These days, exercise and physical activity are big buzz words. People are physically active—or know they should be—because they’ve heard the message: Exercise is good for everyone, whether we are young children or older adults. Exercise builds muscles, improves heart and lung function, helps prevent osteoporosis, and improves mood and overall well-being. Exercise is good for those who are already healthy, and it can improve the health of people with chronic conditions, including hypertension, diabetes, arthritis, obesity, and cardiovascular disease (Daniels, 2006; Klieman et al., 2006; McDermott and Mernitz, 2006; Michael and Shaughnessy, 2006).
So, it is not surprising that scientists began to think that if exercise benefited all parts of the body from the neck down, it surely must benefit the brain as well. They have conducted a number of epidemiologic studies to examine the associations between exercise, cognitive function, and risk of AD (Abbott et al., 2004; Larson et al., 2006), as well as a number of small clinical trials to assess the impact of exercise on cognitive function (Colcombe and Kramer, 2003). Findings have been intriguing.
Epidemiologic studies have examined whether exercise and physical activity are associated with beneficial effects on cognitive performance. For example, in an NIA-funded study, researchers at the Harvard School of Public Health analyzed data from almost 19,000 women aged 70-81 who participated in the Nurses’ Health Study, a large study funded by the National Heart, Lung, and Blood Institute (NHLBI) in which nearly 122,000 nurses are asked questions every 2 years about their health, illnesses, diet, and lifestyles (Weuve et al., 2004). Comparing women at various levels of long-term (over several years) physical activity, they found that women at higher activity levels had better cognitive performance and reduced cognitive decline than women at lower activity levels. The cognitive benefit was similar to being about 3 years younger in age. And the association wasn’t confined only to the vigorous exercisers. Walking the equivalent of at least 1½ hours per week at a 21-30 minute-per-mile pace also was associated with better cognitive performance. Researchers at the University of Pittsburgh found similar results when they studied exercise patterns and cognitive function among rural residents in a relatively low socioeconomic area (Lytle et al., 2004).
Other investigators have gone further and looked at the possible association of physical activity and risk of developing dementia among older adults (Abbott et al., 2004). Researchers at the Kuakini Medical Center in Hawaii examined data from the men in the Honolulu-Asia Aging Study (HAAS), a long-term epidemiologic study of stroke, neurodegenerative diseases, and aging in older Japanese-American men (see "Managing Chronic Illness: A Possible Preventive Strategy for AD?" for other studies using HAAS data). The investigators found that walking less than a quarter of a mile every day was associated with almost twice the risk of developing dementia compared to walking more than two miles a day. A group of researchers from the Johns Hopkins University and the University of Pittsburgh examined this issue using data from older participants in the Cardiovascular Health Cognition Study (CHCS). The NIA-funded CHCS is an add-on study to NHLBI’s Cardiovascular Health Study (CHS). Since 1988, the CHS has examined risk factors for the development of heart disease and stroke in elderly adults. The Johns Hopkins and University of Pittsburgh investigators found that the highest energy expenditure and the greatest number of physical activities pursued were associated with a reduced risk of dementia, AD, and vascular dementia (Podewils et al., 2005). This association was stronger in people who did not have the APOE-e4 allele than in people who did have it. These researchers speculate that the number of physical activities may be as important, or even more important, to risk of dementia than the frequency, duration, or intensity of the activities. A third group of researchers at the Group Health Cooperative in Seattle, Washington, followed older adults for 6 years and found that regular exercise (defined in this study as 3 or more times a week) was associated with about one-third the risk of developing dementia as less frequent exercise (Larson et al., 2006). Interestingly, they found that the greatest risk reduction occurred in those who were least physically fit at the beginning of the study.
These observational studies suggest that physical activity and exercise may protect the health of the brain in some way, especially as physical activity and exercise were associated with cognitive health in each of the studies. However, other kinds of studies are needed to firm up these associations and clarify why exercise might reduce the risk of cognitive decline and dementia.
Scientists have looked to studies with experimental animals for some of the answers. To date, several studies have shown positive effects of aerobic exercise on the structure and function of the brain in older animals. For example, in research with rats and mice, investigators have found that exercise increases the number of capillaries that supply blood to the brain and the number of connections between neuronal synapses. It also increases levels of brain-derived neurotrophic factor (BDNF) in the hippocampus, the brain region most affected by AD. BDNF is a protein that supports the survival of existing neurons and encourages the development of new neurons. In a recent study with rats, researchers at the University of California at Irvine found that both daily exercise on a running wheel and exercise on alternate days increased BDNF levels and that BDNF levels remained elevated even after several days of rest (Berchtold et al., 2005). Moreover, animals that had exercised enough to raise BDNF levels and then had rested for a number of days needed only a brief return to exercise to increase BDNF to levels that would take a “couch potato” rat several weeks to reach.
Using these clues, investigators have used animal studies to probe even more deeply into the relationships between physiological changes in the brain and effects on cognitive performance and progression of AD pathology. A group of researchers at the Salk Institute for Biological Studies in La Jolla, California, for example, wanted to see whether the age of the animal and the age at which they began to exercise made a difference (van Praag et al., 2005). They found a beneficial effect even in mice that became active later in life—these mice learned and remembered a maze better than did old mice that weren’t exercisers. They also found that the older running mice also were able to form healthy new neurons at a similar rate to those of younger mice, suggesting that voluntary exercise can restore learning and neuronal formation in aged mice.
