Amyloid beta, tau, synaptic, neurodegeneration, and glial biomarkers in the preclinical stage of the Alzheimer's continuum.

ABSTRACT

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-ß (Aß)42, Aß40, 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 Aß-positive individuals, whereas NfL and glial biomarkers increase with aging regardless of Aß status. We modelled biomarker changes as a function of CSF Aß42/40, p-tau and p-tau/Aß42 as proxies of disease progression. The first change observed in the Alzheimer's continuum was a decrease in the CSF Aß42/40 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.