Comprehensive association analysis of APOE regulatory region polymorphisms in Alzheimer disease

Several recent case-control studies have examined the association between single nucleotide polymorphisms (SNPs) in the promoter region of the apolipoprotein E gene (APOE) and risk of Alzheimer disease (AD), with conflicting results. We assessed the relation between five APOE region SNPs and risk of AD in both case-control and family-based analyses. We observed a statistically significant association with the +5361T allele in the overall case-control analysis (P value=0.04) after adjusting for the known effect of the APOE4 allele. Further analysis revealed this association to be limited to carriers of the APOE-4 allele. Age-stratified analyses in the patients with age at onset of 80 years or greater and age-matched controls showed that the -219T allele (P value=0.009) and the +113C allele (P value=0.03) are associated with increased risk of AD. De-spite these. findings, haplotype and family-based association analyses were unable to provide evidence that the APOE region SNPs influenced risk of AD independent of the APOE4 allele. In addition to risk. we tested for association between the SNPs and age at onset of AD. but found no association in the case-control or family based analyses. In conclusion, SNPs +5361. or a SNP in strong link-age, disequilibrium, may confer some additional risk for developing AD beyond the fisk due to APOE4: however. the effect independent of APOE4 is likely to be small.