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From the Departments of Medicine, the Genetics Program (Drs. Guo, Green, and Farrer), Epidemiology and Biostatistics (Drs. Cupples and Farrer), and Neurology (Drs. Auerbach, Green, and Farrer), Boston University Schools of Medicine and Public Health, Boston, MA; the Psychiatrische Klinik der Technischen Universität (Dr. Kurz), Munich, Germany; the Geriatric Research Education and Clinical Center (Dr. Volicer), Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA; the Geriatric Neurobehavior and Alzheimer’s Center (Dr. Chui), Rancho Los Amigos Medical Center, Downey, CA; the Department of Medical Genetics (Dr. Sadovnick), University of British Columbia, Vancouver, Canada; the Wien Center for Alzheimer’s Disease and Memory Disorders (Dr. Duara), Mount Sinai Medical Center, University of Miami School of Medicine, Miami, FL; the Department of Neurology (Dr. DeCarli), University of Kansas Medical Center, Kansas City, KS; the Mayo Clinic (Dr. K. Johnson), Rochester, MN; the Department of Epidemiology (Dr. Guo), University of Alabama, Birmingham, AL; the Department of Neurology (Dr. Growdon), Massachusetts General Hospital, Boston, MA; the Program in Human Genetics (Dr. Haines), Vanderbilt University School of Medicine, Nashville, TN; the Department of Epidemiology (Dr. Kukull), University of Washington, Seattle, WA.
Address correspondence and reprint requests to Dr. Lindsay A. Farrer, Genetics Program, L320, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118; e-mail: farrer{at}neugen.bu.edu
OBJECTIVES: It has been suggested in some studies that head injury is a risk factor for AD, and that this risk is heightened among carriers of the APOE-
4 allele. We examined the effects of head injury and APOE genotype on AD risk in a large family study.
SUBJECTS: A total of 2,233 probands who met criteria for probable or definite AD and their 14,668 first-degree family members (4,465 parents, 7,694 siblings, and 2,509 spouses) were ascertained at 13 centers in the United States, Canada, and Germany participating in the MIRAGE (Multi-Institutional Research in Alzheimer Genetic Epidemiology) project. Information on head injury was collected by interview of multiple informants and review of medical records. Nondemented relatives and spouses served as control subjects for this study.
METHODS: Odds of AD for head trauma with or without loss of consciousness were computed by comparing probands with unaffected spouses using conditional logistic regression analysis. To account for the unique biologic relationship between probands and their parents and siblings, odds of AD were computed using a generalized estimating equation (GEE) Poisson regression approach. GEE logistic regression was used to examine the joint effects of APOE genotype and head injury on the odds of AD in probands and a control group comprised of unaffected siblings and spouses.
RESULTS: Comparison of probands with their unaffected spouses yielded odds ratios for AD of 9.9 (95% CI, 6.5 to 15.1) for head injury with loss of consciousness and 3.1 (2.3 to 4.0) for head injury without loss of consciousness. The corresponding odds derived from the comparison of probands with their parents and sibs were 4.0 (2.9 to 5.5) for head injury with loss of consciousness and 2.0 (1.5 to 2.7) for head injury without loss of consciousness. Head injury without loss of consciousness did not significantly increase the risk of AD in spouses (OR = 1.3; 95% CI, 0.4 to 4.1). The joint effects of head injury and APOE genotype were evaluated in a subsample of 942 probands and 327 controls (spouses and siblings). Head injury increased the odds of AD to a greater extent among those lacking 4 (OR = 3.3) than among 4 heterozygotes (OR = 1.8) or homozygotes (OR = 1.3).
CONCLUSION: Head injury is a risk factor for AD. The magnitude of the risk is proportional to severity and heightened among first-degree relatives of AD patients. The influence of head injury on the risk of AD appears to be greater among persons lacking APOE-4 compared with those having one or two 4 alleles, suggesting that these risk factors may have a common biologic underpinning.
Key words: AD—Head injury—APOE genotype.
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