z
• dc.date.issued 2024
• dc.description Data de publicació electrònica: 09-10-2024
• dc.description.abstract Glial 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.
• dc.description.sponsorship This publication is part of the ALFA study (ALzheimer and FAmilies). The authors would like to express their sincerest gratitude to the ALFA project participants, without whom this research would have not been possible. Collaborators of the ALFA study are: Federica Anastasi, Annabella Beteta, Anna Brugulat-Serrat, Raffaele Cacciaglia, Irene Cumplido-Mayoral, Alba Cañas, Marta del Campo, Carme Deulofeu, Ruth Dominguez, Maria Emilio, Ana Fernández-Arcos, Sherezade Fuentes, Patricia Genius, Armand González-Escalante, Laura Hernández, Felipe Hernández-Villamizar, Jordi Huguet, David López-Martos, Ferran Lugo, Paula Marne, Tania Menchón, Carolina Minguillon, Paula Ortiz, Wiesje Pelkmans, Albina Polo, Sandra Pradas, Blanca Rodríguez-Fernandez, Gonzalo Sánchez-Benavides, Mahnaz Shekari, Anna Soteras, Laura Stankeviciute, Marc Vilanova and Natalia Vilor-Tejedor. The authors would like to thank Jordi Huguet (Barcelonaβeta Brain Research Center, Barcelona) and Robin de Flores (INSERM, Caen, France) for their contributions to hippocampal subfield segmentation with Automated Segmentation of Hippocampal Subfields (ASHS). The Roche NeuroToolKit is a panel of exploratory prototype assays designed to robustly evaluate biomarkers associated with key pathologic events characteristic of AD and other neurological disorders, used for research purposes only and not approved for clinical use. Elecsys β-amyloid (1–42) CSF, Elecsys Phospho-Tau (181P) CSF and Elecsys Total-Tau CSF assays are approved for clinical use. COBAS and ELECSYS are trademarks of Roche. All other product names and trademarks are the property of their respective owners. The research leading to these results has received 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 00913. The research leading to these results has received funding by the Ministry of Science and Innovation (PID2019-111514RA-I00) and the Alzheimer’s Association research grants (AARG 2019-AARG-644641, AARG 2019-AARG-644641-RAPID) to EMA-U. EMA-U is supported by the Spanish Ministry of Science and Innovation - State Research Agency (RYC2018-026053-I), co-funded by the European Social Fund (ESF). EMA-U receives support from EU Joint Programme-Neurodegenerative Disease Research J(PND2022-138). EP is funded by the Spanish Ministry of Science and Innovation (PRE2020-095827). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022-01018 and #2019-02397), the European Union’s Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C, and #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and the UK Dementia Research Institute at UCL (UKDRI-1003). OG-R is supported by the Spanish Ministry of Science and Innovation –State Research Agency (IJC2020-043417-I/MCIN/AEI/10.13039/501100011033) and the European Union laquoNextGenerationEUraquo/PRTR. MSC receives funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (Grant agreement No. 948677), the Instituto de Salud Carlos III through the projects PI19/00155 and PI22/00456 (Co-funded by European Regional Development Fund (FEDER) “A way to make Europe”), and receives the support of a fellowship from ”la Caixa” Foundation (ID 100010434) and from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 847648 (fellowship code LCF/BQ/PR21/11840004). CV-C is supported by a grant from the National Institute on Aging (K99AG073452).
• dc.format.mimetype application/pdf
• dc.identifier.citation Vila-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/s41380-024-02753-9
• dc.identifier.doi http://dx.doi.org/10.1038/s41380-024-02753-9
• dc.identifier.issn 1359-4184
• dc.identifier.uri http://hdl.handle.net/10230/68846
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Mol Psychiatry. 2024 Oct 9
• dc.relation.projectID info:eu-repo/grantAgreement/EC/HE/101053962
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-111514RA-I00
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/860197
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/948677
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/847648
• dc.rights © 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/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword Diagnostic markers
• dc.subject.keyword Diseases
• dc.title Sex/gender effects of glial reactivity on preclinical Alzheimer's disease pathology
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion