INTRODUCTION: 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.

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Keywords Alzheimer's disease, biomarker, neurodegeneration, neuroinflammation, preclinical
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Journal Alzheimer's & Dementia
Milà-Alomà, M. (Marta), Salvadó, G. (Gemma), Gispert, J.D. (Juan Domingo), Vilor-Tejedor, N, Grau-Rivera, O, Sala-Vila, A. (Aleix), … Molinuevo, J.L. (José Luis). (2020). Amyloid beta, tau, synaptic, neurodegeneration, and glial biomarkers in the preclinical stage of the Alzheimer's continuum. Alzheimer's & Dementia. doi:10.1002/alz.12131