While multiple mechanisms are likely to contribute to the vulnerability of this pathway in neurons during aging and early in AD pathobiology, two extensively studied genetic causes of AD-like endosomal changes are chromosome 21 trisomy in DS (Cataldo et al., 2000, 2004, 2008; Takahashi et al., 2004; Jiang et al., 2010) and inheritance of the APOE4 allele (Cataldo et al., 2000; Nuriel et al., 2017; Zhao et al., 2017), the most important genetic risk factor for AD (Corder et al., 1993; Farrer et al., 1997; Bu, 2009; Liu et al., 2013). Here, APOE is linked to Alzheimer disease.