The dynamics of plasma biomarkers across the Alzheimer's continuum

Failures in drug trials strengthen the necessity to further determine the neuropathological events during the development of Alzheimer's disease (AD). We sought to investigate the dynamic changes and performance of plasma biomarkers across the entire Alzheimer's continuum in the Chinese population.

Plasma amyloid-β (Αβ)42, Aβ40, Aβ42/Aβ40, phosphorylated tau (p-tau)181, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were measured utilizing the ultrasensitive single-molecule array technology across the AD continuum (n=206), wherein Aβ status was defined by the values of cerebrospinal fluid (CSF) Aβ42 or Aβ positron emission tomography (PET). Their trajectories were compared with those of putative CSF biomarkers.

Plasma GFAP and p-tau181 increased only in Aβ-positive individuals throughout aging, whereas NfL increased with aging regardless of Aβ status. Among the plasma biomarkers studied, GFAP was the one that changed first. It had a prominent elevation early in the cognitively unimpaired (CU) A+T- phase (CU A+T- phase: 97.10±41.29 pg/ml; CU A-T- phase: 49.18±14.39 pg/ml; p<0.001). From preclinical to symptomatic stages of AD, plasma GFAP started to rise sharply as soon as CSF Aβ became abnormal and continued to increase until reaching its highest level during the AD dementia phase. The greatest slope of change was seen in plasma GFAP. This is followed by CSF p-tau181 and total-tau, and, to a lesser extent, then plasma p-tau181. In contrast, the changes in plasma NfL, Aβ42/Aβ40, Aβ42, and Aβ40 were less pronounced. Of note, these plasma biomarkers exhibited smaller dynamic ranges than their CSF counterparts, except for GFAP which was the opposite. Plasma GFAP and p-tau181 were tightly associated with AD pathologies and amyloid tracer uptake in widespread brain areas. Plasma GFAP could accurately identify CSF Aβ42 (area under the curve (AUC)=0.911) and Aβ PET (AUC=0.971) positivity. Plasma p-tau181 also performed well in discriminating Aβ PET status (AUC=0.916), whereas the discriminative accuracy was relatively low for other plasma biomarkers.

This study is the first to delineate the trajectories of plasma biomarkers throughout the Alzheimer's continuum in the Chinese population, providing important implications for future trials targeting plasma GFAP to facilitate AD prevention and treatment.