ApoE-4 is Associated With Traumatic Encephalopathy and Alzheimer’s Disease
abstracts & commentary
Sources: Luukinen H, et al. Head injuries and cognitive decline among older adults: A population-based study. Neurology 1999;52:557-562; Teasdale GM, et al. Association of apolipoprotein E polymorphism with outcome after head injury. Lancet 1997;350:1069-1071; Roberts GW, et al. Amyloid protein deposition in the brain after severe head injury: Implications for the pathogenesis of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1994;57:419-425; Friedman G, et al. Apolipoprotein E-4 genotype predicts a poor outcome in survivors of traumatic injury. Neurology 1999;52:244-248; Nicoll JAR, et al. Apolipoprotein E-4 allele is associated with deposition of amyloid beta-protein following head injury. Nature Med 1995;1:135-137.
For several years, investigators have conjectured that early head injury may contribute to late incidence of Alzheimer’s disease (AD). Mayeux and colleagues substantiated the earlier suggestions by identifying AD as having a significantly higher incidence in patients older than age 65 who had suffered severe head injuries during early life compared to nontraumatized controls.1 In fact, Roberts and colleagues already had identified large numbers of beta amyloid protein plaques in the brains of middle-aged and older boxers who died following months to years after developing dementia pugilistica.2 The plaques were characterized as indistinguishable from those found in AD.
Subsequent studies by Roberts et al confirmed at postmortem the relationship of beta amyloid plaques in approximately 30% of 152 persons following severe head trauma.3 Patients showing post-traumatic beta amyloid plaques at death ranged in age from 8 weeks to 81 years. Post-traumatic survival time ranged from four hours to 2.5 years. Increased age correlated roughly to increasing beta AP deposits in the brain. Roberts et al proposed that beta amyloid precursor protein identified in the perikaryon of neurons adjacent to beta amyloid plaques may possibly reflect an acute phase response to neuronal injury.
Against the above background, three relatively recent reports emphasize the influence of apolipoprotein E (apoE) polymorphism on both immediate and long-term outcomes from brain trauma. Cementing the relationship of the apoE-4 to brain vulnerability, Nicoll and associates pointed out that approximately one-third of persons dying from acute head injury not only contain excess amounts of amyloid beta protein in the brain, but with a frequency (0.52) that is measurably higher than the apoE-4 allele appears in the general population. The figures imply that the apoE-4 allele presents a specific genetic vulnerability to the effects of brain injury. Two large clinical series support this opinion.
Teasdale and associates reported the results of a prospective clinical study to test the above conclusion. Among 89 patients, Teasdale et al found that 30 possessed the apoE-4 allele: at six months, post-trauma 17 (57%) of these died or remained either vegetative or severely disabled. Of 59 similarly injured patients without the apoE-4 allele, only 16 (27%) had similarly poor outcomes (P = 0.006). Immediate severity of the degree of initial trauma did not influence the significant difference in outcome. As noted above, the significantly worse outcomes of persons with the apoE-4 allele exceeded that found in the general population. Teasdale et al conclude that the possession of the apoE-4 allele specifically contributes to the severity of acquired brain trauma.
Friedman and associates buttress the generic accuracy of the above findings. Their report exclusively describes patients who reached the Israel Rehabilitation Hospital following acute hospital care. Accordingly, the selection necessarily omits earlier post-traumatic deaths and patients who made prompt improvement following acute brain injury. Friedman et al evaluated 69 surviving patients and divided them into two outcomes: good outcome designated those who recovered independence from nursing-physical care and expressed functional cognition and behavior; unfavorable late outcomes identified patients who remained fully dependent on caregivers or suffered severe cognitive impairments. Patients harboring the apoE-4 had an odds ratio of 5.69 of remaining unconscious for more than seven days compared to those who lacked the allele. Furthermore, only one of 27 persons with the 4-allele had a good outcome compared to 13 of 42 comparably injured persons who reached a good functional recovery.
Commentary
Most neurologists, psychiatrists, and general physicians are now aware that possession of the apoE-4 allele has a high probability of predicting late-life AD. These important reports, however, indicate two additional major risks associated with the poisonous allele. First is that possession of the apoE-4 allele materially worsens the potential neurological outcome of traumatic brain injury. The second is that the incidence of severe brain injury in persons with the apoE-4 greatly exceeds the rate of the allele in the general population. These two adverse qualities have important implications for preventive medicine. Neurology Alert asks, "Should amateur and professional boxers be screened for the apoE-4 allele and advised of its implications? Should skiers and other athletes be made aware of this risk factor?" Given the knowledge we neurologists now possess, should we begin to discuss it publicly in this coming Century of the Brain?
References
1. Mayeux, et al. Genetic susceptibility and head injury as risk factors for Alzheimer’s disease among community-dwelling eldery persons and their first-degree relatives. Ann Neurol 1993;33:494-501.
2. Roberts GW, et al. The occult aftermath of boxing. J Neurol Neurosurg Psychiatry 1990;53:373-378.
3. Roberts GW, et al. Beta A4 amyloid protein deposition in brain after head trauma. Lancet 1991;2:1422-1423.
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