Two other research groups set out to test the effects of exercise and an enriched environment on the progression of AD pathology itself. One group, from the University of California at Irvine, divided transgenic AD mice into two groups—one had access to an exercise wheel and the other did not (Adlard et al., 2005). The scientists found that the exercising mice were better able to learn than the non-exercisers. Five months after the experiment began, the scientists examined the brains of the mice and found that the exercising mice also had significantly fewer beta-amyloid deposits in the hippocampus and cortex than did the non-exercisers. Using a different transgenic AD mouse model, researchers funded by NIA and the National Center for Research Resources found that mice living in an “enriched” environment that challenged them mentally as well as physically had significantly less beta-amyloid in the cortex and hippocampus compared to those housed in standard conditions (Lazarov et al., 2005). Upon further analysis, the University of Chicago investigators determined that long-term exposure to the enriched environment led to an increase in the brain’s capacity to degrade beta-amyloid and stimulated the expression of genes associated with learning and memory, cell survival, and generation of new neurons.
What’s the Difference Between an Association and Cause and Effect?
You may have noticed in this section that we’ve always been careful to say that one thing is associated with another thing, rather than to use other words that might suggest a more definitive cause-and-effect relationship. Why do the words matter? It’s because of the type of research we’re describing.
In this section and in several others, we highlight findings from epidemiologic studies. This type of research compares the lifestyles, behaviors, and characteristics of groups of people. Scientists have used these studies to identify risk and protective factors for many types of diseases. For example, in the early days of heart disease research, epidemiologic studies were crucial to naming high-fat diets and smoking as major risk factors.
However, epidemiologic studies are observational, gathering information about people who are going about their daily lives. Study participants follow many behaviors and practices. It’s difficult, therefore, to tease out the exact benefits or risks of one particular behavior from all the healthy or harmful behaviors followed by the participants. That’s why, in epidemiologic studies of AD, scientists restrict themselves to saying that a behavior is associated with AD, or not. The epidemiologic evidence linking a behavior and AD is, at best, suggestive, but we don’t know whether the behavior actually helps to cause or prevent AD.
Other types of research—test tube studies, studies in animals, and clinical trials—add to the findings from epidemiologic studies. Scientists use these to examine the same issue but in circumstances in which the various factors that might influence a result are controlled to a greater degree. This element of control allows them to be more certain about why they get the results they do. It also allows them to use more definitive words to describe their results. (To see what we mean, take a look at the animal studies described in this section and Full-scale AD Treatment Clinical Trials in the section "Putting Treatment Hypotheses to the Test in Clinical Trials".) Of course, showing a cause-and-effect relationship in tissue culture or even in animal studies still does not mean that this result will be the same in humans. Clinical trials in humans are the gold standard for deciding whether a specific treatment actually prevents or delays AD. |
All of these epidemiologic and animal studies have suggested that regular exercise may, indeed, have benefits from the neck up as well as the neck down. Further, they point to some possible reasons why these benefits exist. However, some major questions remain. For example, does a person have to be fit throughout life, or can physical activity late in life still help? How much does a person have to exercise to reap the benefits? How do the benefits change with a person’s level of fitness? How long do the positive effects last? Does exercise interact in some way with cognitively stimulating activities (such as doing games and puzzles or participating in social networks) to benefit the brain, and if so, how do those interactions work? Are sedentary people who later develop dementia and AD less active because they are already in the early stages of the disease, or is it the reverse—the dementia is partially due to a history of physical inactivity? Another avenue of research—clinical trials—is well suited to examine some of these questions and provide some concrete answers.
NIA supports several clinical trials to explore issues related to exercise, cognitive function, and dementia risk:
- Aerobic exercise to improve executive function in sedentary older adults. This trial is examining the impact of a 6-month cardiovascular training program (walking briskly on a treadmill) on the ability of 80 older adults to carry out selected types of executive function tasks (for example, ability to block out irrelevant information and ability to switch easily from task to task) and on brain electrical activity.
- Aerobic exercise to improve cognitive and brain function in sedentary older adults. This clinical trial is exploring the hypothesis that improvements in aerobic fitness in older adults will benefit cognitive function and brain structure and activity. One hundred and forty sedentary older adults will be enrolled in a 1-year aerobic fitness intervention (walking briskly on a treadmill) and assessed for changes in brain and cognitive function.
- Aerobic fitness to maintain or improve cognitive function in people with amnestic MCI. A small-scale 12-week trial is examining the effect of an aerobic fitness program on cognitive function in 102 sedentary older adults with MCI. The investigators are studying the impact of exercise in delaying, arresting, or reversing the progression of age-related cognitive decline.
- Combination of group exercise and health education to improve cognitive function in people with amnestic MCI. This trial of 170 sedentary older adults with MCI is testing a combined intervention of group exercise and a health promotion program over 36 months. Individuals will be evaluated for the effectiveness of this intervention on cognitive, emotional, and physical function, as well as quality of life and rate of conversion from MCI to dementia.
Because the research area of physical activity and cognitive function is so important, NIA also is considering adding a cognitive component to future exercise trials that ask questions about exercise effects on other body systems. Scientists hope that the results of these lines of research not only will answer questions about the cause and development of MCI and AD, but also will provide motivation for individuals to become and stay physically active to promote and preserve the health of their brains as well as their bodies.
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