Mutations in the MAPT gene encoding tau protein cause neurodegenerative tauopathies. Recently, PET imaging with synaptic tracers revealed clinically relevant loss of synapses in primary tauopathies; however, the molecular mechanisms leading to synapse degeneration remain largely unknown. In this study, we examined post-mortem brain tissue from people who died with frontotemporal dementia with tau pathology (FTDtau) caused by the MAPT intronic exon 10+16 mutation, which increases splice variants containing exon 10 resulting in higher levels of tau with four microtubule binding domains. We used RNA sequencing and histopathology to examine temporal cortex and visual cortex, to look for molecular phenotypes compared to age, sex, and RNA integrity matched participants who died without neurological disease (n=12 per group). RNAseq reveals substantial downregulation of gene expression involved in synaptic function including downregulation of pathways involved in synaptic function. Examination of single cell sequencing data from organoids grown from people with the MAPT 10+16 mutation shows similar molecular pathways involved in synaptic function are downregulated by this mutation, indicating synaptic dysfunction is not only an end-stage phenomenon of the disease. Upregulated biological pathways in human MAPT 10+16 brain included those involved in transcriptional regulation, DNA damage response, and neuroinflammation. Histopathology confirmed increased pathological tau accumulation in temporal cortex, a loss of presynaptic protein staining, and region-specific increased colocalization of phospho-tau with synapses in temporal cortex. Our data indicate that synaptic pathology likely contributes to pathogenesis in frontotemporal dementia with tau pathology caused by the MAPT 10+16 mutation.