Recent studies in preclinical systems have demonstrated that an extra copy of other genes on Hsa21 can modulate APP biology (Garcia-Cerro et al., 2017; Wiseman et al., 2018, Alic et al., 2020, Tosh et al., 2021) and thus may alter the earliest stages of AD in individuals who have DS. The gene discussed is APP; the disease is Alzheimer disease.