APOE and Alzheimer disease: Given the importance of the endosomal–lysosomal pathway in both the production of Aβ (see review by Thinakaran and Koo, 2008) and the clearance of pathogenic proteins (see review by Nixon, 2017), we believe that APOE4-associated endosomal–lysosomal system dysregulation may be an early instigator of AD pathogenesis among APOE4 carriers.