Exercise and the Brain

Recent large-scale observational studies in various groups, including nurses, people living in rural areas, and older adults, have found reduced risk of cognitive decline and dementia among those who exercised regularly. These findings provide much valuable information, but can't tell us whether a cause-and-effect relationship exists between exercise and Alzheimer's disease risk. Other factors may be involved; for example, people who exercise may also have a more healthful diet or take better care of their health in other ways. Epidemiological studies like these need to be followed by other kinds of research, such as controlled clinical trials, to reinforce the findings and explore the reasons behind them.

Dr. Carl Cotman, a biochemist and the director of both the Institute for Brain Aging and Dementia at the University of California Irvine and the Alzheimer's Disease Center there, has focused much of his long career on how the brain ages and how lifestyle interventions might influence that process. He is fascinated by how the brain withstands the pressures of the aging process.

"The fact that a neuron has to live for a lifetime is a real challenge to a cell," Dr. Cotman said. "Most cells in the body don't have an infinite lifetime. The one-hundred-year-old neuron is a hero to me because it's self-repairing. It doesn't get to jump out of the circuit and get fixed at the local doctor or the local garage. It has to be maintained, and it does this through self-repair mechanisms. It's looking out for its own future while it maintains its own performance. That's a real triumph."

One of the mechanisms by which neurons repair themselves involves BDNF, or brain-derived neurotrophic factor, a protein that supports the survival of existing neurons and encourages the development of new ones. Dr. Cotman wondered if BDNF might help increase the longevity of neurons and prevent cognitive decline. "What would be the most ideal change that you could induce in the brain to help it maintain function longer and learn better? Several years ago, I thought it might be exercise. At the time, we knew that exercise improved muscle function, but there wasn't literature to show that it would have any impact on the brain beyond causing it to burn more energy. However, I thought that a growth factor like BDNF, a kind of a nutrient or a fertilizer to neurons, might be naturally increased with exercise."

He and his colleagues conducted a series of studies on rats to test that hypothesis. They separated them into two groups: an active group in cages with exercise wheels and a sedentary group in cages without exercise wheels. When his team examined the brains of the physically active animals, they found that levels of BDNF had increased not so much in the regions related to motor and sensory functions, which might have been expected, but, surprisingly, in the regions most integral to thinking and learning. These same regions are vulnerable to aging and AD. "The brain knew how to look out for itself in a way we had had no idea about. It has a self-preservation mechanism that allows it to learn better." Another study looked for behavioral changes. "We know that a mouse bred to develop AD finds it more and more difficult to learn as it ages. We wanted to know whether exercise improved the ability to learn." The mice were provided with exercise wheels when they were young. In late middle age, their learning and memory were challenged with a water maze. "It tests their ability to identify a particular space in a big area." At first, through trial and error, mice find an "invisible" platform located just below the surface in a pool of water made opaque by adding powdered milk. In subsequent trials, the mice use geometric shapes and symbols situated around the maze to recall how to navigate to the platform. "It's very similar to what you do when you're trying to find your car in a parking lot. You can't see your car, so you have to use cues around you to identify the correct location. The mice utilize the cues around the maze to find the platform. When they stand on it, they're happy because they're not wet anymore and they're not cold." The mice that had exercised were quickly able to remember the platform's location on later attempts, whereas the sedentary animals swam in circles, unable to locate the platform.

For a follow-up study, transgenic mice (specially bred to express a mutant gene associated with the development of AD), began exercising late in life, when they had already developed AD pathology. "Much to our surprise and delight, the exercise effect worked even after the animals had a fair amount of pathology." Dr. Cotman found less accumulation of beta-amyloid in the brains of the mice that had been allowed to exercise throughout their lives, and even in those that began to run later in life, compared to the amount of beta-amyloid in sedentary animals.

Dr. Cotman's follow-up studies have suggested that an increased level of BDNF may improve the ability of nerve cells to receive signals. He has discovered that BDNF builds synaptic structure, and he and others have shown that BDNF induces the growth of bud-like structures called spines on the dendrites that extend out from the nerve cell body. An increased number of spines allow neurons to signal to each other more efficiently.

In older rats and mice, other research has found that exercise increases the number of small vessels that supply blood to the brain. The brain benefits by having more energy for its metabolic functions from greater vascular flow.

