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APOE and Alzheimer disease: a major gene with semi-dominant inheritance

Molecular Psychiatry volume 16, pages 903–907 (2011)Cite this article

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Abstract

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.

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References

  1. Saunders AM, Strittmatter WJ, Schmechel D, St George-Hyslop P, Pericack-Vance MA, Joo SH et al. Association of ApolipoproteinE allele 4 with late-onset familial and sporadic Alzheimer disease. Neurology 1997; 60: 439–446.

    Google Scholar 

  2. Farrer LA, Cupples A, Haines JH, Hyman B, Kukull WA, Mayeux R et al. Effects of age, sex and ethnicity on the association between Apolipoprotein E genotype and Alzheimer Disease. JAMA 1997; 278: 1349–1555.

    Article  CAS  Google Scholar 

  3. Corneveaux JJ, Myers AJ, Allen AN, Pruzin JJ, Ramirez M, Engel A et al. Association of CR, CLU and PICALM with Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals. Hum Mol Genet 2010; 19: 3295–3301.

    Article  CAS  Google Scholar 

  4. Bickeboller H, Campion D, Brice A, Amouyel P, Hannequin D, Didierjean O et al. Apolipoprotein E and Alzheimer disease: genotype-specific risks by age and sex. Am J Hum Genet 1997; 60: 439–446.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Myers RH, Schaefer EJ, Wilson P, D’Agostino R, Ordovas JM, Espino A et al. Apolipoprotein E element 4 association with dementia in a population based study: the Framingham Study. Neurology 1996; 46: 673–677.

    Article  CAS  Google Scholar 

  6. Seshadri S, Drachman DA, Lippa C . Apolipoprotein E4 allele and the lifetime risk of Alzheimer's disease. Arch Neurol 1995; 52: 1074–1079.

    Article  CAS  Google Scholar 

  7. Cupples A, Farrer LA, Sadovnick A, Relkin N, Whitehouse P, Green RC . Estimating risk curves for first degree relative of patients with Alzheimer's disease; the REVEAL study. Genet Med 2004; 6: 192–196.

    Article  Google Scholar 

  8. Thompson WD, Weissman M . Quantifying lifetime risk of psychiatric disorder. J Psychiatr Res 1981; 16: 113–126.

    Article  CAS  Google Scholar 

  9. Satagopan JM, Offit K, Foulkes W, Robson ME, Wacholder S, Eng CM et al. The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev 2001; 10: 467–473.

    CAS  PubMed  Google Scholar 

  10. Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet 2009; 41: 1094–1099.

    Article  CAS  Google Scholar 

  11. Gerdes LU, Jeune B, Ranberg KA, Nybo H, Vaupel JW . Estimation of apolipoprotein E genotype-specific relative mortality risks from the distribution of genotypes in centenarians and middle-aged men: apolipoprotein E gene is a ‘frailty gene,’ not a ‘longevity gene’. Genet Epidemiol 2000; 19: 202–210.

    Article  CAS  Google Scholar 

  12. Rocca WA, Cha RH, Waring SC, Kokmen E . Incidence of dementia and Alzheimer's disease: a reanalysis of data from Rochester, Minnesota, 1975-1984. Am J Epidemiol 1998; 148: 51–62.

    Article  CAS  Google Scholar 

  13. Letenneur L, Gilleron V, Commenges D, Helmer C, Orgogozo JM, Dartigues JF . Are sex and educational level independent predictors of dementia and Alzheimer's disease? Incidence data from the PAQUID project. J Neurol Neurosurg Psychiatry 1999; 66: 177–183.

    Article  CAS  Google Scholar 

  14. Chen S, Parmigiani G . Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 2007; 25: 1329–1333.

    Article  Google Scholar 

  15. Kamboh MI . Apolipoprotein E polymorphism as susceptibility to Alzheimer ‘s disease. Hum Biol 1995; 67: 195–215.

    CAS  PubMed  Google Scholar 

  16. Fullerton SM, Clark AG, Weiss KM, Nickerson DA, Taylor SL, Stengard JH et al. Apolipoprotein E variation at the sequence haplotype level: implications for the origin and maintenance of a major human polymorphism. Am J Hum Genet 2000; 67: 881–900.

    Article  CAS  Google Scholar 

  17. Yang Q, Flanders WD, Moonesinghe R, Ioannidis J, Guessous I, Khoury M . Using lifetime risk estimates in personal genomic profiles: estimation of uncertainty. Am J Hum Genet 2009; 85: 786–800.

    Article  CAS  Google Scholar 

  18. Schachter F, Faure-Delanef L, Guenot F, Rouger H, Froguel P, Lesueur-Ginot L et al. Genetic associations with human longevity at the APOE and ACE loci. Nat Genet 1994; 6: 29–32.

    Article  CAS  Google Scholar 

  19. Sebastiani P, Solovieff N, Puca A, Hartley SW, Melista E, Andersen S et al. Genetic signatures of exceptional longevity in humans. Science 2010: e-pub ahead of print.

