A central unresolved problem in research on Alzheimer disease is the nature of the molecular entity causing dementia. Here we provide the first direct experimental evidence that a defined molecular species of the amyloid-B protein interferes with cognitive function. Soluble oligomeric forms of amyloid-B, including trimers and dimers, were both necessary and sufficient to disrupt learned behavior in a manner that was rapid, potent and transient; they produced impaired cognitive function without inducing permanent neurological deficits. Although B-amyloidosis has long been hypothesized to affect cognition, the abnormally folded protein species associated with this or any other neurodegeneratve disease has not previously been isolated, defined biochemically and then specifically characterized with regard to its effects on cognitive function. The biochemical isolation of discrete amyolid-B moieties with pathophysiological properties sets the stage for a nex approach to studying the molecular mechanisms of cognitive impairment in Alzheimer disease and related neurodegenerative disorders.