PRONOUNCED IMPACT OF TH1 E47CS MUTATION COMPARED WITH -491 AT MUTATION ON NEURAL APOE GENE-EXPRESSION AND RISK OF DEVELOPING ALZHEIMERS-DISEASE/

Possession of the apolipoprotein E (APOE) epsilon 4 allele is the most frequently associated genetic susceptibility factor for Alzheimer's d isease (AD), Recently, new polymorphisms in the regulatory region of t he 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 exp ression in brain tissues, The Th1/E47cs T allele was associated with a n increased risk of occurrence of AD, while the -491 T allele was asso ciated with a decreased risk, independently of the APOE epsilon 2/epsi lon 3/epsilon 4 polymorphism effect, However, the impact of the Th1/E4 7cs mutation was the strongest. The -427 CT polymorphism was not assoc iated with the disease, In AD subjects heterozygous for the epsilon 4 allele, analysis of allelic expression showed that the relative expres sion levels of the epsilon 4 allele were higher than those of the corr esponding 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, ind icating, in vivo, the deleterious effect of the Th1/E47cs T allele and the protective effect of the -491 T allele in population.