, Volume 5, Issue 4, pp 201–208 | Cite as

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. MartinEmail author
Original Article


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.


Alzheimer disease  APOE Single nucleotide polymorphisms Haplotype Age at onset 



We thank all the families whose participation made this project possible. This research was supported by grants from the National Institutes of Health: R01 AG20135, R01 NS31153, R01 AG19757, R01 AG021547, and grants from the Alzheimer Association, including a Zenith award ZEN-01–2935. We also gratefully acknowledge the personnel at the Duke Center for Human Genetics who played an important part in this research.


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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Kristin K. Nicodemus
    • 1
    • 2
  • Judith E. Stenger
    • 1
  • Donald E. Schmechel
    • 3
    • 4
  • Kathleen A. Welsh-Bohmer
    • 3
    • 4
  • Ann M. Saunders
    • 5
  • Allen D. Roses
    • 5
  • John R. Gilbert
    • 1
  • Jeffery M. Vance
    • 1
  • Jonathan L. Haines
    • 6
  • Margaret A. Pericak-Vance
    • 1
  • Eden R. Martin
    • 7
    Email author
  1. 1.Department of Medicine and Center for Human GeneticsDuke University Medical CenterDurhamUSA
  2. 2.Department of EpidemiologyJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  3. 3.Department of Psychiatry and Behavioral SciencesDuke University Medical CenterDurhamUSA
  4. 4.Joseph and Kathleen Bryan Alzheimer’s Disease Research CenterUSA
  5. 5.GlaxoSmithKline Research and DevelopmentUSA
  6. 6.Program in Human GeneticsVanderbilt University Medical CenterNashvilleUSA
  7. 7.Department of Medicine and Center for Human GeneticsDuke University Medical CenterDurhamUSA

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