Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder characterized by neuronal loss in the frontal and temporal lobes. Despite progress in understanding which genes are associated with the aetiology of FTD (C9orf72, GRN and MAPT), the biological basis of how mutations in these genes lead to cell loss in specific cortical regions remains unclear. In this work we combined gene expression data for 16,912 genes from the Allen Institute for Brain Science atlas with brain maps of gray matter atrophy in symptomatic C9orf72, GRN and MAPT carriers obtained from the Genetic FTD Initiative study. A set of 405 and 250 genes showed significant positive and negative correlation, respectively, with atrophy patterns in all three maps. The gene set with increased expression in spared cortical regions, i.e., signaling regional resilience to atrophy, is enriched for neuronal genes, while the gene set with increased expression in atrophied regions, i.e., signaling regional vulnerability, is enriched for astrocyte genes. Notably, these results extend earlier findings from proteomic analyses in the same cortical regions of interest comparing healthy controls and patients with FTD. Thus, our analysis indicates that cortical regions showing the most severe atrophy in genetic FTD are those with the highest astrocyte density in healthy subjects. Therefore, astrocytes may play a more active role in the onset of neurodegeneration in FTD than previously assumed, e.g., through emergence of neurotoxic (A1) astrocytes.

Analysis of brain atrophy and local gene expression implicates astrocytes in Frontotemporal dementia