Strong genetic evidence has been accumulated in favor of a central role of beta-amyloid precursor protein (APP) and beta-amyloid peptide (betaA4) in the pathogenesis of Alzheimer's disease (AD). We employed four newly developed APP and betaA4 antibodies and performed a comparative neuropathological study of patients with Down's syndrome (DS), early-onset familial AD and sporadic AD to investigate the distribution of APP and betaA4 plaque densities in the cerebral cortex of these disorders. Quantitative analysis of APP versus betaA4 plaques revealed that brains with early-onset familial AD and sporadic AD showed significantly more betaA4 plaques than brains with DS (P < 0.05). In contrast, APP plaques were more abundant in DS cerebral cortex (P < 0.02). These observations suggest that the development of pathological changes in DS brains does not parallel that observed in AD, which might be attributable to different causes in the pathogenesis of betaA4 formation. A comparison of these disorders may be useful to further complement our knowledge of the mechanisms leading to plaque development.