Summary: a head injury may increase your risk of dementia, or cause dementia to develop at an earlier age. Head injuries also have some of the same pathologies as Alzheimer’s disease. This means that treatments developed to reduce brain damage caused by head trauma may help those whose dementia is not associated with an injury.
Dolly Knowles fell last week while she was walking the dog. She hit her head on the pavement, and has two black eyes and a broken rib. Dolly, 85, is John’s father Bud's girlfriend, and an important part of our family.
Dolly and Bud
She tells me this isn’t the first time she’s bumped her head. When she was living by herself in Wisconsin, she hit her head on the corner of an antique wardrobe. “The next thing I knew, I was on the floor and it was dark outside. Must have knocked me out. I wasn’t sure what had happened,” she says, “so I just went to bed.” Her doctor checked her over and said she was fine.
But Dolly thinks that blow to her head three years ago may have caused her to lose her sense of smell. She’s also starting to have trouble with short term memory and with finding words. “I think that’s just age,” she says. But it may also have something to do with her run-in with the furniture.
Professional Athletes, Head Injuries and Dementia
Researchers have long known that boxers have a high rate of dementia. Playing other sports where head injuries are common may also increase the risk of developing dementia, or perhaps cause it to develop at an earlier age. In an article published in NeuroSurgery in 2005, University of North Carolina scientists tested more than 2500 retired professional football players. They found those with three or more concussions were five times as likely to have Mild Cognitive Impairment and three times as likely to have significant memory problems compared to retirees without a history of concussion.
“Although there was not an association between recurrent concussion and Alzheimer's disease, we observed an earlier onset of Alzheimer's disease in the retirees than in the general American male population,” the researchers wrote. “Our findings suggest that the onset of dementia-related syndromes may be initiated by repetitive cerebral concussions in professional football players.”
Football players who haven’t suffered concussions may still have an increased risk of cognitive problems. In 2006, University of Pittsburgh researchers published case studies of two former football players who didn’t have a record of multiple concussions, but did have cognitive impairment. Both men also had “Major Depressive Disorder.”
The prevalence of dementia among football players was highlighted this year by the retirement of Ted Johnson of the New England Patriots at age 34 due to the memory loss, depression and other problems his doctor says were caused by repeated head injuries. And last week, a New York Times article profiled the efforts of the wives of two retired professional football players to encourage the National Football League to help pay for the care of their husbands and other retired players with dementia. The NFL has now established a fund for this purpose.
Not Just for Professional Athletes
What about those of us who don’t box or play professional football? Recent studies of general populations show that moderate to severe (but maybe not mild) head injuries may increase the risk of dementia:
- "Head injury with loss of consciousness, although uncommon in this sample, was associated with increased risk of Alzheimer's disease. "University of Washington, 1997 study in which 32 of 349 people with probable Alzheimer’s had had head injury, as compared to 16 of 342 control subjects
- “This study suggests that mild head trauma is not a major risk factor for dementia or AD in the elderly.” Erasmus University, The Netherlands, 1999 review of data from The Rotterdam Study of more than 6000 people
- “Moderate and severe head injuries in young men may be associated with increased risk of AD and other dementias in late life. However, the authors cannot exclude the possibility that other unmeasured factors may be influencing this association.” Duke University, 2000 study of the medical records of approximately 1800 retired military personnel, 548 of whom had had head injuries
- “Head injury is a risk factor for AD. The magnitude of the risk is proportional to severity and heightened among first-degree relatives of AD patients.” Boston University, 2000 review of data from over 2000 persons with probable Alzheimer’s and over 14,000 of their family members from the Multi-Institutional Research in Alzheimer Genetic Epidemiology project.
The APOE Connection
Researchers are still working to understand why some people with head injuries don’t develop memory problems. More than twenty years ago, scientists found a possible link between APOE4 (the genetic variation associated with an increased risk of Alzheimer’s) and higher rates of dementia after head injury, as well as a higher risk of increased accumulation of beta amyloid plaques. But the link isn’t clear - none of the population studies above found a significant link between APOE4 and an increased risk of dementia in people with head injuries.
How might APOE status make a difference? Dr. Daniel Laskowitz, Associate Professor of Medicine and Director of the Neurovascular Laboratories at Duke University Medical Center, says he thinks there’s a synergistic relationship between APOE4 and head injury. “I think it’s likely that inflammation (perhaps exacerbated by amyloid deposition) plays an important role in neuronal injury…. APOE4 predisposes to inflammation, which causes neuronal injury and cognitive loss. Head injury associated with inflammation accelerates this process.”
Daniel Laskowitz, MD
In his lab, Dr. Laskowitz is working to understand how the brain is damaged after head injury, and to develop new treatments for both patients with head injuries and those with various types of dementia. In an article published in Neuroscience last month, he and his colleagues describe how a treatment based on a protein similar to the APOE protein [produced according to instructions contained in the APOE gene] reduced inflammation and Alzheimer’s-like pathology in mice following head injury. But in their experiments, mice bred to have the APOE4 variation didn’t have the same physiological and functional improvement after treatment as those with APOE2 and APOE3 did. More work is needed to confirm the role of this gene in determining the effectiveness of treatment.
“The data suggests that there may be a pharmacogenomic interaction between the APOE therapy and E4 - you may, for example, need higher doses of drug if you have E4…the bottom line is that it is too early to tell,” Dr. Laskowitz says. Pharmacogenomics is the study of how your genes affect how you respond to drugs.]
What does this have to do with Alzheimer’s and other types of dementia? “We used head injury as a model to accelerate Alzheimer’s disease pathology,” he explains, “but the results would be relevant to those without injury, as well as those with other forms of injury (bleeds, etc) that may have provoked the inflammatory response, regardless of genotype.”
If my father were still living, treatments based on this research might have been able to reduce the brain damage from microbleeds caused by his cerebral amyloid angiopathy. Drugs might be available for people with head injuries like Dolly’s if brain damage is detected. But these treatments will probably not be available in her lifetime, and maybe not within mine.
As with most Alzheimer’s research, funding is a major obstacle. At this point, Dr. Laskowitz says, “there is not much forward movement on this…. If there were funding, it could be put in preclinical development tomorrow, and be ready for clinical testing within several years.”
I just came back from the Alzheimer’s Association’s Public Policy Forum, during which several hundred of us went to Capitol Hill to ask for increased NIH funding for research on new Alzheimer’s treatments like this. Maybe that will make a difference for the next generation.
