Notch-1 is a protein that influences cell fate decisions, with its expression occurring primarily during embryogenesis and development. However, Notch-1 is also expressed in the adult brain, in regions with high synaptic plasticity, particularly the hippocampus. Its role in adults is unknown; however, it may impact neurite outgrowth or cell differentiation in adult brain regions undergoing neurogenesis. Notch-1 is increased in Alzheimer's disease (AD); however, its expression in other CNS degenerative diseases has not been described. To begin to define the range of degenerative disorders where Notch-1 expression is altered, we examined Notch-1 immunoreactivity in a variety of neurodegenerative diseases to determine whether its increase is selective for AD. We examined sections of hippocampus from 13 AD, 13 classical Pick's disease (PiD; with Pick bodies), 4 dementia lacking distinctive histopathology (DLDH) and 8 control brains, emphasizing hippocampal (dentate gyrus) pathology. We determined that Notch-1 immunoexpression is increased in AD and PiD relative to control cases. DLDH cases were not significantly different than control cases with respect to Notch-1 expression. Given the increase in Notch-1 immunoexpression in AD and PiD, two diseases where abnormal tau aggregates are present, and the lack of Notch-1 immunoexpression in DLDH (where tau aggregates are absent), we cannot rule out the possibility that tau aggregates are associated with Notch-1 expression in neurodegenerative diseases.