Pelkmans, WiesjeShekari, MahnazBrugulat Serrat, Anna, 1986-Sánchez Benavides, GonzaloMinguillón, CarolinaFauria, KarineMolinuevo, José LuisGrau-Rivera, OriolGonzález Escalante, ArmandKollmorgen, GwendlynCarboni, MargheritaAshton, Nicholas J.Zetterberg, HenrikBlennow, KajSuárez-Calvet, MarcGispert López, Juan DomingoALFA Study2024-04-242024-04-242024Pelkmans 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.134501552-5260http://hdl.handle.net/10230/59883Introduction: 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.application/pdfeng© 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.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1002/alz.13450AD cascadeAstrogliosisBiomarkersChitinase-3-like protein 1 (YKL-40)Glial fibrillary acidic protein (GFAP)Preclinical Alzheimer's diseaseStructural equation modelinginfo:eu-repo/semantics/openAccess