Raised levels of APP or Aβ have not been seen in mouse models lacking three-copies of App, including the Tc1, Ts1Cje, Dp2Tyb, Dp3Tyb, Dp10Yey, and Dp17Yey models (Salehi et al., 2006; Wiseman et al., 2018; Tosh et al., 2021), consistent with human clinical-genetic data that indicates that three-copies of APP are necessary for the development of AD-pathology in people who have DS (Korbel et al., 2009; Doran et al., 2017). This evidence concerns the gene APP and Alzheimer disease.