In summary, by using a targeted exome-sequencing approach, we discovered a rare SEZ6 variant exclusive to AD members of a large Italian family carrying no typical FAD-linked mutations that might have a role in disease onset, in particular taking into account the already described involvement of SEZ6 in AD pathogenic mechanisms linked to amyloid-β (A4) precursor protein (APP) and brain physiology, even though the exact molecular pathway linking SEZ6 to AD is still unclear. Here, APP is linked to Alzheimer disease.