When the National Institutes of Health convened a panel of independent experts this past April on how to prevent Alzheimer’s disease, the conclusions were pretty grim. The panel determined that “no evidence of even moderate scientific quality” links anything—from herbal or nutritional supplements to prescription medications to social, economic or environmental conditions—with the slightest decrease in the risk of developing Alzheimer’s. Furthermore, the committee argued, there is little credible evidence that you can do anything to delay the kinds of memory problems that are often associated with aging. The researchers’ conclusions made headlines around the world and struck a blow at the many purveyors of “brain boosters,” “memory enhancers” and “cognitive-training software” that advertise their wares on the Web and on television. One of the panel experts later told reporters in a conference call that the group wanted to “dissuade folks from spending extraordinary amounts of money on stuff that doesn’t work.”
But did the panel overstate its case? Some memory and cognition researchers privately grumbled that the conclusions were too negative—particularly with respect to the potential benefits of not smoking, treating high blood pressure and engaging in physical activity. In late September the British Journal of Sports Medicine published a few of these criticisms. As a longtime science journalist, I suspected that this is the kind of instructive controversy—with top-level people taking opposing positions—that often occurs at the leading edge of research. As I spoke with various researchers, I realized that the disagreements signaled newly emerging views of how the brain ages. Investigators are exploring whether they need to look beyond the brain to the heart to understand what happens to nerve cells over the course of decades. In the process, they are uncovering new roles for the cardiovascular system, including ones that go beyond supplying the brain with plenty of oxygen-rich blood. The findings could suggest useful avenues for delaying dementia or less severe memory problems.
Dementia, of course, is a complex biological phenomenon. Although Alzheimer’s is the most common cause of dementia in older adults, it is not the only cause. Other conditions can contribute to dementia as well, says Eric B. Larson, executive director of the Group Health Research Institute in Seattle. For example, physicians have long known that suffering a stroke, in which blood flow to the brain has been interrupted by a clot or a hemorrhage, can lead to dementia. But research over the past few years has documented the importance of very tiny strokes—strokes so small they can be detected only under a microscope after death—as another possible cause for dementia. Studies at autopsy of people who had dementia have detected many of these so-called microvascular infarcts either by themselves or along with the plaques and tangles more typical of Alzheimer’s in the brains of people with dementia. These findings suggest that most dementias, even those caused by Alzheimer’s, are triggered by multiple pathological processes and will require more than one treatment.
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Proving that cardiovascular treatment is one of those approaches will take some doing. Just because microinfarcts may make dementia worse does not mean that preventing them will delay the brain’s overall deterioration. Maybe severe dementia makes people more vulnerable to microinfarcts. And just because better control of high blood pressure and increased physical activity seem to decrease a person’s risk of stroke, that does not necessarily mean they are less likely to suffer microinfarcts. Correlation, after all, does not necessarily imply causation. That scientific truism was the problem that kept bothering the panel of outside experts put together by the NIH. Thus, the expert panel concluded, with one exception, that “all existing evidence suggests that antihypertensive treatment results in no cognitive benefit.” Data showing the benefits of boosting physical activity in folks with confirmed memory problems were “preliminary.”
The controversy boils down to semantics, says Martha L. Daviglus, chair of the consensus panel and a preventive cardiology researcher at Northwestern University’s School of Medicine. “Obviously, smoking and hypertension are risk factors for cardiovascular disease,” she says. “And they may turn out to be risk factors for Alzheimer’s disease as well,” she says. But after reviewing all the evidence, Daviglus and her fellow panelists concluded that it “failed to provide convincing evidence” of the link, whereas other researchers see “some evidence” of a link.
Getting better data may be a problem, however. One of the best ways scientists have to prove cause and effect in medicine is to conduct a randomized controlled trial, in which study subjects are randomly assigned to two groups. One group—the so-called control group—receives the usual standard of care. The other group—the so-called experimental group—gets whichever intervention is being tested. The simplest way to prove that treating high blood pressure helps to delay the onset of dementia would be to treat one group for hypertension and leave the other group deliberately untreated for the sake of the experiment. No ethical physician would participate in such a study.
One way out of this dilemma, Daviglus notes, is to design a study in which patients suffering from hypertension get treatment, and doctors analyze the results based on how well the patients’ blood pressure was controlled. If the amount by which blood pressure dropped closely paralleled the decrease in dementia risk, that would be powerful evidence of a beneficial link. Such a so-called dose-response study has not been done yet—it is a complex and expensive undertaking—but there is reason to believe it could be worth the investment.
Observational studies, which follow people as they get older without directly intervening in their treatment, have uncovered some suggestive trends. Larson and others have shown that people who have good control of their blood pressure from age 65 to 80 are less likely to develop dementia. After age 85, controlling blood pressure does not have much effect on dementia risk. That doesn’t mean anyone older than 85 should stop taking blood pressure medication. Lowering high blood pressure still prevents congestive heart failure and promotes kidney health. But these studies suggest that doctors do not have to take aggressive measures when treating patients older than 85 for hypertension.
As for physical activity, the best evidence in favor of its benefits for the brain comes from Australia. Two years ago researchers there published the results of a randomized controlled trial of physical activity in 170 older adults who had started showing greater memory problems than their peers and were thus at increased risk of developing dementia. Study participants averaged an extra 20 minutes a day of physical activity over six months. The study was so rigorously designed that individuals undertook the extra exercise by themselves at home to preclude the possibility that the true benefit had come from socializing with other people during group activities. The benefits of extra exercise were obvious and lasted—albeit at a diminishing level—for 12 months after the exercise program ended. Not only did the experimental group score better on tests of their cognition compared with the control group, but the improvement was twice as great as the one that had previously been shown for the antidementia drug donepezil (brand name Aricept). This was the first time that anyone had proved in a randomized controlled trial that exercise could improve mental functioning in people with some cognitive problems.
No one understands on a biochemical level why physical activity might help the brain. The best explanation so far, says Henrietta van Praag, a neurobiologist at the National Institute on Aging, is that exercising the heart somehow stimulates growth factors to produce new nerve cells in the brain. In 1999 van Praag showed that more new nerves formed in the hippocampus—one of the key centers in the brain for memory and learning—in physically active mice than in inactive ones. (She was working at the time as a postdoctoral researcher in Fred Gage’s laboratory at the Salk Institute.) She has since shown that the new cell growth is associated with a marked improvement in learning and memory. The new nerves also show qualitative differences from their older counterparts. The younger cells are better at establishing new connections with other cells. The effect is somewhat temporary. After a couple of months, the new cells start acting like the older cells, although they do not die off.
Maybe 10 or 15 years in the future, we will know for sure whether quitting smoking and exercising regularly help to delay dementia. That leaves the rest of us—who may have seen the devastating effects of dementia on older family and friends and cannot afford to wait for a definitive scientific answer on how we might avoid a similar fate—in an uncomfortable state of ignorance. Even if these steps never end up helping your brain, however, they will do your heart a world of good.
Editor's note: This article was published in the print issue with the title, "The Heart-Brain Connection".