Abstract Background Increased CSF levels of a number of synaptic markers have been reported in Alzheimer’s disease (AD), but little is known about their concentrations in frontotemporal dementia (FTD). We investigated this in three synaptic proteins, neurogranin, SNAP-25, and synaptotagmin-1. Methods CSF samples were analysed from 66 patients with a disorder in the FTD spectrum and 19 healthy controls. Patients were stratified by their tau to Aβ₄₂ ratio: those with a ratio of > 1 considered as having likely AD pathology, i.e. an atypical form of AD (‘AD biomarker’ group [n = 18]), and < 1 as likely FTD pathology (‘FTD biomarker’ group [n = 48]). A subgroup analysis compared those in the FTD group with likely tau (n = 7) and TDP-43 (n = 18) pathology. Concentrations of neurogranin were measured using two different ELISAs (Ng22 and Ng36), and concentrations of two SNAP-25 fragments (SNAP-25tot and SNAP-25aa40) and synaptotagmin-1 were measured via mass spectrometry. Results The AD biomarker group had significantly higher concentrations of all synaptic proteins compared to controls except for synaptotagmin-1 where there was only a trend to increased levels—Ng22, AD mean 232.2 (standard deviation 138.9) pg/ml, controls 137.6 (95.9); Ng36, 225.5 (148.8) pg/ml, 130.0 (80.9); SNAP-25tot, 71.4 (27.9) pM, 53.5 (11.7); SNAP-25aa40, 14.0 (6.3), 7.9 (2.3) pM; and synaptotagmin-1, 287.7 (156.0) pM, 238.3 (71.4). All synaptic measures were significantly higher in the atypical AD group than the FTD biomarker group except for Ng36 where there was only a trend to increased levels—Ng22, 114.0 (117.5); Ng36, 171.1 (75.2); SNAP-25tot, 49.2 (16.7); SNAP-25aa40, 8.2 (3.4); and synaptotagmin-1, 197.1 (78.9). No markers were higher in the FTD biomarker group than controls. No significant differences were seen in the subgroup analysis, but there was a trend to increased levels in those with likely tau pathology. Conclusions No CSF synaptic proteins have been shown to be abnormal in those with likely FTD pathologically. Higher CSF synaptic protein concentrations of neurogranin, SNAP-25, and synaptotagmin-1 appear to be related to AD pathology.