APP is central in the study of AD-DS, however, three-copies of other Hsa21 genes modulate aspects of AD pathology in preclinical animal models (Sheppard et al., 2012; García-Cerro et al., 2017; Naert et al., 2018; Wiseman et al., 2018; Tosh et al., 2021). This evidence concerns the gene APP and Alzheimer disease.