Background: A clear understanding of the neuropathological causes of RPD is needed to inform the diagnosis and treatment of patients with rapidly progressive dementia (RPD). Methods: Patients with <4.0 years from symptom onset to death were identified within the Mayo Clinic Neurodegenerative Brain Bank (1998-2020). Relevant clinical details were extracted from available records. Neuropathological diagnoses were assigned following standard protocols. Results: 310/8586 (3.6%) cases met RPD criteria. Relative to typically progressive cases, prion disease most commonly presented as RPD (74%, 32/43), followed by progressive supranuclear palsy/corticobasal degeneration (PSP/CBD: 7.5%, 142/1894), other frontotemporal lobar degeneration (FTLD: 5.7%, 32/561), Lewy body disease (LBD: 4.1%, 49/1202), and Alzheimer disease (AD: 1.8%, 48/2687). Average age-at-symptom onset was 69.5±10.4 years. Average disease duration was 2.9±1.0 years. Prion diseases had the most rapid disease course (1.6±1.3 years). Comorbid cerebrovascular disease (25.5%), and clinically symptomatic depression (41.3%), psychoses (37.1%), and sleep disturbances (39.4%) were common across groups. Only psychosis was associated with shorter disease duration (β=-0.31 years, CI95% -0.53, -0.082, controlling for age-at-symptomatic onset). Conclusions: Although prion disease commonly presented as RPD, atypical presentations of more prevalent neurodegenerative diseases accounted for most cases of RPD. Rapidly progressive variants of typical neurodegenerative diseases warrant consideration in clinical practice.