Pronounced impact of Th1/E47cs mutation compared with -491 AT mutation on neural APOE gene expression and risk of developing Alzheimer's disease

Possession of the apolipoprotein E (APOE) epsilon 4 allele is the most frequently associated genetic susceptibility factor for Alzheimer's disease (AD), Recently, new polymorphisms in the regulatory region of the APOE gene have been described. We analysed the effects of three of these mutations (-491 AT, -427 CT and Th1/E47cs) on disease risk in a large case-control study, and tested their impacts on APOE allelic expression in brain tissues, The Th1/E47cs T allele was associated with an increased risk of occurrence of AD, while the -491 T allele was associated with a decreased risk, independently of the APOE epsilon 2/epsilon 3/epsilon 4 polymorphism effect, However, the impact of the Th1/E47cs mutation was the strongest. The -427 CT polymorphism was not associated with the disease, In AD subjects heterozygous for the epsilon 4 allele, analysis of allelic expression showed that the relative expression levels of the epsilon 4 allele were higher than those of the corresponding controls, Consistent with epidemiological data, the relative level of expression of the epsilon 4 allele was modified accordingly to the presence or absence of the two main promoter polymorphisms, indicating, in vivo, the deleterious effect of the Th1/E47cs T allele and the protective effect of the -491 T allele in population.