Understanding the molecular mechanisms underlying frontotemporal dementia (FTD) is essential for the development of successful therapies. Here we integrated transcriptomic and epigenomic analyses of postmortem human brains of FTD patients with mutations in MAPT, GRN and C9orf72 and detected common and distinct dysregulated cellular pathways between patient groups. Our results highlight that excitatory neurons are the most vulnerable neuronal cell type and that vascular aberrations are a common hallmark in FTD. Via integration of multi-omics data, we detected several transcription factors and pathways which regulate the strong neuroinflammation observed in FTD-GRN. Small RNA-seq data and verification experiments in cellular models identified up-regulated miRNAs that inhibit cellular trafficking pathways in FTD and lead to microglial activation. These findings shed light on novel mechanistic and pathophysiological hallmarks of FTD. The data represent the 1st phase of a multi-omics, multi-model data resource for FTD research which allows in-depth molecular research into disease mechanisms that will further mechanistic FTD research.