The Association of Amyloid‐β and Tau With Synaptic Dysfunction in Alzheimer's Disease

Abstract

ABSTRACT Objective To clarify the relative contributions of amyloid and tau to synaptic dysfunction in Alzheimer's disease (AD). Methods We included 109 cognitively unimpaired and impaired individuals from the Geneva Memory Center with available CSF synaptic biomarkers (neurogranin, SNAP‐25, GAP‐43). Participants were stratified according to amyloid (A) and tau (T) status, and group comparisons and correlations between synaptic and AD biomarkers were assessed. Multiple linear regression models evaluated the independent associations of amyloid and tau with synaptic markers: Model I (n = 109) included CSF Aβ42 and p‐tau181, while Model II (n = 69) included amyloid PET centiloid and CSF p‐tau181. Mediation analyses were performed to further investigate these relationships. Findings were replicated in the ADNI cohort (n = 787). Results Synaptic biomarker levels were significantly higher in A+/T+ individuals compared with A−/T− and A+/T− groups (p < 0.001). CSF p‐tau181 strongly correlated with synaptic markers. In Model I, GAP43 was positively associated with both CSF Aβ42 (β = 0.31, 95% CI 0.23–0.40) and p‐tau181 (β = 0.94, 95% CI 0.84–1.04; p < 0.001). In Model II, lower amyloid PET centiloid (β = −0.31, 95% CI −0.46 to −0.16) and higher p‐tau181 (β = 1.02, 95% CI 0.86–1.19) predicted increased GAP43 (p < 0.001), with the same pattern of associations observed for neurogranin and SNAP‐25. The association between amyloid burden and synaptic biomarkers was largely indirect, statistically mediated by CSF p‐tau181. Results were replicated in ADNI. Interpretation Tau pathology showed strong associations with synaptic biomarkers, with a potential mediating role in the association between amyloid pathology and synaptic dysfunction. These findings support a central role of tau‐related processes in synaptic dysfunction in AD.