Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and dementia with Lewy bodies (DLB) are diseases associated with the accumulation of tau or alpha-synuclein. In AD, beta-amyloid (Abeta)-associated caspase activation and cleavage of tau at Asp421 (DeltaTau) may be an early step in neurofibrillary tangle (NFT) formation. To examine whether DeltaTau accumulates in other diseases not characterized by extracellular Abeta accumulation, we examined PiD, PSP, and CBD cases in comparison to those without extensive tau accumulation including frontotemporal lobar degeneration without Pick bodies (FTLD) and control cases. Additionally, we studied DeltaTau accumulation in DLB cases associated with intracellular alpha-synuclein. DeltaTau was observed in all disease cases except non-PiD FTLD and controls. These results demonstrate that the accumulation of DeltaTau may represent a common pathway associated with abnormal accumulation of intracellular tau or alpha-synuclein and may be relatively less dependent on the extracellular accumulation of Abeta in non-AD dementias.