Regulatory region single nucleotide polymorphisms of the apolipoprotein E gene and the rate of cognitive decline in Alzheimer's disease

Abstract

The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) in the regulatory regions of the apolipoprotein E (APOE) gene modify the well-established epsilon4-associated risk for Alzheimer's disease (AD). Sequencing of the APOE gene regulatory regions revealed four previously reported promoter SNPs and one novel SNP in the previously described macrophage enhancer (ME.1). In addition, we also studied the two classic allelic missense SNPs that define epsilon2/epsilon3/epsilon4 status in a case-control association study. Analysis of pair-wise linkage disequilibrium (LD) of the five regulatory region SNPs with classic APOE SNPs revealed a previously unreported 7 kb LD block covering the entire APOE gene, part of the promoter and 3' enhancer region. We report here that in a case-control association study (N=719) of the seven SNPs, the genotype at codon 112 captures all the information required to assess disease risk. To explore correlations with quantitative traits, 169 patients were studied in whom rates of cognitive decline were available. In addition to the epsilon4 allele, two regulatory region SNPs were associated with the rate of cognitive decline in AD patients. This study highlights the effect of APOE gene variation on risk of AD and rate of cognitive decline and demonstrates that a single SNP, which confers epsilon4 status, captures all of the risk of developing AD but two SNPs in the regulatory region may affect the rate of cognitive decline in AD patients.

Age-related macular degeneration and functional promoter and coding variants of the apolipoprotein E gene

“…In that context, LD was demonstrated between the promoter variants and the e-haplotypes, suggesting a diseasemodifying role of the cis-regulatory variants [Belbin et al, 2007;Yu et al, 2007].…”

Promoter polymorphisms which modulate BACE1 expression are associated with sporadic Alzheimer's disease

“…Insight into the regulation of BACE1 expression may aid identification of mechanisms that lead to disease, illuminate the role of BACE1 in normal biology, and suggest approaches to inhibit BACE1 therapeutically. Moreover, polymorphic variability within a gene promoter can affect gene expression and has previously been associated with age-related neurodegeneration [Lambert et al, 2001;Belbin et al, 2007;Guyant-Mar echal et al, 2007;Rodr ıguez-Rodr ıguez et al, 2007]. Genetic variants in the BACE1 promoter region are therefore appropriate for study to elucidate mechanisms of AD.…”

Apolipoprotein E ε-4 as a genetic determinant of Alzheimer’s disease heterogeneity

“…14 The APOE gene is highly polymorphic, with the two most extensively studied single nucleotide polymorphisms resulting in an interchangeable arginine (Arg) to cysteine (Cys) substitution at amino acid positions 112 and 158, corresponding to the ε-2 (rs7412) and ε-4 (rs429358) alleles (and therefore E2 and E4 protein isoforms), respectively. 15 Individuals with the APOE ε-4 allele are 15 times more likely to develop AD compared with noncarriers.…”