The findings in post‐mortem human brain, the Dp16 mouse model brain, and in vitro mechanistic studies combine to support our hypothesis that in DS increased APP gene dose–induced RAB5 hyperactivation acts as the central hub for dysregulation of endolysosomal function, changes which appear to contribute to AD‐linked pathogenesis in DS. The gene discussed is RAB5A; the disease is Dravet syndrome.