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Laurie Barclay, MD, is a neurologist who has published more than 60 peer-reviewed journal articles concerning her research on Alzheimer's disease and other dementia. She is editor and author of several chapters in Clinical Geriatric Neurology. This report appeared in Medscape, where she is a regular contributor.

Exercise helps maintain brain structure and function with aging and may delay onset of Alzheimer's disease and other dementias, according to a review presented at the 114th annual convention of the American Psychological Association (APA).

"There is a diverse body of evidence from retrospective and prospective clinical studies, as well as from animal research, all of which suggests that exercise has beneficial effects from middle age to old age,"Arthur F. Kramer, a faculty member in neuroscience and psychology at the University of Illinois at Urbana in Champaign, told Medscape.

"Exercise has neuroprotective effects enabling higher levels of cognition and delaying the onset of various forms of dementia such as Alzheimer's disease in prospective epidemiological studies. It also has positive effects on brain structure and function, both from human research with magnetic resonance imaging (MRI), functional MRI, and event-related potentials, and especially from the animal literature showing proliferation of active capillary beds, new dendritic connections, and even new neurons in selective areas such as the hippocampus."

Along with co-authors Kirk I. Erickson and Stanley J. Colcombe, Dr. Kramer reviewed research evidence accumulated during the past four decades, including epidemiologic studies of the relationship between exercise and physical activity at various ages with cognitive ability and subsequent probability of developing Alzheimer's disease or other age-related neurological diseases. They also reviewed longitudinal randomized trials studying the effect of specific fitness training on cognition and brain function in older adults, as well as animal studies of the molecular and cellular basis of exercise effects on brain structure and function.

"Clinical data show that people who exercise several times per week show a reduced rate of cognitive decline with age compared with those who have low levels of activity," Carl Cotman, director of the Institute for Brain Aging at the University of California, Irvine, told Medscape. Dr. Cotman was not involved with Dr. Kramer's presentation but reviewed it for Medscape as an independent expert. "The best evidence, though, comes from animal studies, where it has been established that voluntary running increases neuroprotective molecules in the brain, such as brain-derived neurotrophic factor (BDNF), and also reduces the accumulation of molecules associated with Alzheimer's disease, such as beta-amyloid."

In the review by Dr. Kramer and colleagues, the epidemiologic literature showed a significant protective effect of physical activity on cognitive function and on decreased incidence of dementia, with the benefits lasting up to several decades. A few studies of human subjects older than 65 years showed that exercise lasting at least 15 to 30 minutes, three times weekly, reduced the probability of developing Alzheimer's disease, even in subjects who were genetically predisposed.

Clinical trials also suggest a relationship between fitness training and improved cognition, more efficient brain function, and prevention of brain atrophy in the elderly. A 4-year study of the relationship between physical activity and cognition and brain function in subjects aged 62 to 70 years showed that those who were still employed and retirees who exercised regularly had sustained levels of cerebral blood flow and superior performance on general measures of cognition compared with inactive retirees. In a 6-month study, elderly subjects who participated in aerobic exercise had a significant increase in gray matter volume in regions of the frontal and superior temporal lobe compared with controls.


"With the human data, there have been enough meta-analyses over the last ten years suggesting that exercise does have neuroprotective effects and also does tend to decrease depression ratings," Dr. Kramer said. "I don't see any downside to recommending exercise, even if the effects aren't as large or as robust as we think they are, because we already know that exercise tends to reduce mortality and decrease the incidence of cardiovascular disease, type 2 diabetes, and osteoporosis. I think there is no reason not to come up with a set of recommendations based upon both the disease literature and the animal literature."

Aerobic exercise appears to confer more positive effects on brain function with aging than do other forms of exercise. In a study of older adults, those who were randomized to a walking group for six months performed better on a distractibility task than did those randomized to a stretching and toning control group. Furthermore, the aerobically trained group had increased neural activities in frontal and parietal brain regions mediating attention, and reduced activity in the dorsal region of the anterior cingulate cortex, which is thought to be sensitive to behavioral conflict, or the need for increased cognitive control. Aerobic exercise also appears to help the brain maintain its plasticity.

"Physical activities that have a fairly strong aerobic component appear to be associated with spared cognition and delayed onset of dementia," Dr. Kramer said. "Other forms of exercise that have to do with toning and stretching, that lead to increased flexibility and decreased falls in older adults, are also beneficial, but they don't seem to be implicated in the cognitive-sparing effects. The animal literature suggests that learning new psychomotor skills can be beneficial in increasing new dendritic connections."

Animal studies offer additional insight into the neuroprotective effects of physical activity because they allow direct observation of morphologic, neurochemical and neurophysiologic changes associated with exercise. In studies using voluntary wheel running as a measure of aerobic activity, animals with increased wheel running performed better on spatial learning tasks mediated by the hippocampus. In other studies, aged rodents that exercised in a water maze learned and retained information about a hidden platform better than did age-matched controls. Both young and aged animals benefited from exercise, as reflected in increases in nerve growth factor levels that can offset or prevent certain age-related diseases.


In terms of clinical implications of these findings, certain questions remain unanswered.

"There are certainly unknowns, such as dose-response relationship in humans: how much exercise leads to how much cognitive benefit or decrease in odds ratios for Alzheimer's disease or vascular dementias," Dr. Kramer pointed out. "We also need studies that combine various lifestyle choices or interventions that research suggests are neuroprotective for humans, such as intellectual engagement, nutritional choices, use of antioxidants and other supplements, to determine the way these various interventions are additive or multiplicative."

Dr. Cotman agreed that clinical trials are needed to answer these questions. He recommended that exercise should have some type of aerobic component, but that the exact type is probably not as critical.

"The current data support that levels of activity will help but they do not provide an exact prescription," he concluded. "Based on epidemiological data and animal data, however, it is likely that exercise for three or more times per week is beneficial . . . Walking three or more times per week for 30 to 45 minutes also is beneficial."

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