IDENTIFICATION OF A RARE GENE VARIANT THAT IS ASSOCIATED WITH FAMILIAL ALZHEIMER DISEASE AND REGULATES APP EXPRESSION

Background
Genetic mutations leading to familial forms of Alzheimer disease (AD) have so far been reported for a few genes including APP, PSEN1 and PSEN2, UNC5C, PLD3, ABCA7, TTC3, and possibly ADAM10. With the advent of whole exome and whole genome sequencing approaches new genes and mutations are likely to be identified.
Methods
We analyzed the genetic cause of AD in a large multiplex family with an autosomal-dominant pattern of inheritance with LOAD. The family lacked pathogenic mutations of known AD genes. We performed whole-genome sequencing (WGS) in six family members (two affected and four unaffected) and prioritized rare, potential damaging, variants that segregated with disease. Variants were further characterized by subsequent molecular analyzes in human brain and cell culture models.
Results
We identified a single rare nonsynonymous variant co-segregating with AD. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to a loss-of-function of the gene. We further found a strong negative correlation between the identified gene and APP gene expression in human brain and in cells over-expressing the gene. The negative regulation of APP expression was only observed for the wt gene, but not for mutated forms, thus causing beside the loss of enzyme function a decoupling of both APPexpression and subsequent beta-amyloid formation. The identity of the gene will be presented on the conference.
Conclusions
This novel pathway strongly supports a causative association of the identified gene with the pathogenesis of AD.