Synaptic dysfunction, Tau pathology and Neurodegeneration

Abstract Background Tau plays a prominent role in the synapse and has been shown to be closely related to neurodegeneration. Recent evidence show that cerebrospinal fluid (CSF) synaptic markers are related to CSF tau and degeneration. However, it is not clear whether synaptic dysfunction in combination with tau tangles is associated with neurodegeneration in the same brain regions. Our study aims to map in the brain the association of synaptic markers with tau and degeneration. Method We evaluated 147 individuals from the TRIAD cohort with CSF GAP43, SYT1, SNAP25, neurogranin (Ng), ptau217, neurofilament light protein (NfL) quantification, as well as tau positron emission tomography (PET), magnetic resonance imaging, and clinical assessments. One‐way ANOVA tested group differences on synaptic levels. Spearman correlation tested the association among synaptic proteins. Linear regressions tested the association between biomarkers. Voxel‐based morphometry (VBM) was considered as an index of neurodegeneration. Result We observed an increase in synaptic markers across age and the AD spectrum, reaching a plateau when cognition is affected (Figure 1A) . Among the synaptic markers, SNAP25 showed the greatest magnitude of change, on average, between young, aged cognitively unimpaired, mild cognitive impaired, and AD individuals (mean 62.44%). (Figure 1B‐C) . In addition, we found that all synaptic markers are significantly intercorrelated (Figure 1D) . Moreover, CSF ptau217 correlated with all synaptic biomarkers, GAP43 (β = ‐044), SYT1 (β = ‐0.41), SNAP25 (β = ‐0.59) and Ng (β = ‐0.25). Conversely, CSF NfL was strongly but only correlated with GAP43 (β = 0.62) (Figure 2) . Voxel‐wise correlation revealed that tau tangles measured by [ 18 F]‐MK6240 PET, was positively associated with SNAP25 in AD‐related regions, and VBM was associated with all synaptic markers, but more closely with GAP43. Furthermore, the interaction between synaptic markers and temporal meta‐ROI [ 18 F]‐MK6240 on VBM was significant for Ng and GAP43 (Figure 3) . Conclusion Our results support a heterogenous role of synaptic markers in the AD continuum and suggest that synaptic dysfunction in the presence of tau pathology may not be driving atrophy.