First, Down syndrome (DS), with three copies of APP, produces neuropathology virtually identical to AD (Glenner and Wong, 1984; Delabar et al., 1987) and APP locus duplications are sufficient to cause familial AD (Rovelet-Lecrux et al., 2006; Sleegers et al., 2006; McNaughton et al., 2012). Here, APP is linked to Down syndrome.