Familial AD (FAD) is most frequently caused by mutations in the genes encoding the γ-secretase-component, one of the three components of the amyloid precursor protein (APP) processing pathway, which is encoded by the presenilin-1 (PS1) and presenilin-2 (PS2) genes, or by mutations in the APP gene itself, whereas a growing consensus suggests that sporadic AD (SAD) is more likely caused by impaired clearance of Aβ. This evidence concerns the gene PSEN2 and familial Alzheimer disease.