'Exercise in a Pill' Has Cognitive Implications

by Sandra A. Swanson

November, 2008

Earlier this year, couch potatoes found renewed hope in an unlikely source: mice on a treadmill. Researchers at the California-based Salk Institute administered a drug which altered the rodents’ metabolism, giving their physical endurance a turbo boost.

It’s no small step from mouse to mankind. But if the effects of this drug—dubbed “exercise in a pill”— apply to humans, there could be more at stake than athletic prowess. With mounting evidence that links cognitive health to exercise and metabolism, a drug that mimics exercise could mean good news for our brains.

Addressing Alzheimer’s

 Although doctors tell Alzheimer’s patients to stay active, there’s no proof that exercise slows the disease progression, says Jeffrey Burns, a University of Kansas neurologist.

He’s working to close that information gap. In a study published in the July 15 issue of Neurology, Burns and his colleagues recruited 121 participants, age 60 and older, about half of whom had early Alzheimer’s. Researchers tested participants’ fitness, then measured their brain volume.

Compared with dementia-free participants, the adults with Alzheimer’s and low fitness levels had four times more brain shrinkage than their counterparts with high fitness levels.

Burns emphasizes that the research leaves many questions unanswered. For starters, the study looked at fitness, not exercise—and it does not prove a cause-effect relationship. Still, “It suggests that we may be able to use exercise to maintain fitness, and by maintaining fitness we may slow the brain shrinkage of Alzheimer’s.”

Now his team is tracking the same participants for a two-year study, to see if changes in fitness levels affect brain atrophy. They also plan to study whether aerobic exercise slows Alzheimer’s progression.

 A Walk for Brain Health

In a study published in the September 3 issue of the Journal of the American Medical Association, Australian researchers conducted a randomized, controlled trial to assess how physical activity affected adults who reported memory problems (but had not been diagnosed with dementia). The control group did not change their activity level, while another group was encouraged to walk or do moderate exercise three times a week.

On average, the latter group exercised 20 minutes more per day than the control group. When the researchers conducted clinical assessments for Alzheimer’s and dementia, the exercise group posted a healthier score.

Those cognitive benefits had staying power. After the 24-week exercise regimen stopped, the adults’ memory improvements remained for 12 months.

More evidence is needed to solidify the relationship between exercise and brain health. Notes Burns: “If we knew precisely what cellular or hormonal changes occur with exercise and result in benefits to the brain, then maybe we could capitalize on that.”

Metabolic mysteries

 One undisputed effect of exercise is its influence on metabolism. AMPK, an enzyme in the hypothalamus that’s activated by exercise, instructs the body to burn fat and absorb glucose.

The “exercise in a pill” research, led by Ron Evans, used a drug to activate AMPK and alter mouse metabolism. In humans, such metabolic control could affect not just obesity and diabetes, but also cognitive disorders.

“The study of the brain’s role in regulating metabolism is just beginning,” says Qingchun Tong of the Beth Israel Deaconess Medical Center in Boston. Tong and his colleagues conducted research, published online August 10 in Nature Neuroscience, suggesting that the neurotransmitter GABA may be more important than previously thought in regulating energy balance.

Metabolic disorders may also influence brain health. A study in the September issue of the Journal of Alzheimer’s Disease showed that obesity and type 2 diabetes can lead to brain shrinkage. The problem may stem from excess nutrient availability, which can lead to metabolic stress—cells can’t burn enough fuel, and that toxic effect can hasten cell death. If researchers found a way to alter human metabolism, it could help eliminate that excess fuel and reduce cell degeneration.

Gary Schwartz, a neuroscientist at the Albert Einstein College of Medicine in New York, notes that neurons located in the hippocampus and hypothalamus may be especially sensitive to metabolic status. “There have been proposed linkages between nutrient excess, aging, metabolic stress in neurons, insulin sensitivity, and cell degeneration accompanied by declines in cognition,” he says. To connect those dots, Schwartz and his colleagues have begun to investigate whether metabolic stress in targeted neuronal populations will change energy balance in healthy animals.

At the University of Kansas, Burns and his team are investigating the metabolism- related hormone insulin’s effect on the brain and Alzheimer’s. “People are starting to think about [Alzheimer’s disease] more as a disease driven by abnormalities in metabolism,” says Burns. “It’s not really a mainstream idea yet, but [it is] certainly of interest to us. … We know that people with Alzheimer’s disease lose weight, and they start losing weight before they start having memory problems. What’s driving that is unclear.”