Abstract: DS is the most common cause of Alzheimer’s disease (AD) and has a known AD-causing genetic variation which is trisomy of the whole or part of Homo sapiens chromosome 21 (HSA21) (Chen and Mobley, 2019a). Compared with AD, DS usually present with various symptoms and manifestations which are related to dysfunction of multiple body systems; the extra copies of the many genes present in HSA21 in DS can cause various developmental problems including neurodevelopmental deficits, which underlie the physical features in DS and may also contribute to the AD-related neurological symptoms of DS like cognition decline (Antonarakis et al., 2020). However, DS and AD share many pathological hallmarks including amyloid plaques and neurofibrillary tangles, synaptic and neuronal loss, dysregulation of endosomal pathway and others (Chen and Mobley, 2019a). The plaques and tangles have been studied extensively, while the dysfunction of early endosome has been found to be impacted long before appearance of amyloid deposits and neurofibrillary tangles with amyloid beta (Aβ) of varing length and phosphorylated tau as the main components, respectively (Nixon, 2017; Chen and Mobley, 2019a). Deficient endosome-mediated retrograde axonal transport of neurotrophic signals plays an important role in the neuropathogenesis in both DS and AD as continuing neurotrophic support is required for maintenance of mature neurons including the basal forebrain cholinergic neurons (BFCNs) whose degeneration has been linked to age-related cognitive dysfunction in DS and AD (Chen and Mobley, 2019b). HSA21 contains about 233 protein-coding genes with several encoding protein products demonstrated to contribute to different phenotypes in DS (Antonarakis et al., 2020) from the extensive researches in the different mouse models of DS, including Ts65Dn mouse which are segmentally trisomic for orthologs of about half of the protein coding genes located on HSA21 (Antonarakis et al., 2020). Accumulated evidence have attributed AD pathogenesis to toxic oligomeric Aβ and tau (Chen and Mobley, 2019a), however, recent clinical trials intending to target them in AD have yet to demonstrate considerable efficacy. Importantly, the 99 amino acid C-terminal fragment (β-CTF) of amyloid precursor protein (APP) was recently found to dysregulate endosomal and lysosomal systems as well as induce cholinergic neurodegeneration in an Aβ-independent manner (Xu et al., 2016; Nixon, 2017; Chen and Mobley, 2019b). Thus, reviewing the hypotheses for AD and discovering novel targets will be beneficial to combat AD and AD in DS.