Immediate Communication

Molecular Psychiatry (2011) 16, 903–907; doi:10.1038/mp.2011.52; published online 10 May 2011

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

E Genin1,2, D Hannequin3,4, D Wallon3,4, K Sleegers5,6, M Hiltunen7, O Combarros8, M J Bullido9, S Engelborghs6,10, P De Deyn6,10, C Berr11, F Pasquier12,4, B Dubois13,4, G Tognoni14, N Fiévet15,16, N Brouwers5,6, K Bettens5,6, B Arosio17, E Coto18, M Del Zompo19, I Mateo8, J Epelbaum20, A Frank-Garcia21, S Helisalmi7, E Porcellini22, A Pilotto23, P Forti24, R Ferri25, E Scarpini26, G Siciliano14, V Solfrizzi27, S Sorbi28, G Spalletta29, F Valdivieso9, S Vepsäläinen7, V Alvarez18, P Bosco25, M Mancuso14, F Panza27, B Nacmias28, P Bossù29, O Hanon30, P Piccardi19, G Annoni31, D Seripa23, D Galimberti26, F Licastro22, H Soininen7, J-F Dartigues32, M I Kamboh33, C Van Broeckhoven5,6, J C Lambert12,15,16, P Amouyel12,13,15,16 and D Campion3,4,34

  1. 1Inserm UMRS-946, Paris, France
  2. 2Institut Universitaire d’Hématologie, Univ Paris Diderot, Paris, France
  3. 3INSERM U 614, Faculté de Médecine, Rouen, France
  4. 4Centre National de Référence maladie d’Alzheimer du sujet jeune, France
  5. 5Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium
  6. 6Institute Born-Bunge and University of Antwerp, Antwerp, Belgium
  7. 7Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
  8. 8Neurology Service and CIBERNED, ‘Marqués de Valdecilla’ University Hospital (University of Cantabria), Santander, Spain
  9. 9Centro de Biologia Molecular Severo Ochoa (UAM-CSIC) and CIBERNED, Universidad Autonoma, Cantoblanco, Madrid, Spain
  10. 10Memory Clinic and Department of Neurology, ZNA Middelheim, Antwerpen, Belgium
  11. 11INSERM U1061, University Montpellier 1, Montpellier, France
  12. 12Department of Nemology, CHRU de Lille, Lille, France
  13. 13Hopital Pitié Salpetriere, Paris, France
  14. 14Department of Neuroscience, Neurological Clinic, University of Pisa, Pisa, Italy
  15. 15INSERM U744, Lille, France
  16. 16Institut Pasteur de Lille, Lille, France
  17. 17Department of Internal Medicine,Universita degli Studi di Milano, Fondazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan Italy
  18. 18Genetic Molecular Unit, Hospital Universitario Central de Asturias, Oviedo, Spain
  19. 19Section of Clinical Pharmacology, Department of Neuroscience, University of Cagliari, Cagliari, Italy
  20. 20UMR 894, INSERM Faculté de Médecine, Université Paris Descartes, Paris, France
  21. 21Servicio de Neurologia, Hospital Universitario La Paz (UAM) and CIBERNED, Madrid, Spain
  22. 22Department of Experimental Pathology, School of Medicine, University of Bologna, Bologna, Italy
  23. 23Geriatric Unit & Gerontology-Geriatric Research Laboratory, Department of Medical Science, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
  24. 24Department of Internal Medicine Cardiology and Hepatology, University Hospital S. Orsola-Malpighi, Bologna, Italy
  25. 25IRCCS Oasi Maria SS, Troina, Italy
  26. 26Department of Neurological Sciences, Dino Ferrari Center, University of Milan, Fondazione Ca Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
  27. 27Department of Geriatrics, Centre for Aging Brain, Memory Unit, University of Bari, Bari, Italy
  28. 28Department of Neurological, Psychiatric Sciences, University of Florence, Florence, Italy
  29. 29Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Roma, Italy
  30. 30Broca Hospital, University Paris Descartes, Paris, France
  31. 31Department of Clinical Medicine and Prevention, University of Milano-Bicocca, Monza, Italy
  32. 32INSERM U897, Victor Segalen University, Bordeaux, France
  33. 33Department of Human Genetics and Alzheimer's Disease Research Centre, University of Pittsburgh, Pittsburgh, PA, USA
  34. 34Department of Research, Centre Hospitalier du Rouvray, Sotteville les Rouen, France

Correspondence: Dr D Campion, INSERM U 614, Faculté de Médecine, Centre Hospitalier du Rouvray, Sotteville les Rouen 76300, France. E-mail: dominique.campion@univ-rouen.fr

Received 28 March 2011; Accepted 1 April 2011; Published online 10 May 2011.

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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 10132 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.

Keywords:

APOE; Alzheimer; genetics; lifetime risks; epidemiology