APP and Alzheimer disease: Trisomy 21 Down syndrome (DS), which leads to AD in adulthood, is associated with early endosome disruption and early emerging cholinergic neurodegeneration in the basal forebrain due to intracellular accumulation of APP-βCTF, a C-terminal fragment of amyloid precursor protein (APP; Jiang et al., 2016, 2019; Kim et al., 2016; Colacurcio et al., 2018; Lauritzen et al., 2019).