To identify the neuropathological causes of rapidly progressive dementia (RPD) in a large neurodegenerative brain bank.

A clear understanding of the underlying causes of RPD is needed to prioritize diagnostic testing, enhance diagnostic accuracy, and improve clinical management; yet most studies of RPD rely on clinical diagnoses with limited neuropathological confirmation. This approach may underestimate the contributions of rapidly progressive presentations of common age-related neurodegenerative diseases to RPD.

408/11738 (3.5 %) cases met RPD criteria. Patients with prion disease commonly presented with RPD (71%, 40/56), followed by patients with progressive supranuclear palsy/corticobasal degeneration (PSP/CBD: 6.8%, 162/2362) and other forms of frontotemporal lobar degeneration (FTLD: 8.5%, 50/585), Lewy body disease (LBD: 4.4%, 78/1762), and Alzheimer disease (AD: 1.7%, 68/3807). Average age-at-symptom onset was 69.1±10.4 years and disease duration 2.9±1.0 years. Symptomatic duration was fastest in patients with RPD due to prion disease (1.4±1.2 years). Comorbid cerebrovascular disease was reported in 23.5% of cases but was not associated with symptomatic duration. Although depression, psychosis, and sleep disturbances were common across all neuropathological groups, depression was most common in patients with FTLD (58%, p<0.015), whereas psychosis (75.6%, p<0.001) and sleep disturbance (60.3%, p<0.35) were most frequent in patients with LBD.

Rapidly progressive forms of neurodegenerative diseases accounted for 3.5% of cases in this neurodegenerative brain bank, with 87.7% of cases of RPD attributed to rapid presentations of common age-related neurodegenerative diseases. These findings highlight the need to consider neurodegenerative diseases in patients with RPD.