  20. Green R, Roberts J, Cupples A, Relkin N, Whitehouse P, Brown T et al. Disclosure of APOE genotype for risk of Alzheimer's disease. N Engl J Med 2009; 361: 245–254.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by PHRC-GMAJ grants and by the US National Institute on Aging grants AG030653 and AG005133 (MIK). We thank F Clerget-Darpoux for helpful dissussions.

Author information

Authors and Affiliations

  1. Inserm UMRS-946, Paris, France

    E Genin

  2. Institut Universitaire d’Hématologie, Univ Paris Diderot, Paris, France

    E Genin

  3. INSERM U 614, Faculté de Médecine, Rouen, France

    D Hannequin, D Wallon & D Campion

  4. Centre National de Référence maladie d’Alzheimer du sujet jeune, France

    D Hannequin, D Wallon, F Pasquier, B Dubois & D Campion

  5. Department of Molecular Genetics, Neurodegenerative Brain Diseases Group, VIB, Antwerp, Belgium

    K Sleegers, N Brouwers, K Bettens & C Van Broeckhoven

  6. Institute Born-Bunge and University of Antwerp, Antwerp, Belgium

    K Sleegers, S Engelborghs, P De Deyn, N Brouwers, K Bettens & C Van Broeckhoven

  7. Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland

    M Hiltunen, S Helisalmi, S Vepsäläinen & H Soininen

  8. Neurology Service and CIBERNED, ‘Marqués de Valdecilla’ University Hospital (University of Cantabria), Santander, Spain

    O Combarros & I Mateo

  9. Centro de Biologia Molecular Severo Ochoa (UAM-CSIC) and CIBERNED, Universidad Autonoma, Cantoblanco, Madrid, Spain

    M J Bullido & F Valdivieso

  10. Memory Clinic and Department of Neurology, ZNA Middelheim, Antwerpen, Belgium

    S Engelborghs & P De Deyn

  11. INSERM U1061, University Montpellier 1, Montpellier, France

    C Berr

  12. Department of Nemology, CHRU de Lille, Lille, France

    F Pasquier, J C Lambert & P Amouyel

  13. Hopital Pitié Salpetriere, Paris, France

    B Dubois & P Amouyel

  14. Department of Neuroscience, Neurological Clinic, University of Pisa, Pisa, Italy

    G Tognoni, G Siciliano & M Mancuso

  15. INSERM U744, Lille, France

    N Fiévet, J C Lambert & P Amouyel

  16. Institut Pasteur de Lille, Lille, France

    N Fiévet, J C Lambert & P Amouyel

  17. Department of Internal Medicine,Universita degli Studi di Milano, Fondazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy

    B Arosio

  18. Genetic Molecular Unit, Hospital Universitario Central de Asturias, Oviedo, Spain

    E Coto & V Alvarez

  19. Department of Neuroscience, Section of Clinical Pharmacology, University of Cagliari, Cagliari, Italy

    M Del Zompo & P Piccardi

  20. UMR 894, INSERM Faculté de Médecine, Université Paris Descartes, Paris, France

    J Epelbaum

  21. Servicio de Neurologia, Hospital Universitario La Paz (UAM) and CIBERNED, Madrid, Spain

    A Frank-Garcia

  22. Department of Experimental Pathology, School of Medicine, University of Bologna, Bologna, Italy

    E Porcellini & F Licastro

  23. Department of Medical Science, Geriatric Unit & Gerontology-Geriatric Research Laboratory, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy

    A Pilotto & D Seripa

  24. Department of Internal Medicine Cardiology and Hepatology, University Hospital S. Orsola-Malpighi, Bologna, Italy

    P Forti

  25. IRCCS Oasi Maria SS, Troina, Italy

    R Ferri & P Bosco

  26. Department of Neurological Sciences, Dino Ferrari Center, University of Milan, Fondazione Ca Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy

    E Scarpini & D Galimberti

  27. Department of Geriatrics, Centre for Aging Brain, Memory Unit, University of Bari, Bari, Italy

    V Solfrizzi & F Panza

  28. Department of Neurological, Psychiatric Sciences, University of Florence, Florence, Italy

    S Sorbi & B Nacmias

  29. Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Roma, Italy

    G Spalletta & P Bossù

  30. Broca Hospital, University Paris Descartes, Paris, France

    O Hanon

  31. Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza, Italy

    G Annoni

  32. INSERM U897, Victor Segalen University, Bordeaux, France

    J-F Dartigues

  33. Department of Human Genetics and Alzheimer's Disease Research Centre, University of Pittsburgh, Pittsburgh, PA, USA

    M I Kamboh

  34. Department of Research, Centre Hospitalier du Rouvray, Sotteville les Rouen, France

    D Campion

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  1. E Genin
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  2. D Hannequin
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  46. F Licastro
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  47. H Soininen
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  48. J-F Dartigues
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  49. M I Kamboh
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  50. C Van Broeckhoven
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  51. J C Lambert
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  53. D Campion
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Corresponding author

Correspondence to D Campion.

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The authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website

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Genin, E., Hannequin, D., Wallon, D. et al. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry 16, 903–907 (2011). https://doi.org/10.1038/mp.2011.52

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