RISK FOR ALZHEIMERS-DISEASE CORRELATES WITH TRANSCRIPTIONAL ACTIVITY OF THE APOE GENE

While the epsilon 4 allele of apolipoprotein E (APOE, gene; ApoE, prot ein) is widely accepted as a major genetic risk factor for the late on set form of Alzheimer's disease (AD), recent evidence points to variat ions in ApoE levels as another important factor. We have previously re ported that a common variant in the regulatory region of APOE(-491A) i s associated with risk for late onset AD. In this report we analyze th e association of another APOE promoter polymorphism (-427T/C) with AD in two case-control clinical samples and demonstrate a correlation bet ween APOE promoter transcriptional activity and risk for AD. The assoc iation studies show that the allelic variant (-427C) and the haplotype [-491A-427C] of the APOE promoter are associated with increased risk for AD. Study of the transcriptional activity of the common haplotypes defined by combination of the -491 and -427 alleles indicated that th e risk for late onset AD positively correlates with transcriptional ac tivity of the APOE gene, suggesting that increases in the local expres sion of ApoE could be responsible for the association of APOE promoter polymorphism with AD.