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March 01, 1995; 45 (3) Brief Communications

Synergistic Effects of Traumatic Head Injury and Apolipoprotein-epsilon4 in Patients With Alzheimer's Disease

R. Mayeux, R. Ottman, G. Maestre, C. Ngai, M.-X. Tang, H. Ginsberg, M. Chun, B. Tycko, M. Shelanski
First published March 1, 1995, DOI: https://doi.org/10.1212/WNL.45.3.555
R. Mayeux
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R. Ottman
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G. Maestre
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C. Ngai
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M.-X. Tang
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H. Ginsberg
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M. Chun
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B. Tycko
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M. Shelanski
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Synergistic Effects of Traumatic Head Injury and Apolipoprotein-epsilon4 in Patients With Alzheimer's Disease
R. Mayeux, R. Ottman, G. Maestre, C. Ngai, M.-X. Tang, H. Ginsberg, M. Chun, B. Tycko, M. Shelanski
Neurology Mar 1995, 45 (3) 555-557; DOI: 10.1212/WNL.45.3.555

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Abstract

Article abstract-The apolipoprotein-epsilon4 allele increases the risk of Alzheimer's disease (AD), but cerebral deposition of beta-amyloid with age, a genetic mutation, or head injury may contribute to the pathogenesis of this disease. We examined the risks of AD associated with traumatic head injury and apolipoprotein-epsilon4 in 236 community-dwelling elderly persons. A 10-fold increase in the risk of AD was associated with both apolipoprotein-epsilon4 and a history of traumatic head injury, compared with a two-fold increase in risk with apolipoprotein-epsilon4 alone. Head injury in the absence of an apolipoprotein-epsilon4 allele did not increase risk. These data imply that the biological effects of head injury may increase the risk of AD, but only through a synergistic relationship with apolipoprotein-epsilon4.

NEUROLOGY 1995;45: 555-557

Roberts et al [1] observed cerebral beta-amyloid (betaAP) deposits and neurofibrillary tangles in the brains of professional and amateur boxers who were demented before death and in individuals who died as a result of severe head injury. Further, some but not all epidemiologic studies have found an association between Alzheimer's disease (AD) and head injury [2]. Roberts et al [1] also found increased expression of beta-amyloid precursor protein (betaAPP) following trauma to the brain; this has been interpreted as an acute response to neuronal injury. They considered these observations to be compatible with a major role for amyloid deposition in the pathogenesis of AD because cerebral betaAP deposition is considered a key step in a "neurotoxic" cascade leading to neuritic plaques and neuronal death [3].

Because individuals homozygous or heterozygous for apolipoprotein-epsilon4 (Apo-epsilon4) are at significantly higher risk for AD than individuals with other genotypes, [4] and because the amount of cerebral betaAP deposition in AD may be related to the specific Apo-Epsilon genotype, [5] we hypothesized that a history of traumatic head injury and the presence of an Apo-epsilon4 allele would have a synergistic effect on the risk of AD among community-dwelling elderly people.

Methods. Blood for genomic DNA testing was obtained from 113 patients meeting research criteria for AD and from 123 healthy elderly persons. Both groups of subjects resided in the same region of northern Manhattan and were identified in a population-based study of AD and related dementias. Eight of the 113 cases of AD were autopsy confirmed. Cases and controls were matched for age (within 5 years), gender, and ethnic group (African American, Hispanic, or white).

Genomic DNA was amplified by polymerase chain reaction, using reaction conditions modified from those described by Hixson and Vernier [6]. The genotypes were determined by the sizes of DNA fragments present, viewed and photographed under ultraviolet light after staining with 0.5 micrograms/ml of ethidium bromide. All genotypes were determined without knowledge of patient-control status.

Data collection. A semi-structured interview, previously established as reliable, was used to inquire about head injury with loss of consciousness [2]. For ethnic group classification, we used the format suggested by the 1990 United States Census Bureau.

Data analysis. Allele frequencies for patients with AD and controls were estimated by counting alleles and calculating sample proportions. Frequencies of Apo-Epsilon genotypes in patients and controls were compared using the chi-square test. The frequencies for the demographic variables (including ethnic group) and risk factors were compared between cases and controls using chi-square analyses. Both univariate and multivariate odds ratios for AD associated with Apo-epsilon4 were calculated from logistic regression adjusting for age and ethnic group.

Results. Patients with AD and controls were similar in age (AD 74.0 +-\10.5 (SD), controls 72.0 +-\9.1 (SD)), gender (% women: AD 74.5%, controls 69.1%), and ethnic group (African American: AD 50.7%, controls 49.3%; Hispanic: AD 48.9%, controls 51.1%; and white: AD 44%, controls 56%). AD patients had significantly fewer years of education than did controls (AD 8.5 +-\5.6, controls 10.4 +-\4.8; p < 0.01).

The allele frequency of Apo-epsilon4 was significantly greater among patients with AD than in controls (0.29 versus 0.16; chi squared (chi sup 2) = 13.4, p < 0.001). The Apo-epsilon4 allele frequency did not differ by age, gender, or years of education within either cases or controls. Apo-epsilon4 allele frequency was similar for patients with AD regardless of ethnic group (African American 0.33, Hispanic 0.34, and white 0.30), but differed significantly among controls (African American 0.28, Hispanic 0.13, and white 0.10; chi squared (chi2) = 11.2, p < 0.05). The odds ratio (OR) for AD associated with homozygosity for Apo-epsilon4 was 3.9 (95% CI, 1.2 to 13.2, p < 0.01) and that associated with heterozygosity was 2.0 (95% CI, 1.2 to 3.6, p < 0.01) compared with other Apo-Epsilon genotypes. Adjustments for age, education, and ethnic group did not result in a change in the magnitude of the OR for AD associated with Apo-epsilon4 homozygosity or heterozygosity.

