To investigate the effect of the overexpression of beta-amyloid precursor protein (APP) on the production of two major amyloid beta protein (Abeta) species, Abeta40 and Abeta42(43), we measured amounts of Abeta1-40 and Abeta1-42(43) in the plasma from 44 patients with Down's syndrome (DS) (age, 19-61 years) and 66 age-matched normal controls using enzyme-linked immunosorbent assays. Plasma concentrations of both Abeta1-40 and Abeta1-42(43) were increased about 3-fold and 2-fold, respectively, in DS patients compared with normal controls. Especially, the increases in plasma Abeta1-40 in DS patients were statistically higher than the 1.5-fold increase one might predict based on the gene dose of APP in DS. These findings showed that both Abeta1-40 and Abeta1-42(43) are increased in plasma in DS patients, the former more than the latter, suggesting that overexpression of APP and/or other genes may have different effects on the production of these two Abeta species in DS.