Early-onset Alzheimer disease in an Italian family with presenilin-1 double mutation E318G and G394V.

The genetic form of Alzheimer disease (FAD) accounts for about 5% of total Alzheimer disease (AD) cases, and the discovery of FAD-linked genes has shed new light on AD pathogenic mechanism. The presenilins genes (PSEN-1 and PSEN-2) carry the large majority of FAD-linked mutations. Here, we report an Italian kindred with FAD and PSEN-1 double mutation E318G + G394V that clearly cosegregates with the pathology. The E318G mutation has not an assessed pathogenic function, but some data have highlighted a role as a risk factor for AD in a predisposed familiar background. The G394V mutation was still described in association to an AD case with reported (but not demonstrated) familiar cosegregation. In an attempt to better characterize the biochemical effect of this double mutation, we assessed Aβ(1-40) and Aβ(1-42) concentrations in conditioned media from primary skin fibroblasts obtained from AD-affected and healthy family members. We did not find any modification of the Aβ(1-42)/Aβ(1-40) ratio, suggesting that this double mutation might be involved in early-onset AD etiopathogenesis by affecting a PSEN-1 function other than γ-secretase activity.