A novel SORL1 mutation in a pedigree affected by early-onset Alzheimer's disease.

Familial cases of Alzheimer's disease (AD) with autosomal dominant transmission and early onset have a prevalence around 1%. Since only a small fraction of them has a monogenic inheritance due to APP, PSEN1, and PSEN2 genes, genetic studies are ongoing to unravel the missing heritability. By sequencing panels including multiple dementia-related genes, we identified a novel likely pathogenic mutation in SORL1 in a pedigree including five members affected by AD. This loss of function mutation may lead to a reduction of SORL1 receptor, worsening amyloidogenic burden. As the contribution of SORL1 mutations to heritability of AD is presently not well established, we think that it is very important to signal new familial (likely) pathogenic SORL1 mutations in order to define the actual genetic involvement of SORL1 in AD pathogenesis.