APP and Alzheimer disease: Though the increase in γ-secretase activity caused by RAP1 overexpression was modest, it is important considering AD can be caused by an increase in overall γ-secretase activity as seen in the APPswe mutation (Citron et al. 1992; Weggen and Beher 2012) or in trisomy 21, in which there is a 50% increase in the number of APP genes.