Whether other risk factors for AD-driven early endosome and synaptic dysfunction, such as APOE4, BIN1, CD2AP, PICALM, RIN3, SORL1, and others (Nixon, 2017; Perdigão et al., 2020), act through APPL1 is unknown; nevertheless, the Thy1-APPL1 model further demonstrates that multiple molecular mechanisms leading to AD-like early endosome dysfunction are known to converge on rab5 and its regulation. This evidence concerns the gene PICALM and Alzheimer disease.