Thirteen patients (11.5%) with AD had a history of head trauma associated with loss of consciousness that preceded onset of dementia by at least 2 years, whereas 10 (8.1%) controls reported a similar injury. The distribution of head injury was similar across ethnic groups. The OR for AD associated with head injury was 1.5 (95% CI, 0.5 to 3.5, p = 0.5). To examine the relationship between the presence of Apo-epsilon4 and head injury in terms of their joint and independent effects on the risk of AD, we stratified the cases and controls by these two variables (table 1). There was no difference in age, gender, or ethnic group among the cases and controls across the four strata. Using as the reference group persons with neither a history of head injury nor an Apo-epsilon4 allele, we estimated the OR for AD associated with both a history of traumatic head injury and the presence of at least one Apo-epsilon4 allele (OR = 10.5; 95% CI, 1.3 to 87.8), traumatic head injury alone (OR = 1.0; 95% CI, 0.3 to 2.9), and the presence of Apo-epsilon4 alone (OR = 2.0; 95% CI, 1.1 to 3.5), adjusting for age by logistic regression. Thus, the OR for the joint effect of head injury and Apo-epsilon4 exceeded that expected from the independent effects of both risk factors (ie, 1.0 x 2.0 = 2.0), suggesting a synergistic relationship. We also formally tested for interaction using logistic regression. In this model, the OR for Apo-epsilon4 was 2.1 (95% CI, 1.2 to 3.6, p < 0.01), that for head injury was 1.0 (95% CI, 0.3 to 3.1, p = 1.0), and that for the interaction (ie, Apo-epsilon4*head injury) was 5.1 (95% CI, 0.6 to 43.8, p = 0.1).

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Table 1. Independent effects of apolipoprotein-epsilon4 (Apo- epsilon4) and head injury among patients and controls

Discussion. This investigation provides evidence to suggest a synergistic relationship between an environmental risk factor (head injury) and a marker of genetic susceptibility to AD (Apo-epsilon4). Although the number of patients and controls with head injury we report is modest, the frequency of this risk factor approximates the lifetime frequency we observed in a previous study in this community [2]. In the absence of Apo-epsilon4, the OR for head injury was not elevated; thus, our results indicate that the effect of head injury on AD risk may be restricted to persons either homozygous or heterozygous for Apo-epsilon4. The findings are most consistent with a model in which an environmental risk factor has no effect alone, yet it exacerbates the effect of genetic susceptibility [7]. The OR for interaction using logistic regression was elevated; however, it was not statistically significant, but this analysis was very conservative. To detect a significant interaction of the same magnitude using this approach we would need nearly twice as many subjects [8]. As such, our conclusions must remain tentative, but they are consistent with two major views on the pathogenesis of AD.

The pathology of dementia in boxers was considered to consist mostly of neurofibrillary tangle formation, but Roberts et al, [1] using immunostaining, identified betaAP deposits in brain as well. Moreover, they also detected diffuse deposits of betaAP, not neurofibrillary tangles, in the upper layers of the neocortex of patients with fatal head injuries but no history of dementia, as well as increased betaAPP immunoreactivity in all head-injury cases examined [1]. The latter observation might suggest that betaAPP is increased as an acute-phase response to neuronal injury, which, in turn, leads to betaAP deposition in cortex. The amyloid hypothesis converges on the role of cerebral betaAP deposition as the initial event leading to the formation of neuritic plaques and subsequent neuronal death. betaAP deposition may result in cell death by binding to specific molecules on the cell surface or by rendering neurons more susceptible to excitotoxic, ischemic, or other metabolic constituents [3]. Because Apo-Epsilon is involved in cholesterol transport, it may sequester proteins such as amyloid in response to brain injury [4]. Poirier et al [9] found Apo-Epsilon mRNA and the number of Apo-Epsilon immunoreactive cells increased following electrolytic lesions of rat hippocampus, and proposed that Apo-Epsilon could be a trophic factor secreted by astrocytes for membrane synthesis and synaptogenesis in response to injury. Thus, individuals with one or more copies of the Apo-epsilon4 allele might be more likely to deposit betaAP in cortex following head injury than individuals with other genotypes.

Our results would also be compatible with a recent hypothesis forwarded by Strittmatter et al, [10] who proposed that the absence of Apo-epsilon3 results in more rapid tau phosphorylation, leading to instability of the microtubule system in neurons and the formation of paired helical filaments and neurofibrillary tangles, thereby increasing the risk of AD. Thus, the formation of neurofibrillary tangles in people with a history of head injury who become demented might be related to their Apo-Epsilon genotype as well to any direct effect of the trauma.

The exact mechanism underlying the role of Apo-Epsilon in the pathogenesis of AD remains unresolved, but the Apo-Epsilon genotype may specify a degree of genetic susceptibility to AD that can be exacerbated by the effects of other genes or environmental risk factors such as traumatic head injury.

Acknowledgments

The authors thank Drs. Steven Albert, Nicole Schupf, and Karen Marder for their critical review of the manuscript.

  • Copyright 1995 by Modern Medicine Publications, Inc., a subsidiary of Edgell Communications, Inc.

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    Hixson J, Vernier D. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhAl. J Lipid Res 1991;31:545-548.
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    Ottman R. An epidemiologic approach to gene-environment interaction. Genet Epidemiol 1990;7:177-185.
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