. APOE {varepsilon}4 Status and Traumatic Brain Injury on the Gridiron or the Battlefield. Sci Transl Med. 2012 May 16;4(134):134ed4. PubMed.

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  1. Given what Lee Goldstein, Ann McKee, and colleagues observed in the brains of blast victims and athletes who suffered severe concussions in our recent study, we need to be much more cognizant of how to protect our military and those playing violent contact sports from head trauma. Knowing you are ApoE4 postive may be a start toward increased vigilance in these activities. But those who do not carry the ApoE4 allele must still be equally concerned with protecting themselves from head injury to avoid downstream risk for CTE and dementia.

  2. The editorial makes several important points. Perhaps the most important is that we need a much larger database to understand risks that transform TBI into CTE and its various clinical expressions among people at risk due to sports, war, or other situations. A long-term investment in studying cohorts prospectively could provide appropriate information for counseling and risk assessment. Initiatives such as lifetime TBI diaries among athletes, amateur and professional, in sports that are associated with increased risk of TBI, would be extremely valuable. Some of the expense could be deferred by piggy-backing these studies onto existing cohort studies, but specific funding for registries or cohort studies would be worth considering.

    The editorial highlights ApoE4 as a risk factor for CTE. The data from which this conclusion is drawn are limited: For example, reference 4 in the editorial is a study of 30 boxers, and should be viewed as preliminary.

    Many studies of ApoE have come from major TBI and its outcomes. For example, Ponsford et al., 2011, was an Australian study of TBI in more than 600 adults. It reported no association between initial severity of clinical deficits from TBI and ApoE4, but an association between worse longer-term recovery and ApoE4. Follow-up of this cohort was not long enough to consider the long-term risk of CTE and its consequences.

    Alexander et al., 2007, followed 123 adults with severe TBI for up to 24 months and documented a slower recovery rate for people with an ApoE4 allele, controlling for other potential predictors. It is tempting to extrapolate from the data on severe TBI about the additional influence of ApoE, but the questions raised by milder TBI and CTE may not be identical.

    More data are needed to inform and develop public health policy, particularly regarding sensitive issues that surround genetic testing and disclosure. As an inverse of advising people who are ApoE4 carriers to consider avoiding contact sports with higher risk of TBI, would the knowledge that one lacks an ApoE4 allele give a false sense of security to other athletes? Reducing the risk of TBI, regardless of ApoE genotype, is an imperative of further research related to CTE.

    References:

    . The association between apolipoprotein E and traumatic brain injury severity and functional outcome in a rehabilitation sample. J Neurotrauma. 2011 Sep;28(9):1683-92. PubMed.

    . Apolipoprotein E4 allele presence and functional outcome after severe traumatic brain injury. J Neurotrauma. 2007 May;24(5):790-7. PubMed.

  3. The editorial by Drs. Gandy and DeKosky very appropriately raises concerns about the effects of traumatic brain injury to produce chronic traumatic encephalopathy and as a long-term risk factor for Alzheimer's disease. Furthermore, the editorial raises questions concerning the role of ApoE4 as an added or interactive risk factor for future brain damage. Recently, the ADNI team was funded by the Department of Defense to begin a study of the effects of traumatic brain injury and post-traumatic stress disorder on Alzheimer's disease in veterans using imaging and biomarkers in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We will enroll 210 Vietnam War veterans (70 in each group) who: 1) have a documented history of moderate to severe concussion, 2) documented post-traumatic stress disorder, or 3) healthy controls and study them with the identical clinical, cognitive, MRI, PET, and CSF biomarkers as subjects in ADNI2. Of course, ApoE4 testing, GWAS, or even whole-genome sequencing will also be performed on DNA from these subjects. We expect that the results of this study will provide new insights into the relationship of TBI and PTSD to the development of cognitive decline, Alzheimer's disease, and dementia.

    Millions of Americans have served in the Armed Forces, many of whom have been subjected to exposures such as TBI and PTSD that may increase their risk for dementia. The Veterans Administration runs the largest single healthcare system in the U.S. In my view, considering the magnitude, prevalence, and severity of Alzheimer's disease in veterans, the DOD and VA have not provided sufficient funding for research concerning Alzheimer's disease.

    Therefore, this very important editorial further raises awareness and concerns about several important issues. Hopefully, this will result in new research and additional funding, which will lead to improved diagnostic methods and treatments to prevent cognitive decline and dementia.

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