Regular Aerobic Exercise for the Mitigation of Alzheimer Dementia

By Susan Marcolina MD, FACP, Dr. Marcolina is a board-certified internist and geriatrician in Issaquah, WA; she reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.

Part 2 of a Series on Alzheimer's Disease

Alzheimer's disease (AD) is the most common cause of adult-onset dementia and one of the most dreaded sequelae of the aging process.1 Its clinical features include insidious but progressive memory loss and severe cognitive decline, which result in the loss of independent functioning and increased caregiver burden. Patients experiencing such cognitive decline often eventually need long-term nursing home care with its attendant increased costs. Approximately 75% of dementias are diagnosed as the Alzheimer type.2

Several risk factors for cognitive impairment (see Table),3 specifically cardiovascular disease, are amenable to lifestyle modifications.4 The relationship between physical fitness levels, cognition, and overall general health in older adults is well established; therefore, regular physical exercise can be a common pathway through which to prolong neurocognitive health in the context of improved overall health.5

Changes in Cognition and the Brain with Aging

There is considerable heterogeneity in the patterns of cognitive senescence among individuals due both to genetic as well as environmental factors (see Table).6 The aging process also does not affect the central nervous system uniformly. Between the ages of 30 and 90, approximately 15% of the cerebral cortex and 25% of the cerebral white matter of the average human brain has diminished disproportionately in the areas of the prefrontal, frontal, and temporal brain regions. Because these areas control executive thought processes, language, memory, and learning, this pattern of loss is closely matched by declines in cognitive performance.7,8

Colcombe et al demonstrated this localized pattern of cortical loss in an MRI morphometric imaging study of 55 community-dwelling older adults aged 55-79. Notably, persons with the best aerobic fitness as measured by VO2 scores experienced significant gray and white matter tissue sparing in these crucial areas even after correction for alcohol and caffeine consumption, hormone replacement therapy, years of education, and hypertension.9

Definition of Types of Brain-Enhancing Exercise

Aerobic exercises (e.g., walking, hiking, bicycling, calisthenics, cross country skiing, and swimming) are defined as those that require continuous and rhythmic use of large muscle groups and increase resting heart rate by at least 60% of heart rate reserve. Optimal cardiovascular benefit is obtained when these exercises are done for at least 30 minutes on most but preferably all days of the week.10

Physiologic Effects of Exercise on Brain Function

Regular exercise has been postulated to enhance brain function through various physiological mechanisms including decreased brain deposition of beta amyloid plaques, increased cerebral blood flow, and reduced accumulation of reactive oxygen species. All of these processes have been implicated in the pathogenesis of AD.11,12 Regular physical exercise upgrades neural growth proteins, especially brain-derived neurotrophic factor (BDNF) and fibroblast growth factor-2 (FGF-2) in the hippocampus, an area particularly vulnerable to the effects of AD and other dementias. These growth factors have roles in promoting proliferation and reactivity of astrocytes, as well as survival and growth of neurons and capillary formation.13,14

Regular exercise also reduces the incidence of cardiovascular disease and stroke. Spirduso noted that higher levels of fitness enhance the activity of monoamine neurotransmitters in the brain, particularly dopamine. Such enhancement moderates the effects of aging, which decreases the levels of these neurotransmitters.15

Additionally, the physical training of regular exercise can have a direct beneficial effect on psychological variables such as improved self-image and sense of control and elevated mood. Some of these psychological variables may mediate patterns of chronic cardiovascular reactivity in response to stress.16

Several lines of evidence deal with a pathogenetic role of stress hormones on the occurrence and progression of cognitive disorders in elderly subjects. The hippocampus is particularly sensitive to stress hormones due to its high concentration of corticosteroid receptors. Magri et al studied cortisol secretion in clinically healthy old subjects, age-matched demented patients, and young controls. Both healthy elderly and the demented patients, especially those with AD, had significantly higher cortisol levels at nighttime compared to the healthy young controls. Qualitative and quantitative changes of the adrenal secretory pattern were significantly and directly correlated with a decrement in hippocampal volumes as measured by MRI.17

Gender Susceptibility and AD

Epidemiologic studies have shown higher prevalence rates of AD in women, but the underlying physiologic reason for the gender predilection is not known. A meta-analysis by Colcombe and Kramer revealed that fitness training programs had a larger impact on cognition if the study samples had at least 50% female enrollment. They speculated that this effect may be due to the influence of estrogen (as estrogen replacement therapy) on BDNF: Estrogen causes the up-regulation of BDNF.13,18 Both estrogen and BDNF are important for synaptogenesis and neurogenesis, particularly in the region of the hippocampus.19,20

This speculation, however, was not borne out clinically by the recent Women's Health Initiative Memory Study, which showed no improvement in memory or other cognitive abilities for women older than age 65 on hormone replacement therapy.21

Clinical Studies

A Fratiglioni et al review of nine observational studies concluded that physical exercise in the elderly is inversely correlated with risk for all-cause dementia and Alzheimer disease.22 Over a follow-up period of 5-7 years, risk reductions varied from 20% to 50%. The limitation of the included studies was the fact that they enrolled healthy persons free of dementia and evaluated the association of baseline physical activity with subsequent onset of dementia. Although these studies measured baseline physical activity prior to the clinical onset of dementia, they could not exclude the possibility that lower baseline exercise levels were a consequence of early, subclinical cognitive impairment. Such reverse causation bias, which can occur in the context of chronic diseases such as dementia, makes it difficult to know for certain whether the diminished physical activity was an epiphenomenon of the preclinical dementia or a cause of subsequent dementia.22,23

Larson et al made a special effort to overcome this bias in their prospective longitudinal cohort study of 1,740 persons 65 years and older followed biennially over six years by setting a high threshold score for participants in the Cognitive Ability Screening Instrument (CASI).24 Only participants with scores between 91 and 100 were enrolled in an effort to exclude persons with incipient dementia. (The CASI scores range from 1 to 100; a score of 86 corresponds to a Mini-Mental Status Examination score of 25-26).

