Aims: This immunohistochemical study quantified synaptic changes (synaptophysin and SNAP-25) in the frontal lobe of subjects with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD), and related these to APOE genotype and MAPT haplotype. Methods: Frontal neocortex (BA9) of post mortem brains from subjects with FTLD (n = 20), AD (n = 10) and age-matched controls (n = 9) were studied immunohistochemically for synaptophysin and SNAP-25. Results: We report that patients with FTLD have a significant increase in synaptophysin and depletion in SNAP-25 proteins compared to both control subjects and individuals with AD (P < 0.001). The FTLD up-regulation of synaptophysin is disease specific (P < 0.0001), and is not influenced by age (P = 0.787) or cortical atrophy (P = 0.248). The SNAP-25 depletion is influenced by a number of factors, including family history and histological characteristics of FTLD, APOE genotype, MAPT haplotype and gender. Thus, more profound loss of SNAP-25 occurred in tau-negative FTLD, and was associated with female gender and lack of family history of FTLD. Presence of APOE epsilon 4 allele and MAPT H2 haplotype in FTLD had a significant influence on the expression of synaptic proteins, specifically invoking a decrease in SNAP-25. Conclusions: Our results suggest that synaptic expression in FTLD is influenced by a number of genetic factors which need to be taken into account in future neuropathological and biochemical studies dealing with altered neuronal mechanisms of the disease. The selective loss of SNAP-25 in FTLD may be closely related to the core clinical non-cognitive features of the disease.