Behavior, Stress Affect Alzheimer’s Disease Risk

by Rabiya S. Tuma

November, 2006

In some of the more than 500 Alzheimer’s-related presentations at SfN, researchers shed new light on how diet, exercise, red wine consumption, and stress may lower or raise disease risk.

Findings from one study suggest why people who have high cholesterol are at higher risk of developing Alzheimer’s disease. Narayan Bhat of the neurosciences department at the Medical University of South Carolina in Charleston and colleagues found that excess cholesterol in the diet of mice triggered both physical changes in the brain and memory problems.

During the study, the researchers fed one group of mice a high-fat, high-cholesterol diet and the other group their normal, healthy chow. After two months, they tested the animals in a task that required them to remember which parts of a maze they had visited before.

Early in the experiment, when they had only a few previously visited spots to remember, all of the animals did equally well. But as the task became more difficult and the animals needed to remember more information, the mice on the unhealthy diet made more mistakes.

“These were big differences in behavior,” Bhat said. The fact that the animals’ performance worsened only as the difficulty of the memory task increased suggests that the high-cholesterol diet impaired the animals’ working memory, which temporarily stores information we need to complete a task and is lost early in Alzheimer’s disease.

Moreover, when Bhat’s team looked at the animals’ brain tissue, they found an increase in biochemical markers of inflammation relative to the control animals, as well as an increase in the number of activated immune cells. Given these changes in the brain tissue, the scientists think the extra cholesterol causes physical damage to the neurons or the blood vessels that run through the brain.

Separately, Kathryn Nichol, a postgraduate researcher working with Carl Cotman at the Institute for Brain Aging and Dementia at the University of California at Irvine, and colleagues found that exercise protects animals from developing Alzheimer’s-like symptoms by reducing the presence of harmful inflammatory markers in the brain.

Nichol studied a type of mutant mice that develop a pathology similar to Alzheimer’s and have both memory problems and a buildup of beta-amyloid plaques in their brain tissue, a hallmark of the disease. To find out what effect exercise might have, the researchers housed normal and mutant animals in cages with or without running wheels.

After three weeks, the animals were tested on the same memory task that Bhat’s group used. The sedentary mutant animals had significantly more problems remembering where they had been than either the mutant animals that had been running on the exercise wheel or the genetically normal ones.

When she examined the brain tissue, Nichol saw a much higher level of harmful inflammatory markers in the brains of the sedentary mice than in those of active ones. In fact, the brains of the exercised mutant animals looked like those belonging to the genetically normal ones. She also saw that beneficial inflammatory markers, which promote neuronal survival, were more prevalent in the exercised mutant and normal mice than in the sedentary ones.

Nichol said the new data might help explain why people who regularly take anti-inflammatory drugs such as ibuprofen have a lower risk of Alzheimer’s disease. However, those drugs would only lower the negative effects of inflammation, without the added benefit of the pro-survival responses exercise seemed to prompt.

A Positive Role for Red Wine

Another study on behavior and Alzheimer’s risk suggests that a glass of red wine is beneficial. Giulio Pasinetti, a member of the psychiatry department at the Mount Sinai School of Medicine in New York, and colleagues presented findings that red wine consumption by the same type of mutant mice improved their memory function and reduced beta-amyloid plaque formation in their brains, compared to littermates that drank only water.

“There is a lot of epidemiological evidence that the consumption of red wine may decrease the incidence of Alzheimer’s disease,” Pasinetti said. Yet when a postdoctoral researcher working on the project told him that red wine actually helped clear the plaques from the brains of mutant mice—rather than simply prevent their formation—Pasinetti was skeptical at best.

Now, though, he says the data clearly support that theory. The mice that were given a red wine-water mix daily for 11 months performed significantly better in a maze memory test than did their littermates that drank only water, and when the team looked at the animals’ brains, they saw fewer plaques in the animals that had been exposed to red wine.
  Just how the red wine leads to this reduction is not yet clear, but it likely has to do with the high concentration of antioxidants in red grapes.

“Indeed we cannot proceed with a pharmacological approach or therapeutic application with wine,” Pasinetti said. “It is impossible to prescribe cabernet sauvignon.” With that in mind, his group is now working with unfermented purple grape juice to see if it has a similar protective effect in mice.  

Good for the Heart, Good for the Brain

In addition to studying what might help lower the risk of Alzheimer’s disease, scientists are also looking at what may increase the risk. Many are arriving at a one-word answer: stress.

Researchers led by neurologist David Holtzman at Washington University in St. Louis reported that short-term stress leads to an increase in the amount of beta-amyloid protein in the brains of mice. Mice housed in a smaller-than-normal cage for three months, three days, or even 16 hours had increased levels of the beta-amyloid peptide.

The increased peptide levels appeared to alter synaptic activity in the brain. It is not yet clear how stress increases beta-amyloid production, but it is likely that stress hormones act as a trigger.

If so, “this might be an area where you could develop drug targets, to block the effects that stress is having,” Holtzman said. Drugs that are already used to treat mental health disorders such as anxiety and depression may help prevent Alzheimer’s, Holtzman’s model suggests.

While scientists and physicians are teasing out the mechanisms that underlie these new observations, Cotman points out that there is a simple theme in these new studies: what is good for the heart—low cholesterol, wine, and stress reduction—is good for the brain.