Alzheimer's disease (AD) has become a leading public health issue due to our nation's burgeoning aging population. These issues are further complicated by the fact that neither preventive measure and effective treatment nor definitive in vivo diagnostic tool for this burdensome disease is currently available. Genetic, biochemical, and neuropathological data argue that Abeta amyloidosis, which originates from the Abeta amyloidogenic processing of a metalloprotein-amyloid precursor protein (APP), is the key event in AD pathology. However, neurochemical factors that impact upon this age-dependent protein disorder in brain are not well recognized. Considerable evidence is mounting that dyshomeostasis of the redox-active biometals, Cu and Fe, and oxidative stress contribute to the neuropathology of Alzheimer's disease (AD). Present data suggest that metals can interact directly with Abeta peptide, the principle component of Abeta amyloid that is one of the primary lesions in AD. The binding of metals to Abeta modulates several physiochemical properties of Abeta that are thought to be central to the pathogenicity of the peptide. First, we and others have shown that metals can promote the in vitro aggregation into tinctorial and disordered protein-Abeta amyloid. Studies have confirmed that insoluble amyloid plaques in post-mortem AD brain are abnormally enriched in Cu, Fe, and Zn. Conversely, metal chelators dissolve these proteinaceous deposits from postmortem AD brain tissue and attenuate cerebral Abeta amyloid burden in APP transgenic mouse models of AD. Second, we have demonstrated that redox-active Cu(II), and to a lesser extent, Fe(III), are reduced in the presence of Abeta with concomitant production of reactive oxygen species (ROS)-hydrogen peroxide (H2O2) and hydroxyl radical (OH.). These Abeta/metal redox reactions, which are silenced by redox-inert Zn(II), but exacerbated by biological reducing agents, may lead directly to the widespread oxidation damages observ...