Apolipoprotein E ε4 Allele, Elevated Midlife Total Cholesterol Level, and High Midlife Systolic Blood Pressure Are Independent Risk Factors for Late-Life Alzheimer Disease

  1. Miia Kivipelto, MD;
  2. Eeva-Liisa Helkala, PhD;
  3. Mikko P. Laakso, MD, PhD;
  4. Tuomo Hänninen, PhD;
  5. Merja Hallikainen, MD, PhD;
  6. Kari Alhainen, MD, PhD;
  7. Susan Iivonen, MS;
  8. Arto Mannermaa, PhD;
  9. Jaakko Tuomilehto, MD, PhD;
  10. Aulikki Nissinen, MD, PhD; and
  11. Hilkka Soininen, MD, PhD
  1. From University of Kuopio, and Kuopio University Hospital, Kuopio; North Karelia Central Hospital, Joensuu; and the National Public Health Institute, Helsinki, Finland.

    Abstract

    Background: Presence of the apolipoprotein E (apoE) ε4 allele, which is involved in cholesterol metabolism, is the most important genetic risk factor for Alzheimer disease. Elevated midlife values for total cholesterol level and blood pressure have been implicated recently as risk factors for Alzheimer disease.

    Objective: To study the relative importance and the putative relationship among the apoE ε4 allele, midlife total cholesterol level, and midlife blood pressure as risk factors for late-life Alzheimer disease.

    Design: Prospective population-based study.

    Setting: Kuopio and Joensuu, eastern Finland.

    Participants: Participants were derived from random population surveys from 1972, 1977, 1982, and 1987. A total of 1449 persons (73%), 65 to 79 years of age, participated in the reexamination in 1998 (mean follow-up, 21 years).

    Measurements: Midlife blood pressure and total cholesterol level, apoE genotype, and development of Alzheimer disease during follow-up.

    Results: The apoE ε4 allele was an independent risk factor for Alzheimer disease, even after adjustment for midlife vascular risk factors and other confounders (odds ratio, 2.1 [95% CI, 1.1 to 4.1]). Similarly, elevated midlife values for serum total cholesterol level (odds ratio, 2.8 [CI, 1.2 to 6.7]) and systolic blood pressure (odds ratio, 2.6 [CI, 1.1 to 6.6]) were independent risk factors for Alzheimer disease, even after adjustment for apoE genotype and other confounding factors.

    Conclusions: The association between the apoE ε4 allele and Alzheimer disease does not seem to be mediated by vascular factors. The apoE ε4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for Alzheimer disease. The risk for Alzheimer disease from treatable factors—elevated total cholesterol level and blood pressure—appears to be greater than that from the apoE ε4 allele.

    Article and Author Information

    • Acknowledgments: The authors thank Petra Mäkinen for technical help and Veli Koistinen, Veikko Jokela, and Pirjo Halonen for consultations in statistical analysis.

    • Grant Support: By the Academy of Finland (grants 37573, 63645, 48138, 48950) and by erityisvaltionosuus (EVO) (grant 477268).

    • Requests for Single Reprints: Miia Kivipelto, MD, University of Kuopio, Department of Neuroscience and Neurology, PO Box 1627, 70211 Kuopio, Finland; e-mail, miia.kivipelto{at}uku.fi.

    • Potential Financial Conflicts of Interest: None disclosed.

    • Current Author Addresses: Drs. Kivipelto and Soininen: University of Kuopio, Department of Neuroscience and Neurology, PO Box 1627, 70211 Kuopio, Finland.

    • Dr. Helkala: University of Kuopio, Department of Public Health and General Practice, PO Box 1627, 70211 Kuopio, Finland.

    • Dr. Laakso: Kuopio University Hospital, Departments of Clinical Radiology and Neurology, PO Box 1777, 70211 Kuopio, Finland.

    • Dr. Hänninen: Kuopio University Hospital, Department of Neurology, PO Box 1777, 70211 Kuopio, Finland.

    • Dr. Hallikainen: Kuopio University Hospital, Department of Neurology, Building 4, PO Box 1777, 70211 Kuopio, Finland.

    • Dr. Alhainen: Memory Research Centre, Torikatu 17, 80100 Joensuu, Finland.

    • Ms. Iivonen: University of Kuopio, Department of Neuroscience and Neurology, PO Box 1627, 70211 Kuopio, Finland.

    • Dr. Mannermaa: Kuopio University Hospital, Chromosome and DNA Laboratory of the Division of Diagnostic Services, PO Box 1777, 70211 Kuopio, Finland.

    • Drs. Tuomilehto and Nissinen: National Public Health Institute, Diabetes and Genetic Epidemiology Unit, Mannerheimintie 166, 00300 Helsinki, Finland.

    • Author Contributions: Conception and design: M. Kivipelto, E.-L. Helkala, J. Tuomilehto, A. Nissinen, H. Soininen.

    • Analysis and interpretation of the data: M. Kivipelto, E.-L. Helkala, M.P. Laakso, J. Tuomilehto, A. Nissinen, H. Soininen.

    • Drafting of the article: M. Kivipelto, M.P. Laakso.

    • Critical revision of the article for important intellectual content: M. Kivipelto, E.-L. Helkala, M.P. Laakso, T. Hänninen, M. Hallikainen, K. Alhainen, S. Iivonen, A. Mannermaa, J. Tuomilehto, A. Nissinen, H. Soininen.

    • Final approval of the article: M. Kivipelto, E.-L. Helkala, M.P. Laakso, T. Hänninen, M. Hallikainen, K. Alhainen, S. Iivonen, A. Mannermaa, J. Tuomilehto, A. Nissinen, H. Soininen.

    • Statistical expertise: M. Kivipelto, E.-L. Helkala.

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    1. Ann Intern Med August 6, 2002 vol. 137 no. 3 149-155
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