APP and Alzheimer disease: Here we take a combinatorial approach: assessing the effect of an additional copy of Hsa21 genes, using a series of DS mouse models (O'Doherty et al., 2005; Yu et al., 2010; Lana-Elola et al., 2016) on the biology of endogenous mouse APP and on APP generated from a partially humanized App knock-in allele that also carries AD-causal Swedish (NL) and Iberian (F) point mutations, which does not cause elevated mortality (AppNL-F; Fig. 1) (Saito et al., 2014).