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-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.

Keywords: Alzheimer's disease; biomarker; neurodegeneration; neuroinflammation; preclinical.

FIGURE 1

Comparison of cerebrospinal fluid (CSF) biomarkers between AT groups. Dot and box plots depicting the levels of each CSF biomarker in each of the AT groups. The box plots depict the median (horizontal bar), interquartile range (IQR, hinges), and 1.5 × IQR (whiskers). Because our goal is to assess CSF biomarkers in the Alzheimer's continuum, we did not include the A–T+ group (ie, non‐AD pathologic change) in the analyses, but this group is included in the figure for the sake of completeness. P‐values were assessed by a one‐way analysis of covariance adjusted by age and sex, followed by Tukey corrected pair‐wise post hoc comparisons

FIGURE 2

Association of cerebrospinal fluid (CSF) biomarkers with age. Scatter plots representing the associations of each of the CSF biomarkers with age in the A–T– (ie, normal AD biomarkers) and the A+T* (ie, Alzheimer's continuum) groups. Each point depicts the value of the CSF biomarker of an individual and the solid lines indicate the regression line for each of the groups. The standardized regression coefficients (β) and the P‐values are shown and were computed using a linear model adjusting for age, sex, and apolipoprotein E (APOE)‐ε4. Additionally, we also computed the “Aβ42/40 x age” interaction term. All P‐values are corrected for multiple comparisons using the FDR approach

FIGURE 3

Cerebrospinal fluid (CSF) biomarker trajectories. The graphs represent the z‐scores changes of each CSF biomarker using the mean and the standard deviation of that CSF biomarker in the A–T– group as a reference. The resulting z‐scores are shown as a function of CSF Aβ42/40 (A) p‐tau (B) or p‐tau/Aβ42 (C) using a robust local weighted regression method. The solid lines depict the trajectory of each CSF biomarker. The dashed lines depict the cutoff for CSF Aβ42/40, p‐tau, and p‐tau/Aβ42, respectively. The horizontal axis direction of CSF Aβ42/40 (A) was inverted.