S100-β, a calcium-binding astrocytic protein from chromosome 21, has been implicated in CNS function generally and the hippocampus in particular. Elevated levels of S100-β have been observed reliably in the brains of patients with Alzheimer's Disease and Down Syndrome. Groups of transgenic mice, carrying multiple S100-β gene copies, and nontransgenic controls were administered a series of behavioral tests (delayed spatial and nonspatial non-matching-to-sample, radial arm maze, socially acquired food preference) that assessed a wide range of cognitive functions. Consistent with the widespread presence of S100-β throughout the brain, transgenic mice exhibited learning or memory impairment on all tasks. The dementia-like cognitive profile of S100-β mice represents a promising model for studying comparable cognitive deficits associated with neurodegenerative diseases.