For decades, scientists have postulated a link between traumatic brain injuries and an increased risk for developing Alzheimer’s disease down the line. Now neuroscientists have uncovered a possible mechanism the two conditions shares—and identified a class of Alzheimer’s drugs in testing that may also help minimize the damage that occurs in TBI cases.
The idea first took root in the 1960s, when MacDonald Critchley, a neurologist at King’s College Hospital in London, published a pioneering study outlining the neurological consequences of boxing in the British Medical Journal. Habitual pugilists often became “punch drunk,” he wrote, positing that this might result in memory and other cognitive deficits later in life.
Dozens of epidemiological studies conducted in the wake of his report have also suggested a link, but a direct connection between the two conditions has remained elusive.
Among the evidence associating them is the observation that beta-amyloid deposits—a tell-tale physiological symptom of Alzheimer’s disease—appear in about a third of patients with severe TBI, even some very young children.
“These beta-amyloid deposits don’t occur in all patients with TBI–only in about 30 percent,” says David Brody, a neurologist at Washington University in St. Louis who studies the relationship between TBI and Alzheimer’s. “And the TBI patients’ deposits look a little different too. Mainly, the [amyloid] deposits are more diffuse and less fibrillar than what you see in Alzheimer’s disease.”
Mark Burns, a neuroscientist at Georgetown University, wondered if TBI outcomes could be improved with drugs that arrest the formation of these beta-amyloid plaques. To do so, he decided to target the “injury cascade,” the pattern of escalating damage seen during brain injuries.
In TBI, it’s not the initial trauma that accounts for the bulk of observed brain damage; only some neurons die directly as a result, says David Wright, director of emergency neurosciences at Emory University. But when those cells die, they release chemicals and fluids that ultimately trigger the death of neighboring neurons as well.
If the injury is severe enough, this “cytotoxic” cascade can overwhelm the body’s built-in safeguards, causing widespread swelling and brain damage. This cascade also results in an increase of beta-amyloid in the brain.
“This secondary cascade is your brain reacting to the injury,” Wright says. “Think about when you throw a rock in the water; you’ll see a spreading wave that grows and grows. That’s what you see with TBI, except it’s a wave of dying brain cells.”
Research into the molecular underpinnings of Alzheimer’s disease has shown that beta-amyloid forms when a protein called amyloid precursor protein (APP) is cleaved once by an enzyme called beta secretase and then again by a second enzyme called gamma secretase. Burns hypothesized that the mass release of these proteins and enzymes by dying cells may account for the accumulation of beta-amyloid—and other damage—in TBI as well.
“We thought that if we can step in at an early point of injury and stop these enzymes from producing beta-amyloid, we may be able to stop some of the damage seen in the secondary injury cascade,” Burns says. “The idea is that if you can stop the downstream mechanism that produces beta-amyloid, you can stop the damage before it occurs instead of trying to treat it once it’s already done.”
Burns and his colleagues created a beta secretase knock-out mouse model—animals that were genetically altered to be unable to produce the enzyme. The scientists then compared the animals’ behavior to mice that were given a gamma-secretase-inhibiting drug, as well as normal animals who had suffered a brain injury.
“In the knock-out mice, we saw much better recovery—they could gain much more function back than the normal injured mice. And in some tests, they performed the same as uninjured controls,” Burns says. “We saw similar outcomes with the mice that were given the gamma secretase inhibitor. So it seems that if these enzymes aren’t around, and the beta-amyloid can’t be produced, we can spare a lot of the damage and offer the ability to regain a lot more cognitive and physical function.”
A common set of treatments?
According to experts in the field, the results suggest that Alzheimer’s drugs that target the two secretase enzymes—including several promising compounds currently in development—may also help treat TBI and minimize the later risks of Alzheimer’s.
“Alzheimer’s disease has a very well-defined pipeline of drugs in development that could be of use in the treatment of TBI,” Brody says. “On the flip side, because TBI patients are treated in the ICU and need invasive interventions for treatment, it’s possible for us to do studies that are not possible in any other setting at present.”
But still, both Burns and Brody caution that despite the promising similarities, there is still much that needs to be learned about the role of beta-amyloid in both disorders.
“We have to be cautious. There’s quite a lot of interest in developing a drug treatment for TBI, but the research is still in early stages,” Burns says. “There’s still so much we need to learn about what’s happening in the brain after TBI.”
But both are optimistic. “It’s a very exciting time for TBI research,” Brody says. “And my hope is that recent work in this area will allow people to understand that it is a complex topic that will require intense, interdisciplinary study over a long period of time.”