In contrast to AD-associated residues modulating β-secretase-mediated cleavage of APP, pathogenic mutations such as V717F occurring at the Υ-secretase processing site of APP increase the ratio of Aβ42/Aβ40, lead to elevated secretion of the intrinsically aggregation prone Aβ42, and increase the ratio of Aβ42/Aβ40. This evidence concerns the gene APP and Alzheimer disease.