Plasma biomarkers as core mediators in functional network abnormalities: Evidence from a two-cohort study

Researchers have reported an association among amyloid beta (Aβ), tau deposition, and functional networks. Nevertheless, whether plasma biomarkers mediate this process remains unclear.

Three hundred and forty-eight participants with available plasma biomarkers, Aβ positron emission tomography (PET), and resting-state functional magnetic resonance imaging were obtained from two independent cohorts: SILCODE (n = 147) and ADNI (n = 201). Correlations among plasma biomarkers, functional connectivity, and global standardized uptake value ratio (SUVR) were assessed, and mediating effects were analyzed to explore underlying pathways.

Plasma biomarkers (p-tau181, p-tau217, neurofilament light, glial fibrillary acidic protein, Aβ42/40) demonstrated significant correlations with global SUVR and functional connectivity across networks (p < 0.05). Significant functional connectivity variations in different networks were observed across various Aβ stages, with differences mediated by plasma biomarkers. The crucial pathway exhibited fully mediated effects: Aβ PET SUVR-plasma biomarkers (mainly p-tau181 and p-tau217) - various functional networks.

Our study highlights the core mediating role of plasma biomarkers (mainly p-tau181 and p-tau217) in the progression of Aβ accumulation and in various functional network alterations.

Plasma biomarkers demonstrated significant mediating effects on Aβ deposition and functional network alterations across different Aβ stages in both East Asian and Western cohorts. Significant functional connectivity variations in different brain networks were observed throughout AD progression in two cohorts, particularly across various Aβ stages. Among all plasma biomarkers, p-tau217 and p-tau181 demonstrated more comprehensive and fully mediating effects compared to other biomarkers, influencing connectivity alterations in the various functional networks. The plasma biomarkers exhibited great potential for tracking pathologic progression, functional network alterations, and early disease identification in East Asian and Western cohorts.