The multiple systematic linkage studies performed in the early 90′ allowed the identification of highly penetrant mutations in three main causative genes responsible for the early-onset dominantly inherited forms of AD (i.e., APP, PSEN1, and PSEN2, coding respectively for amyloid precursor protein, presenilin-1 and presenilin-2) [11,12,13]. Here, PSEN2 is linked to Alzheimer disease.