Head injury and the risk of AD in the MIRAGE study

Objectives: It has been suggested in some studies that head injury is a ris k factor for AD, and that this risk is heightened among carriers of the APO E-is an element of 4 allele. We examined the effects of head injury and APO E genotype on AD risk in a large family study. Subjects: A total of 2,233 p robands 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) w ere ascertained at 13 centers in the United States, Canada, and Germany par ticipating in the MIRAGE (Multi-Institutional Research in Alzheimer Genetic Epidemiology) project. Information on head injury was collected by intervi ew of multiple informants and review of medical records. Nondemented relati ves 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 regre ssion analysis. To account for the unique biologic relationship between pro bands and their parents and siblings, odds of AD were computed using a gene ralized 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 unaf fected siblings and spouses. Results: Comparison of probands with their una ffected 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 injur y without loss of consciousness. The corresponding odds derived from the co mparison 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 d id 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 evalua ted 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 lacki ng is an element of 4 (OR = 3.3) than among is an element of 4 heterozygote s (OR = 1.8) or homozygotes (OR = 1.3). Conclusion: Head injury is a risk f actor for AD. The magnitude of the risk is proportional to severity and hei ghtened 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-i s an element of 4 compared with those having one or two is an element of 4 alleles, suggesting that these risk factors may have a common biologic unde rpinning.