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

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

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.

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]).

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.