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.
Milà-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 Oct;16(10):1358-1371. doi: 10.1002/alz.12131. Epub 2020 Jun 23. PMID: 32573951; PMCID: PMC7586814.