The fidelity with which our Thy1-APPL1 replicates the endosomal dysfunction and neurodegenerative consequences seen in AD (Cataldo et al., 1996, 2000; Nixon, 2017), APP-based mouse models of AD and DS (Salehi et al., 2006; Jiang et al., 2010, 2016), and a mouse model of rab5 overactivation (Pensalfini et al., 2020), underscores the important contribution of APPL1 to mediating pathogenic actions of rab5, as suggested by earlier molecular studies of APPL1 in primary neuron cultures (Kim et al., 2016; Xu et al., 2016). Here, APP is linked to Dravet syndrome.