Astrocyte biomarkers GFAP and YKL-40 mediate early Alzheimer's disease progression

Pelkmans, Wiesje; Shekari, Mahnaz; Brugulat Serrat, Anna, 1986-; Sánchez Benavides, Gonzalo; Minguillón, Carolina; Fauria, Karine; Molinuevo, José Luis; Grau-Rivera, Oriol; González Escalante, Armand; Kollmorgen, Gwendlyn; Carboni, Margherita; Ashton, Nicholas J.; Zetterberg, Henrik; Blennow, Kaj; Suárez-Calvet, Marc; Gispert López, Juan Domingo; ALFA Study

Astrocyte biomarkers GFAP and YKL-40 mediate early Alzheimer's disease progression

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dc.contributor.author Pelkmans, Wiesje
dc.contributor.author Shekari, Mahnaz
dc.contributor.author Brugulat Serrat, Anna, 1986-
dc.contributor.author Sánchez Benavides, Gonzalo
dc.contributor.author Minguillón, Carolina
dc.contributor.author Fauria, Karine
dc.contributor.author Molinuevo, José Luis
dc.contributor.author Grau-Rivera, Oriol
dc.contributor.author González Escalante, Armand
dc.contributor.author Kollmorgen, Gwendlyn
dc.contributor.author Carboni, Margherita
dc.contributor.author Ashton, Nicholas J.
dc.contributor.author Zetterberg, Henrik
dc.contributor.author Blennow, Kaj
dc.contributor.author Suárez-Calvet, Marc
dc.contributor.author Gispert López, Juan Domingo
dc.contributor.author ALFA Study
dc.date.accessioned 2024-04-24T06:48:24Z
dc.date.available 2024-04-24T06:48:24Z
dc.date.issued 2024
dc.description.abstract Introduction: We studied how biomarkers of reactive astrogliosis mediate the pathogenic cascade in the earliest Alzheimer's disease (AD) stages. Methods: We performed path analysis on data from 384 cognitively unimpaired individuals from the ALzheimer and FAmilies (ALFA)+ study using structural equation modeling to quantify the relationships between biomarkers of reactive astrogliosis and the AD pathological cascade. Results: Cerebrospinal fluid (CSF) amyloid beta (Aβ)42/40 was associated with Aβ aggregation on positron emission tomography (PET) and with CSF p-tau181 , which was in turn directly associated with CSF neurofilament light (NfL). Plasma glial fibrillary acidic protein (GFAP) mediated the relationship between CSF Aβ42/40 and Aβ-PET, and CSF YKL-40 partly explained the association between Aβ-PET, p-tau181 , and NfL. Discussion: Our results suggest that reactive astrogliosis, as indicated by different fluid biomarkers, influences the pathogenic cascade during the preclinical stage of AD. While plasma GFAP mediates the early association between soluble and insoluble Aβ, CSF YKL-40 mediates the latter association between Aβ and downstream Aβ-induced tau pathology and tau-induced neuronal injury. Highlights: Lower CSF Aβ42/40 was directly linked to higher plasma GFAP concentrations. Plasma GFAP partially explained the relationship between soluble Aβ and insoluble Aβ. CSF YKL-40 mediated Aβ-induced tau phosphorylation and tau-induced neuronal injury.
dc.description.sponsorship 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 grant no. 2017-SGR-892. 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 program under grant agreement 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 program under the Marie Skłodowska-Curie grant agreement 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), and the UK Dementia Research Institute at UCL (UKDRI-1003). KB is supported by the Swedish Research Council (2017‑00915); the Alzheimer Drug Discovery Foundation (ADDF), USA (RDAPB‑201809‑2016615); the Swedish Alzheimer Foundation (AF‑742881); Hjärnfonden, Sweden (FO2017‑0243); the Swedish state under the agreement between the Swedish government and the county councils, the ALF‑agreement (ALFGBG‑715986); the European Union Joint Programme for Neurodegenerative Disorders (JPND2019‑466‑236); the National Institute of Health (NIH), USA (grant 1R01AG068398‑01); and the Alzheimer's Association 2021 Zenith Award (ZEN‑21‑848495). MSC receives funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement 948677), the Instituto de Salud Carlos III (PI19/00155, PI22/00456), and the ERC under the EU's ‘la Caixa’ Foundation (ID 100010434) and from the EU's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant (847648, LCF/BQ/PR21/11840004). JDG is supported by the Spanish Ministry of Science and Innovation (RYC‑2013‑13054). JDG has also received research support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking AMYPAD (grant agreement 115952), EIT Digital (grant 2021), and from Ministerio de Ciencia y Universidades (grant agreement RTI2018‑102261). GS-B receives funding from the Ministerio de Ciencia e Innovacion, Spanish Research Agency, PID2020-119556RA-I00. OGR receives funding from the Alzheimer's Association Research Fellowship Program (2019-AARF-644568), from Instituto de Salud Carlos III (PI19/00117), and from the Spanish Ministry of Science, Innovation and Universities (Juan de la Cierva programme IJC2020-043417-I).
dc.format.mimetype application/pdf
dc.identifier.citation Pelkmans W, Shekari M, Brugulat-Serrat A, Sánchez-Benavides G, Minguillón C, Fauria K, et al. Astrocyte biomarkers GFAP and YKL-40 mediate early Alzheimer's disease progression. Alzheimers Dement. 2024 Jan;20(1):483-93. DOI: 10.1002/alz.13450
dc.identifier.doi http://dx.doi.org/10.1002/alz.13450
dc.identifier.issn 1552-5260
dc.identifier.uri http://hdl.handle.net/10230/59883
dc.language.iso eng
dc.publisher Wiley
dc.relation.ispartof Alzheimers Dement. 2024 Jan;20(1):483-93
dc.relation.projectID info:eu-repo/grantAgreement/EC/HE/101053962
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/RTI2018‑102261
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-119556RA-I00
dc.rights © 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.keyword AD cascade
dc.subject.keyword Astrogliosis
dc.subject.keyword Biomarkers
dc.subject.keyword Chitinase-3-like protein 1 (YKL-40)
dc.subject.keyword Glial fibrillary acidic protein (GFAP)
dc.subject.keyword Preclinical Alzheimer's disease
dc.subject.keyword Structural equation modeling
dc.title Astrocyte biomarkers GFAP and YKL-40 mediate early Alzheimer's disease progression
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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