From this collective evidence, we speculate that in C9orf72 and GRN genetic subgroups, there is a TDP‐43–based neurodegenerative mechanism at play which targets the salience network at very early stages of the disease, with initial proteinopathy burden manifesting as local functional changes (hypoperfusion and connectivity loss) before translating into gross structural atrophy, and finally presenting as bvFTD in the clinic. The gene discussed is C9orf72; the disease is proteostasis deficiencies.