Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

A polymorphism in the regulatory region of APOE associated with risk for Alzheimer's dementia

Abstract

The ε4 allele of the apolipoprotein E gene (APOE) has been associated with an increased risk of developing Alzheimer's disease (AD; refs 1,2). However, it is apparent that the APOEε4 allele alone is neither necessary nor sufficient to cause the disease3–5. We have recently found three new polymorphisms within the APOftranscriptional regulatory region (M.J.A. et al., manuscript submitted) and now establish an association between one of these polymorphisms (−491A/T) and dementia as observed in Alzheimer's disease, in two independent clinical populations. The results suggest that homozygosity of a common variant (−491 A) is associated with increased risk for AD, and that this association is independent of APOEs4 status. In vitro studies suggest that the −491 A/T polymorphism may increase risk for AD by altering the level of ApoE protein expression.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Corder, E.H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of AD in late onset families. Science 261, 921–923 (1993.)

    Article  CAS  Google Scholar 

  2. Strittmatter, W.J. et al. Apolipoprotein E: high avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl. Acad. Sci. USA 90, 1977–1981 (1993).

    Article  CAS  Google Scholar 

  3. Institute on Aging/Alzheimer's Association Working Group. Apolipoprotein E genotyping in Alzheimer's disease. Lancet 347, 1091–1095 (1996).

  4. Payami, H., Kaye, J., Heston, L.L., Bird, T.D. & Schellenberg, G.D. Apolipoprotein E genotypes and Alzheimer's disease. Lancet 342, 737–738 (1993).

    Article  Google Scholar 

  5. Bennet, C. et al. Evidence that the APOE locus influences rate of disease progression in late onset familial Alzheimer's disease but is not causative. Am. J. Med. Genet. 60, 1–6 (1995).

    Article  Google Scholar 

  6. Santana, M.A. et al. Neuropsychology and Apolipoprotein E genotype in Alzheimer's disease. J. Neurol. (Supp. 2) 243, 591 (1996).

  7. Lendon, C.L. et al. Genetic Association studies between dementia of the Alzheimer's type and three receptors for apolipoprotein E in a Caucasian population. Neurosci. Lett. 222, 187 (1997).

    Article  Google Scholar 

  8. Blesa, R. et al. High apolipoprotein E epsilon 4 allele frequency in age-related memory decline. Ann. Neurol. 39, 548–551 (1996).

    Article  CAS  Google Scholar 

  9. Muros, M. & Rodriguez-Ferrer, C. Apolipoprotein E polymorphism influence on lipids, apolipoproteins and Lp(a) in a Spanish population underexpressing apo E4. Atherosclerosis 121, 13–21 (1996).

    Article  CAS  Google Scholar 

  10. Miyata, M. & Smith, J.D. Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and b-amyloid peptides. Nature Genet. 14, 55–61 (1996).

    Article  CAS  Google Scholar 

  11. Yamada, T., Kondo, A., Takamatsu, J., Tateishi, J. & Goto, I. Apolipoprotein E mRIMA in the brains of patients with Alzheimer's disease. J.Neurol. Sci. 129, 56–61 (1995).

    Article  CAS  Google Scholar 

  12. Lambert, J.C. et al. Distortion of allelic expression of apolipoprotein E in Alzheimer's disease. Hum. Mol. Genet. 6, 2151–2154 (1997).

    Article  CAS  Google Scholar 

  13. Taddei, K., Clarnette, R., Gandy, S.E. & Martins, R.N. Increased plasma apolipoprotein E (apoE) levels in Alzheimer's disease. Neurosci. Lett. 223, 29–32 (1997).

    Article  Google Scholar 

  14. McKhann, G. et al. Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's disease. Neurology 34, 939–944 (1984).

    Article  CAS  Google Scholar 

  15. Berg, L. & Morris, J.C. Alzheimer's disease. (Terry, R.D., Katzman, R. & Bick, K., eds.) 9–21 (New York, Raven Press, 1994).

    Google Scholar 

  16. Hixson, J.E. & Vernier, D.T. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with Hha I. J.Lipid Res. 31, 545–548 (1990).

    CAS  PubMed  Google Scholar 

  17. Garcia, M.A., Vázquez, J., Giménez, C., Valdivieso, F. & Zafra, F. Transcriptional factor AP-2 regulates human apolipoprotein E gene expression in astrocytoma cells. J. Neurosci. 16, 7550–7556 (1996).

    Article  CAS  Google Scholar 

  18. Higuchi, R. PCR Protocols. (Innis, M.A., Gelfand, D.H., Sninsky, J.J. & White, T.J., eds.) 177–183 (New York: Academic Press, 1990).

  19. Dignam, J.D., Lebovitz, R.M. & Roeder, R.G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acid Res. 11, 1475–1489 (1983).

    Article  CAS  Google Scholar 

  20. Morris, J.A. & Gardner, M.J. Calculating confidence intervals for relative risks (odds ratios) and standardised ratios and rates. British Med. J. 296, 1313–1316 (1988).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bullido, M., Artiga, M., Recuero, M. et al. A polymorphism in the regulatory region of APOE associated with risk for Alzheimer's dementia. Nat Genet 18, 69–71 (1998). https://doi.org/10.1038/ng0198-69

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0198-69

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing