The mechanism by which mutations in the presenilin (PS) genes cause the most aggressive form of early-onset Alzheimer's disease (AD) is unknown, but fibroblasts from mutation carriers secrete increased levels of the amyloidogenic Aβ42 peptide, the main component of AD plaques. We established transfected cell and transgenic mouse models that coexpress human PS and amyloid β-protein precursor (APP) genes and analyzed quantitatively the effects of PS expression on APP processing. In both models, expression of wild-type PS genes did not alter APP levels, α- and β-secretase activity and Aβ production. In the transfected cells, PS1 and PS2 mutations caused a highly significant increase in Aβ42 secretion in all mutant clones. Likewise, mutant but not wild-type PS1 transgenic mice showed significant overproduction of Aβ42 in the brain, and this effect was detectable as early as 2-4 months of age. Different PS mutations had differential effects on Aβ generation. The extent of Aβ42 increase did not correlate with presenilin expression levels. Our data demonstrate that the presenilin mutations cause a dominant gain of function and may induce AD by enhancing Aβ42 production, thus promoting cerebral β-amyloidosis.