Persons who exercised three or more times per week had a relative hazard of 0.68 for developing dementia compared to those who exercised fewer than three times per week when adjustments were made for the potential covariates of alcohol consumption, smoking, supplement use, education, presence of the apolipoprotein E e4 alleles, diabetes, hypertension, cerebrovascular disease, self-rated health, coronary disease, physical performance, depression, and cognitive functioning. Within this homogeneous, primarily white and well-educated study group, physical exercise resulted in an overall 32% risk reduction for dementia. Interestingly, regular exercise was associated with the greatest risk reduction in participants with a baseline of poor physical functioning.

Teri et al demonstrated in a randomized prospective controlled trial of 153 community-dwelling AD patients and their caregivers that patients assigned to the combined exercise and caregiver training program had improved health outcomes and depression scores after three months when compared to the routine care group.25

Exercise Prescribing

The Centers for Disease Control and Prevention (CDC) and the American College of Sports Medicine (ACSM) currently recommend 30 minutes or more of moderate-intensity physical activity on most or preferably all days of the week for all adults, including the elderly.26 The Institute of Medicine recommends that all adults, including the elderly, perform 60 minutes of moderate-intensity physical activity daily to promote health and vigor and to decrease the risk for chronic illnesses and early death.27

Patients can be started on a walking regimen utilizing the PBS Personal Health and Fitness Program,28 which contains information about starting and ramping up an exercise program to a goal of 10,000 steps or more. This distance approximates the daily exercise recommendations of the CDC and the ACSM. Patients should be encouraged to record their daily exercise and monitor their progress. The ACSM offers patients color brochures on the use of exercise equipment such as a stability balls and resistance bands.29 A free newsletter downloaded from the ACSM web site (available at: gives important information about fitness, diet, and exercise.

In addition to physical exercise, mental exercise activities such as reading, playing board games, assembling puzzles, or playing a musical instrument have been associated with a decreased risk for subsequent dementia among older adults.30

Public Health Initiatives

Successfully changing individual behavior for the long term requires more than personal change strategies. Institutional and public policy changes are critical to achieving sustained behavioral change in individuals. For example, initiatives such as the U.S. Department of Health and Human Services' Steps to a Healthier U.S. encourage families and individuals to take small manageable steps to increase their physical activity within their current lifestyles rather than drastic changes to ensure long-term health. Since its inception in Fiscal Year 2003, the Steps program has awarded $100 million to 40 communities nationwide to implement evidence-based activities that contribute to increased physical fitness. Additionally, Steps funds the YMCA of the USA as a partner to expand the reach of community based programs.31 Specific information about Steps communities throughout the United States is available at

The National Institutes of Health has published an informative and helpful booklet for patients entitled Energize Yourself! Stay Physically Active which can be downloaded from

Both the AARP (formerly the American Association of Retired Persons) and the Alzheimer's Association have started initiatives to increase the awareness of strategies both to preserve and enhance cognitive functioning among older adults. The Alzheimer Association's Maintain Your Brain encourages older adults to make "brain healthy life choices" such as maintaining physical, social, and mental fitness and choosing a diet low in saturated fats and rich in antioxidant-containing fruits and vegetables.32 Similarly, the AARP's Staying Sharp initiative encourages older adults to involve themselves in regular physical, social, and mental exercises and to practice the techniques of repetition, visualization, building associations, planning, and prioritization to sharpen memory. Staying Sharp offers a two-hour forum in certain cities to present these memory-enhancement concepts.33


Regular aerobic physical exercise is a cost-effective addition to the primary preventive and secondary treatment of dementia. Its potential benefits extend beyond cardiovascular risk factor modulation to also positively impact brain health in delaying the onset of age-related cortical grey and white matter frontal, parietal, and temporal losses. This provides another compelling reason to promote its incorporation into a patient's lifestyle prescription.


Physicians should prescribe regular daily aerobic exercise for themselves and for their patients. Exercise benefits all individuals at all levels of ability but is particularly important for persons who currently have functional limitations. Exercise as a therapeutic modality is cost-effective, has few adverse side effects, and provides positive health effects for the entire body. Performing regular mental exercise in the form of board games, crossword puzzles, and playing musical instruments is another useful way to practice cognitive flexibility, thus building cognitive reserve.

To implement specific exercise interventions, physicians should refer patients and their families to the information presented in the NIH, AARP, and Alzheimer Association initiatives mentioned above and follow their progress. Local community resources such as the YMCA and community centers may also have specific fitness programs and personal training professionals that can provide geriatric patients with appropriate and enjoyable physical activities, which, when incorporated into their daily lives, will improve their overall general medical and neurocognitive health.


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