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Traumatic Brain Injury and Risk for Alzheimer's Disease

Posted by MullanMichael on July 24, 2013

Recently, there has been increasing interest in the role of sports head injuries and subsequent cognitive decline. For instance, American football players are being scrutinized more closely because of new research suggesting close links between repeated concussion and decline in cognitive abilities. However, over the last three decades, there has been much work on the relationship between head injury (usually single head injury) and Alzheimer's disease (AD) and other dementias. Many well designed, population based studies have suggested a link between head injury and the development of AD and other dementias. However, there are many discrepancies between these studies and the risk attributed to head injury has varied widely between them. Several key factors are often examined in these studies to try to understand better the relationship between traumatic brain injury (TBI) and AD. One of the areas that has been studied extensively is the effect of gender. Despite the many case control and cohort studies, none have shown an increased risk for AD after TBI for women. Although many TBI studies focus on the male population who are more at risk (for instance, in contact sports or in the military) the finding that women are at no increased risk of AD after TBI suggests that there may be a protective effect of female hormones against the development of AD after head injury. Another area that is extensively studied is the relationship between the degree of injury and the subsequent development of AD or related disorders. Few studies have adequately assessed the degree of injury and so information in this area is limited but, the studies that have, in general, suggest that more moderate or severe injuries predispose to dementia later in life. For instance, one study divided TBI into mild, moderate, and severe categories:  injuries with loss of consciousness (LOC) or post-traumatic amnesia (PTA) of less than 30 minutes (mild); of more than 30 minutes but less than 24 hours (moderate); and of more than 24 hours (severe). Most studies suggested moderate and severe disease is more related to AD and that full recovery of cognitive loss can be regained after mild TBI.

 

Another key area of interest is the relationship between time of injury to the development of subsequent dementia. This has been studied in large populations and there are good data to suggest that TBI in old age is associated with worsening of outcome compared to TBI at a younger age. Nevertheless, even individuals that have TBI in early adulthood (if the injury is severe enough) are at increased risk of AD and other dementias as many as five decades later.

One key question is how the brain "remembers" the injury for so many years and why there may be no signs of cognitive impairment soon after the injury for many decades until AD onsets. The question of the molecular underpinnings of TBI and how the brain continues to register that an injury has occurred is an area of intense study. One such candidate for molecular memory is amyloid, the molecule that is increased in the brains of AD sufferers and occurs early in the pathological sequence that leads to full-blown AD. However, not all TBI victims have increased amyloid in their brain at autopsy, most studies showing that only about a third do so. And, although amyloid is produced acutely after TBI, much of that amyloid does not stay in the brain but is degraded in the weeks and months following injury. Another pathological molecule central to the AD process is tau. Although tau has been implicated in TBI, again, there are inconsistent data between studies -- some showing no increased involvement of tau while others show hyperphosphorylation and/or aggregation of tau. More recently in repetitive head injury (for instance, those occurring in American football) tau has been implicated as it has been seen particularly around blood vessels in the brain.

Whatever the ultimate underlying cause of the link between TBI  and the subsequent development of AD, we can expect that once those links are fully uncovered, they will become new targets for the prevention of AD following TBI.

One other area that deserves attention is the genetic risk for poor recovery after TBI and subsequent risk for AD. Although it is generally accepted that APOE4 is a risk factor for AD, some studies of head injury have been equivocal in demonstrating that APOE4 acts synergistically with TBI to increase risk for AD. However, given the plethora of data on the negative roles of APOE4 in the brain after TBI, it is safe to assume that individuals who carry the E4 are most probably at greater risk for developing AD than those who do not. It has been advocated that those individuals carrying an APOE4 allele should not engage in professions or pastimes with increased risk of TBI. Much more work is needed in this area; but, at this stage, as a precaution, this is probably a position that can be easily endorsed.

 

By Dr. Michael Mullan

CEO of Roskamp Institute

President of Sci-Brain