Association of APOE ε2/ε3/ε4 and promoter gene variants with dementia but not cardiovascular mortality in old age

Authors

  • Bastiaan T. Heijmans,

    Corresponding author
    1. Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands
    2. Gerontology and Geriatrics Section, Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
    Current affiliation:
    1. Molecular Epidemiology Section, Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands.
    • Molecular Epidemiology, Leiden University Medical Centre, PO Box 9503, 2300 RA Leiden, The Netherlands.
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  • P. Eline Slagboom,

    1. Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands
    Current affiliation:
    1. Molecular Epidemiology Section, Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands.
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  • Jacobijn Gussekloo,

    1. Gerontology and Geriatrics Section, Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
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  • Simone Droog,

    1. Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands
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  • A. Margot Lagaay,

    1. Gerontology and Geriatrics Section, Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
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  • Cornelis Kluft,

    1. Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands
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  • Dick L. Knook,

    1. Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands
    2. Gerontology and Geriatrics Section, Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
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  • Rudi G.J. Westendorp

    1. Gerontology and Geriatrics Section, Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
    2. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
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Abstract

The common apolipoprotein E (APOE) alleles ε2, ε3, and ε4 are associated with the risk of dementia and cardiovascular disease. Recently, two functional variants (− 219G/T and −491A/T) were identified in the promoter of the APOE gene that enable a further characterization of the role of the APOE locus in disease. We investigated the contribution of these APOE gene variants to dementia and cardiovascular mortality in old age using a population-based cohort of 648 subjects aged 85 years and over (Leiden 85-Plus Study). Genotypes containing an APOE ε4 allele were associated with a 4.1-fold (95% CI, 2.2–7.7) increased risk of dementia as compared to the ε3/ε3 genotype in old subjects. Moreover, homozygosity for the −219T allele was found to be associated with a 2.4-fold (95% CI, 1.0–5.8) increased risk independently of ε2 and ε4; the −491A/T variant was not associated with dementia. Over a 10-year follow-up period, the risk of cardiovascular mortality was not increased among ε4 carriers (RR, 0.6; 95% CI, 0.4–1.0) or −219T homozygous subjects (RR, 1.1; 95% CI, 0.7–1.7), nor did it decrease among −491T homozygous subjects (RR, 1.4; 95% CI, 0.6–3.1). In conclusion, both the APOE ε2/ε3/ε4 and the −219G/T variant were identified as risk factors for dementia but not cardiovascular mortality in old age. Our results support the hypothesis that both the isoform and the amount of APOE may influence the risk of dementia. Furthermore, they emphasize that variation at the APOE locus has a higher impact on the risk of dementia than on the risk of cardiovascular disease in old age. © 2001 Wiley-Liss, Inc.

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