Comprehensive association analysis of APOE regulatory region polymorphisms in Alzheimer disease

Kristin K Nicodemus, Judith E Stenger, Donald E Schmechel, Kathleen A Welsh-Bohmer, Ann M Saunders, Allen D Roses, John R Gilbert, Jeffery M. Vance, Jonathan L Haines, Margaret A Pericak-Vance, Eden R Martin

Research output: Contribution to journalArticlepeer-review


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 APOE-4 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. Despite 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 APOE-4 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 linkage disequilibrium, may confer some additional risk for developing AD beyond the risk due to APOE-4; however, the effect independent of APOE-4 is likely to be small.

Original languageEnglish
Pages (from-to)201-8
Number of pages8
Issue number4
Publication statusPublished - Dec 2004


  • Age of Onset
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease
  • Apolipoprotein E4
  • Apolipoproteins E
  • Case-Control Studies
  • Family Health
  • Female
  • Genetic Predisposition to Disease
  • Haplotypes
  • Humans
  • Linkage Disequilibrium
  • Male
  • Polymorphism, Genetic
  • Risk Factors
  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.


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