Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer's Disease

The cerebral deposition of A beta(42), a neurotoxic proteolytic derivate of amyloid precursor protein (APP), is a central event in Alzheimer's disease (AD)(Amyloid hypothesis). Given the key role of APP-A beta metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, A beta degradation and clearance. We then used exome and genome sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effect of coding variants in these genes as potential susceptibility factors for AD, in a cohort composed of 332 sporadic and mainly late-onset AD cases and 676 elderly controls from North America and the UK. Our study shows that common coding variability in these genes does not play a major role for the disease development. In the single-variant association analysis, the main hits, none of which statistically significant after multiple testing correction (1.9e(-4)<0.05), were found to be rare coding variants (0.009%<1.4%) with moderate to strong effect size (1.84