A-beta-1-40, a major component of Alzheimer's disease cerebral amyloid, is present in the cerebrospinal fluid and remains relatively soluble at high concentrations (less than or equal to 3.7 mM). Thus, physiological factors which induce A-beta amyloid formation could provide clues to the pathogenesis of the disease. It has been shown that human A-beta specifically and saturably binds zinc. Here, concentrations of zinc above 300 nM rapidly destabilized human A-beta-1-4-0 solutions, inducing tinctorial amyloid formation. However, rat A-beta-1-40 binds zinc less avidly and is immune to these effects, perhaps explaining the scarcity with which these animals form cerebral A-beta amyloid. These data suggest a role for cerebral zinc metabolism in the neuropathogenesis of Alzheimer's disease.