APPL1 and Alzheimer disease: Our findings provide strong in vivo evidence implicating APPL1 as a key molecular intermediate in a pathogenic cascade propelled by causative and risk genes for AD that lead to abnormal rab5 early endosome signaling and neurodegeneration of BFCN, preceding and predicting the cortical spread of Alzheimer's pathology (Schmitz and Nathan Spreng, 2016; Schmitz et al., 2018).