Early endosomal changes, a prominent pathology in neurons early in Alzheimer's disease, also occur in neurons and peripheral tissues in Down syndrome. While in Down syndrome models increased amyloid-β protein precursor (AβPP) expression is known to be a necessary contributor on the trisomic background to this early endosomal pathology, increased AβPP alone has yet to be shown to be sufficient to drive early endosomal alterations in neurons. Comparing two AβPP transgenic mouse models, one that contains the AβPP Swedish K670N/M671L double mutation at the β-cleavage site (APP23) and one that has the AβPP London V717I mutation near the γ-cleavage site (APPLd2), we show significantly altered early endosome morphology in fronto-parietal neurons as well as enlargement of early endosomes in basal forebrain cholinergic neurons of the medial septal nucleus in the APP23 model, which has the higher levels of AβPP β-C-terminal fragment (βCTF) accumulation. Early endosomal changes correlate with a marked loss of the cholinergic population, which is consistent with the known dependence of the large projection cholinergic cells on endosome-mediated retrograde neurotrophic transport. Our findings support the idea that increased expression of AβPP and AβPP metabolites in neurons is sufficient to drive early endosomal abnormalities in vivo, and that disruption of the endocytic system is likely to contribute to basal forebrain cholinergic vulnerability.