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Traumatic brain injury as a risk factor for Alzheimer’s disease
  1. K A Jellinger
  1. Institute of Clinical Neurobiology, Kenyongasse 18, A-1070 Vienna, Austria;

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    In a recent systematic review of case control studies investigating head injury as a risk factor for Alzheimer’s disease (AD), Fleminger et al1 replicated the results of the meta-analysis by Mortimer et al2 in males (OR 2.29; 95% CI from 1.47 to 2.00) but not in females (OR 0.91; 95% CI from 0.56 to1.47). Their findings support in males only an association between a history of previous head injury and the risk of developing AD, but the study could not review the relation between head injury and ApoE gene status as risk factors for AD.

    The review by Fleminger et al was based on clinical studies alone and, as Wilson3 emphasised, did not consider the nature or severity of the original head injury; and the results of the first retrospective autopsy study of the relation between closed traumatic brain injury (TBI), ApoE allele frequency, and AD4,5 unfortunately were not mentioned. This present study has examined:

    • the incidence of AD pathology in 55 consecutive autopsy cases (mean age 77.6 years, SD 7.1) with residuals of closed TBI lesions (old contusions in the frontal, temporal, or other brain areas)

    • the frequency of TBI residuals in 53 age matched AD cases proven at autopsy.

    In both series, ApoE was evaluated from archival brain material embedded in paraffin. The results were as follows.

    In the TBI series, 12.7% (four males and three females) showed CERAD B (Consortium to Establish a Registry for Alzheimer’s Disease) definite AD (Braak stages 5 and 6), and 9.1% showed CERAD B probable AD (Braak stages 3 or 4). TBI history dated back from 10 to 30 years before death; duration of AD ranged from four to seven years. Two of the subjects with AD showed ApoEϵ3/4, and the remainder 3/3 or 3/2; of the remaining 43 subjects without AD, three exhibited 3/4 alleles. The prevalence of AD (21.8%) in this small autopsy cohort was significantly higher than in either a recent large clinical series (3.3%)6 or the general population over the age of 70 years (14%).7

    In the AD cohort (all CERAD B or C, Braak stages 5 and 6), there was an ApoEϵ4 allele frequency of 30% (similar to other AD series). Residuals of TBI were seen in four brains (two males and two females, each 7.5% of the cohort), all four lacking the ApoeEϵ4 allele. These data in small autopsy cohorts confirmed previous clinical studies suggesting that severe TBI is a risk factor for the development of AD, particularly in subjects lacking the ApoEϵ4 allele which is considered a risk factor for AD. No gender differences were found.

    Irrespective of these data, we agree with others1,3 that further work should consider population based cohorts and larger autopsy series of TBI and AD, in order better to elucidate the relationship between TBI, ApoE alleles, and the development of AD.