APP and Alzheimer disease: The facts that heterozygous mutations in the APP and the presenilin (PSEN1 and PSEN2) genes are sufficient to cause rare, early onset forms of AD [13], and that PSEN1/PSEN2 are components of the γ-secretase complex [14] provide compelling evidence that APP abnormality is central to AD pathogenesis [15], at least in the rare familial cases.