Milà Alomà, MartaSalvadó, GemmaGispert López, Juan DomingoVilor Tejedor, Natàlia, 1988-Grau-Rivera, OriolSala Vila, AleixSánchez Benavides, GonzaloArenaza Urquijo, Eider M.Crous-Bou, MartaGonzález de Echávarri, José MariaMinguillón, CarolinaFauria, KarineSimon, MarylineKollmorgen, GwendlynZetterberg, HenrikBlennow, KajSuárez-Calvet, MarcMolinuevo, José LuisALFA Study2020-10-132020-10-132020Milà-Alomà M, Salvadó G, Gispert JD, Vilor-Tejedor N, Grau-Rivera O, Sala-Vila A, Sánchez-Benavides G, Arenaza-Urquijo EM, Crous-Bou M, González-de-Echávarri JM, Minguillon C, Fauria K, Simon M, Kollmorgen G, Zetterberg H, Blennow K, Suárez-Calvet M, Molinuevo JL; ALFA study. Amyloid beta, tau, synaptic, neurodegeneration, and glial biomarkers in the preclinical stage of the Alzheimer's continuum. Alzheimers Dement. 2020; 16(10):1358-71. DOI: 10.1002/alz.121311552-5260http://hdl.handle.net/10230/45463Introduction: The biological pathways involved in the preclinical stage of the Alzheimer's continuum are not well understood. Methods: We used NeuroToolKit and Elecsys® immunoassays to measure cerebrospinal fluid (CSF) amyloid-β (Aβ)42, Aβ40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100, and α-synuclein in cognitively unimpaired participants of the ALFA+ study, many within the Alzheimer's continuum. Results: CSF t-tau, p-tau, and neurogranin increase throughout aging only in Aβ-positive individuals, whereas NfL and glial biomarkers increase with aging regardless of Aβ status. We modelled biomarker changes as a function of CSF Aβ42/40, p-tau and p-tau/Aβ42 as proxies of disease progression. The first change observed in the Alzheimer's continuum was a decrease in the CSF Aβ42/40 ratio. This is followed by a steep increase in CSF p-tau; t-tau; neurogranin; and, to a lesser extent, in NfL and glial biomarkers. Discussion: Multiple biological pathways are altered and could be targeted very early in the Alzheimer's continuum.application/pdfeng© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. 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.12131Alzheimer's diseaseBiomarkerNeurodegenerationNeuroinflammationPreclinicalinfo:eu-repo/semantics/openAccess