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Neurology 2002;59:59-66
© 2002 American Academy of Neurology

Contribution of APOE promoter polymorphisms to Alzheimer’s disease risk

J. C. Lambert, PhD, L. Araria-Goumidi, BSc, L. Myllykangas, MD, C. Ellis, BSc, J. C. Wang, PhD, M. J. Bullido, PhD, J. M. Harris, BSc, M. J. Artiga, PhD, D. Hernandez, BSc, J. M. Kwon, MD, B. Frigard, MD, R. C. Petersen, MD, PhD, A. M. Cumming, PhD, F. Pasquier, MD, PhD, I. Sastre, BSc, P. J. Tienari, MD, PhD, A. Frank, MD, R. Sulkava, MD, PhD, J. C. Morris, MD, D. St. Clair, MD, D. M. Mann, PhD, F. Wavrant-DeVrièze, PhD, M. Ezquerra-Trabalon, PhD, P. Amouyel, MD, PhD, J. Hardy, PhD, M. Haltia, MD, PhD, F. Valdivieso, PhD, A. M. Goate, PhD, J. Pérez-Tur, PhD, C. L. Lendon, PhD and M. C. Chartier-Harlin, PhD

From the INSERM U508 (Drs. Lambert, Ezquerra-Trabalon, Amouyel, and Chartier-Harlin, and L. Araria-Goumidi), Institut Pasteur de Lille, Lille, France; Molecular Psychiatry Department (Drs. Lambert and Lendon and J. Harris), Division of Neuroscience, Queen Elisabeth Psychiatry Hospital, University of Birmingham, United Kingdom; Department of Pathology (Drs. Myllykangas and Haltia), University of Helsinki and Helsinki University Central Hospital, Finland; Department of Neuroscience (C. Ellis, D. Hernandez, and Drs. Wavrant-DeVrièze, Hardy, and Pérez-Tur), Mayo Clinic, Jacksonville, FL; Departments of Psychiatry (Drs. Wang and Goate) and Neurology (Drs. Kwon and Morris), Washington University School of Medicine, St. Louis, MO; Departamento de Biologia Molecular (Drs. Bullido, Artiga, and Valdivieso and I. Sastre) and Centro de Biologia Molecular Severo Ochoa (CSIC-UAM), Cantoblanco, Madrid, Spain; Centre de Gériatrie de Wasquehal-Molinel (Dr. Frigard), Wasquehal, France; Department of Neurology (Dr. Petersen), Mayo Clinic, Rochester, MN; Department of Molecular and Cell Biology (Drs. Cumming and Pérez-Tur), University of Aberdeen, United Kingdom; CHR et Université de Lille (Dr. Pasquier), Clinique Neurologique, Centre de la Mémoire, Hôpital Salengro, Lille, France; Department of Neurology (Dr. Tienari), Helsinki University Central Hospital, Finland; Servicio de Neurologia (Dr. Frank), Hospital Universitario la PAZ (UAM), Madrid, Spain; Department of Public Health and General Practice (Dr. Sulkava), University of Kuopio, Finland; Greater Manchester Neurosciences Centre (Dr. St Clair), Hope Hospital, Salford, United Kingdom; Laboratory Medicine Academic Group (Dr. Mann), Department of Medicine, Stopford Building, University of Manchester, United Kingdom; Unitat de Genètica Molecular (Dr. Pérez-Tur), Institut de Biomedicina de València-CSIC, València, Spain.

Address correspondence and reprint requests to Dr. Marie-Christine Chartier-Harlin, Unite INSERM U508, Institut Pasteur de Lille, 1 rue du Professor Calmette, BP 245, 59019 Lille, Cédex, France; e-mail: marie-christine.chartier{at}pasteur-lille.fr

Objective: To determine whether the effects of APOE promoter polymorphisms on AD are independent of the APOE-{epsilon}4 allele.

Background: Recently, the -491 A->T and -219 G->T polymorphisms located in the APOE promoter have been suggested to be risk factors for AD. However, the effects of these polymorphisms have not always been reproduced in case-control studies, possibly because of the strong linkage disequilibrium existing at this locus or the characteristics of the populations studied.

Methods: Data collection was performed from six independent samples (1,732 patients with AD and 1,926 control subjects) genotyped for APOE exon 4 and the two APOE promoter polymorphisms. The risks associated with the APOE polymorphisms for developing AD were estimated using logistic regression procedures and calculation of odds ratios with 95% CI adjusted by age, sex, and collection center. Independence of the APOE promoter polymorphisms was tested by stratification for APOE-{epsilon}4 and tertile design was used for age stratification.

Results: The independence of the -491 AA genotype was observed in the whole sample whereas the independence of the -219 TT genotype was observed only in the oldest population.

Conclusion: The -491 and -219 APOE promoter polymorphisms incur risk for AD in addition to risk associated with the APOE-{epsilon}4 allele, with age accentuating the effect of the -219 TT genotype. Because these polymorphisms appear to influence apoE levels, these results suggest that APOE expression is an important determinant of AD pathogenesis.




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