Longitudinal changes in Alzheimer's-related plasma biomarkers and brain amyloid

Abstract

Introduction: Understanding longitudinal plasma biomarker trajectories relative to brain amyloid changes can help devise Alzheimer's progression assessment strategies.

Methods: We examined the temporal order of changes in plasma amyloid-β ratio ( ${A\beta }_{42}/{A\beta }_{40}$ ), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau ratios ( $\text{p-tau181}/A{\beta }_{42}$ , $\text{p-tau231}/A{\beta }_{42}$ ) relative to ¹¹ C-Pittsburgh compound B (PiB) positron emission tomography (PET) cortical amyloid burden (PiB-/+). Participants (n = 199) were cognitively normal at index visit with a median 6.1-year follow-up.

Results: PiB groups exhibited different rates of longitudinal change in ${A\beta }_{42}/{A\beta }_{40}\left(\beta =5.41\times {10}^{-4},\mathrm{SE}=1.95\times {10}^{-4},p=0.0073\right)$ . Change in brain amyloid correlated with change in GFAP (r = 0.5, 95% CI = [0.26, 0.68]). The greatest relative decline in ${A\beta }_{42}/{A\beta }_{40}$ (-1%/year) preceded brain amyloid positivity by 41 years (95% CI = [32, 53]).

Discussion: Plasma ${A\beta }_{42}/{A\beta }_{40}$ may begin declining decades prior to brain amyloid accumulation, whereas p-tau ratios, GFAP, and NfL increase closer in time. HIGHLIGHTS Plasma ${A\beta }_{42}/{A\beta }_{40}$ declines over time among PiB- but does not change among PiB+. Phosphorylated-tau to Aβ₄₂ ratios increase over time among PiB+ but do not change among PiB-. Rate of change in brain amyloid is correlated with change in GFAP and neurofilament light chain. The greatest decline in ${A\beta }_{42}/{A\beta }_{40}$ may precede brain amyloid positivity by decades.

Keywords: Pittsburgh compound B; biomarkers; longitudinal; plasma; positron emission tomography.