We show that the synaptic proteins measured in this study are elevated in those with likely AD pathologically (i.e. atypical AD) but not in those with probable FTD pathology. Elevated levels of synaptic proteins in CSF are thought to reflect loss of synapses and therefore decreased concentration in the brain as proteins leak into the surrounding fluid. This pattern is well reported in AD, particularly for neurogranin but also for SNAP-25 and synaptotagmin-1 [2, 4, 5, 7,8,9, 12,13,14]. This study confirms those findings in a group with an atypical form of AD (mainly the logopenic variant of PPA).
It is unclear whether increased synaptic protein concentrations in CSF in AD but not FTD reflect the topography of volume loss, with anatomical targets of AD including areas rich in particular proteins, or instead the pathological process underlying AD [6, 9]. Neurogranin is mainly expressed in the cortex, amygdala, and hippocampus and enhances synaptic plasticity, critical for long term potentiation in the hippocampus and therefore learning and memory [2, 12, 20, 21]. Increased expression in regions affected in AD (i.e. hippocampus and parietal and temporal cortices) may explain the elevated levels of neurogranin in CSF from people with AD but not FTD, with greater synapse loss in these areas. However, in one previous study comparing neurogranin concentrations in typical and atypical AD, concentrations were higher in atypical AD (posterior cortical atrophy) than in controls, but higher still in amnestic AD . Along with a lack of correlation between neurogranin concentrations and regional volumes, this suggests that the specificity of increased neurogranin to AD may be related to both the underlying pathogenesis of AD itself, as well as the anatomical involvement. Less is known about the anatomical distribution of SNAP-25 and synaptotagmin-1, although there appears to be relatively diffuse expression throughout the cortex [22,23,24], again suggestive that there may be some specific association with AD pathology rather than topography.
Synaptic markers were significantly correlated with total-tau concentration in both biomarker groups. Total-tau is significantly increased in the CSF of individuals with AD and to a lesser extent in those with FTD . This correlation with total-tau has been reported elsewhere for each of the synaptic biomarkers, though not in FTD [2, 8, 13, 14], and is likely to represent the association of both total-tau and the synaptic biomarker concentration with the extent of neurodegeneration. Additionally, in the FTD biomarker group only, presynaptic SNAP-25 and synaptotagmin-1 concentrations correlated with Aβ42 concentration. In previous studies, the same correlation has been found with SNAP-25 and synaptotagmin-1 in controls but not in AD (where Aβ42 concentration is reduced) [13, 14]. It is unclear what this correlation represents, although a similar association with Aβ42 in an FTD group has been shown with other proteins .
In the present study, we also stratified participants by their probable frontotemporal lobar degeneration pathology to investigate any relationship with the underlying proteinopathy. While there were no significant differences in synaptic concentrations between those with probable tau and TDP-43 pathology, there was a trend to higher concentrations in the tau group across most synaptic biomarkers. Interestingly, one recent study revealed a positive correlation between CSF neurogranin concentration and postmortem tau neurofibrillary tangle pathology , suggesting a specific association with AD-tau pathology. Further work is therefore needed in larger groups with underlying non-AD tauopathies, as there may be specific associations of synaptic protein concentrations with particular disorders.
The lack of elevation of CSF synaptic protein concentrations in FTD biomarker group remains unexplained, particularly as synaptic dysfunction is well described in FTD . As discussed above, this may represent the anatomical distribution of particular synaptic proteins measured (suggesting investigation of other markers that are expressed more widely across the cortex) or the specificity of their loss to the AD pathological process. It could also represent the extent of dysfunction (e.g. being of lower magnitude in FTD compared with AD, suggesting improvement in the sensitivity of current assays may be important). Another issue is that synaptic proteins are processed into fragments before being released into CSF [10, 21], and therefore, future assays should investigate alternative fragments of these proteins.
The limitations of this study include the relatively small sample size, especially of the FTD subgroups with probable tau and TDP-43 pathology. Additionally, the atypical AD group only included those with PPA clinically, particularly those with lvPPA, although patients with a bvFTD phenotype have also been reported to have underlying AD pathology on occasion . Replication of these findings in a larger cohort would strengthen interpretation of our findings. Moreover, although we have reported a specificity of synaptic biomarkers to AD consistent with the existing literature, this study is the first to explore SNAP-25 and synaptotagmin-1 in FTD and verification is needed from independent cohorts. The cross-sectional design limits our evaluation of these synaptic proteins as prognostic biomarkers. Longitudinal measurements would enable investigations of CSF synaptic concentrations over time and whether these relate to cognitive performance and structural loss, which are important endpoints for clinical trials.