Animal studies help explain the associations identified in epidemiological studies, but there is no guarantee that the same interventions will work with people. The National Institute on Aging has supported several clinical studies to define the biological basis of the possible effects of exercise. To assess brain changes, one trial used fMRI imaging to measure changes in brain activity in older adults before and after a six-month program of brisk walking. Results showed that brain activity increased in specific brain regions as cardiovascular fitness increased. A similar trial showed that brain volume increased as a result of a walking program. These findings support the observational studies and suggest a biological basis for the role of aerobic exercise in helping maintain cognitive function in aging adults, at least in the short term. Other clinical trials are investigating the effects of exercise in cognitively healthy older people, people at risk of MCI, and people with MCI.

Previous: Assessing the Potential Benefits of Exercise and Diet

Next: Diet and the Brain

Excerpted from THE ALZHEIMER'S PROJECT: MOMENTUM IN SCIENCE, published by Public Affairs, www.publicaffairsbooks.com.

Alzheimer's Disease (AD)

A progressive degenerative disease of the brain that causes impairment of memory and other cognitive abilities.

Amyloid Precursor Protein (APP)

The larger protein from which beta-amyloid is formed.

ApoE Gene

A gene that codes for a protein that carries cholesterol to and within cells; different forms of the ApoE gene are associated with differing risks for late-onset Alzheimer's disease. This gene may be referred to as a risk factor gene or a "susceptibility gene" because one form of the gene, called APOE4, is associated with the risk of developing late onset AD.

Beta-Amyloid

Derived from the amyloid precursor protein and found in plaques, the insoluble deposits outside neurons. May also be called A-beta.

Beta-Amyloid Plaque

A largely insoluble deposit found in the space between nerve cells in the brain. The plaques in Alzheimer's disease are made of beta-amyloid and other molecules, surrounded by non-nerve cells (glia) and damaged axons and dendrites from nearby neurons.

Cognitive Reserve

The brain's ability to operate effectively even when some damage to cells or brain cell communications has occurred.

Dementia

A broad term referring to a decline in cognitive function that interferes with daily life and activities. Alzheimer's disease is one form of dementia.

Functional MRI (fMRI)

An adaptation of an MRI (see magnetic resonance imaging) technique that measures brain activity during a mental task, such as one involving memory, language, or attention.

Hippocampal Formation

A structure in the brain that plays a major role in learning and memory and is involved in converting short-term to long-term memory. Also called the hippocampus.

Inflammation

The process by which the body responds to cellular injury by attempting to eliminate foreign matter and damaged tissue.

Insulin Resistance

A condition in which the pancreas makes enough insulin, but the cells do not respond properly to it; characterizes and precedes type 2 diabetes.

Magnetic Resonance Imaging (MRI)

A diagnostic and research technique that uses magnetic fields to generate a computer image of internal structures in the body.

Mild Cognitive Impairment (MCI)

A condition in which a person has cognitive problems greater than those expected for his or her age. Amnestic MCI includes memory problems, but not the personality or other cognitive problems that characterize AD.

Neurodegenerative Disease

A disease characterized by a progressive decline in the structure and function of brain tissue. These diseases include AD, Parkinson's disease, frontotemporal lobar degeneration, and dementia with Lewy bodies. They are usually more common in older people.

Oligomers

Clusters of a small number of beta-amyloid peptides.

Oxidative Damage

Damage that can occur to cells when they are exposed to too many free radicals.

Pittsburgh Compound B (PiB)

The radioactive tracer compound used during a PET (see Positron Emission Tomography) scan of the brain to show beta-amyloid deposits.

Pittsburgh Compound B (PiB)

The radioactive tracer compound used during a PET (see Positron Emission Tomography) scan of the brain to show beta-amyloid deposits.

Synapse

The tiny gap between nerve cells across which neurotransmitters and nerve signals pass.

Tau

A protein that helps to maintain the structure of microtubules in normal nerve cells. Abnormal tau is a principal component of the paired helical filaments in neurofibrillary tangles.

Tangles

A protein that helps to maintain the structure of microtubules in normal nerve cells. Abnormal tau is a principal component of the paired helical filaments in neurofibrillary tangles.

Memory

Normal Aging

Genetic Risk Factor

Dominant and Recessive Genes

Genes and Proteins

Protein-Misfolding Disease

Cholesterol

Biomarkers

Disease-Modifying Drug

Transgenic Mice

An animal that has had a gene (such as the human APP gene) inserted into its chromosomes for the purpose of research. Mice carrying a mutated human APP gene often develop plaques in their brains as they age.

Pathology

Microglia

Insulin & Insulin Resistance

Susceptibility Gene

A variant in a cell's DNA that does not cause a disease by itself but may increase the chance that a person will develop a disease.

Susceptibility Genes

A variant in a cell's DNA that does not cause a disease by itself but may increase the chance that a person will develop a disease.

Genome-Wide Association Study

Vascular Disease

Genetics

Genetics

Normal Aging