Part 1 of two.

Could Alzheimer’s disease be tempered by just by working up a sweat? Speakers at the Alzheimer's Association International Conference 2015, held July 18-23 in Washington, D.C., presented new evidence that regular aerobic exercise can help people in prodromal disease stages maintain their cognition, while for those with full-blown dementia it relieves neuropsychiatric symptoms. Some studies provided hints that exercise can also hone thinking at the dementia stage, but only if the participants reach moderate intensity heart rates during their workout. Exactly how exercise helps the brain is still not known, but several talks reported better cerebral blood flow and improved structural and functional connectivity in exercisers, and even some signs that six months or more of physical activity can slow pathology (see Part 2).

Researchers agreed that the duration and intensity of an exercise intervention are crucial to determining its effects. For aerobic exercise in particular, the field is standardizing methods and narrowing in on the appropriate dose to prescribe. Some believe supervised exercise classes could become part of the standard of care for people with cognitive problems. “Exercise is going to be an important adjunct to pharmacological treatment for patients with dementia,” Kristian Steen Frederiksen at the Danish Dementia Research Centre, Copenhagen, predicted to Alzforum. Overall, interest in this area seems to be growing, as evidenced by 11 talks and 23 posters on the topic at AAIC.

Researchers have few doubts now that exercise protects normal older adults against brain decline. Epidemiological studies suggest regular physical activity wards off future dementia (see Jul 2011 news and AlzRisk analysis). Supporting this, the most athletically fit older adults experience fewer age-related brain changes, and boast better cognition, than less-fit peers (see Nov 2011 conference news). In several small trials, cognitively normal older people who walked or did other aerobic exercise preserved or even increased their volume of brain gray matter compared with sedentary participants (see Sep 2008 newsOct 2010 newsFeb 2011 news). In Finland, cognitively normal participants in the FINGER study, which comprised multiple lifestyle interventions including exercise, also notched cognitive gains (see Jul 2014 conference news). 

Strengthening the Case for Benefits in the Cognitively Impaired
Can exercise also sharpen cognition in people who are already on the downhill slide? Emerging evidence, including several presentations at AAIC, indicates it can. Laura Baker of Wake Forest University Health Sciences, Winston-Salem, North Carolina, previously reported that aerobic exercise boosted executive function in a small cohort of cognitively impaired older adults in the Piedmont Aging, Cognition, and Exercise (PACE) study (see Baker et al., 2010). In Washington, Baker extended these findings to the larger Phase 2 PACE-2 study of 65 older adults with amnestic mild cognitive impairment and high blood sugar. This population is particularly vulnerable to further decline, she noted. Six months of moderate-intensity aerobic exercise, four times per week, enhanced executive performance over baseline measures on several tests. This contrasts with the continued decline seen in the control group, which took non-aerobic stretching classes.

Cognitive impairment can have many causes. In some people, it results from vascular issues, rather than AD pathology. Would exercise help this group? Teresa Liu-Ambrose at the University of British Columbia, Vancouver, has tested this hypothesis. In D.C., she described the PROMOTE study of 60 older adults with clinical diagnoses of mild vascular cognitive impairment. Participants also had evidence of subcortical white matter lesions by MRI (see Erkinjuntti and Rockwell, 2003). The 32 who exercised aerobically three times per week for six months preserved global cognitive function, as measured by the ADAS-Cog11, compared with controls who took an educational seminar once per month. This gain correlated with a drop in blood pressure, suggesting the improvement was due to better vascular health. The exercise did not protect against decline in executive function, which occurs in people with vascular cognitive impairment. However, the trial was powered to detect differences on the ADAS-Cog, and may not have been large enough to reveal an executive effect, Liu-Ambrose told Alzforum. She is following up with a larger, 12-month study in this population.

Do these promising findings in cognitively impaired people extend to those with full-blown dementia? Here the data are more equivocal. Frederiksen and Kristine Hoffman, also at the Danish Dementia Research Centre, presented findings from the Phase 3 ADEX study, a collaboration between eight memory clinics and seven research units in Denmark. In this 16-week trial, 200 people with moderate Alzheimer’s either worked out aerobically three times per week or performed their usual activities. By the end, the exercisers had become less depressed, less anxious, and less irritable than controls. Overall, exercisers saw no cognitive benefit compared to controls, but a subgroup of people who succeeded in working out at the intended intensity of 70 percent or more of maximum heart rate performed better on the Symbol-Digit Modalities test, a measure of executive function. In addition, the more exercise sessions they attended, the greater their improvement, implying a dose effect.

It’s All About that Dose: Finding the Right Prescription
Researchers have struggled to figure out how exercise should be dosed, a prerequisite for it to become a standard therapeutic intervention. For aerobic exercise, at least, the field is closing in on this, Baker said. Two crucial factors are the length of the intervention and the intensity. Several studies indicate a minimum of six months to produce cognitive improvement, Baker noted. At three months, she sees trends in her data, but nothing that reaches significance.

For intensity, data pinpoint moderate exercise as the most efficacious. This means that participants raise their heart rates to between 60 and 80 percent of functional capacity. This is calculated using a formula that takes into account the exercise intensity, resting heart rate, and maximum heart rate. A general rule of thumb is that a person's maximum heart rate per minute is 220 minus their age. For a 60-year-old, the desired zone would be around 125-145 beats per minute. While it is not yet clear why this level of exertion works best for the brain, Stephanie Schultz at the Wisconsin Alzheimer's Institute, Madison, noted that moderate aerobic exercise associated more closely with increased brain glucose metabolism than did vigorous workouts in the UW Fitness, Aging, and the Brain study. Brain glucose use drops during AD, which is thought to reflect ongoing neurodegeneration.

Baker noted several other factors important for standardizing trials of physical activity. For one, researchers must start with sedentary participants in order to see big effects, since fit participants may not have much room for improvement. Baker also stressed the importance of using an appropriate control group to account for the social and cognitive stimulation of participating in exercise sessions. In her trials, the control group takes a stretching class so that members receive the same social interactions as aerobic exercisers. She also instructs trainers to gradually ramp up the intensity of aerobic exercise over six weeks, so that participants do not become discouraged or find the class aversive and drop out. In her study, 92 percent of participants stuck with the intended program. “If we did not have the compliance we do, we would not see these effects,” she said.

On top of this, researchers said that there is a need to agree on which cognitive tests to use. Trials use a plethora of measures, making it difficult to compare them. Some researchers are adopting the NIH Cognitive Toolbox, a standardized and validated cognitive battery that is freely available online, Liu-Ambrose noted.

How close are researchers to delivering a prescription for exercise? Baker is enrolling participants for an 18-month aerobic exercise trial that she hopes will do just that. The Phase 3 EXERT trial will take place at 15 sites around the country and will start this fall. It will use the same parameters and methodology as her previous six-month trial, but will include some additional computerized cognitive outcome measures developed for prevention trials, to facilitate comparisons with other interventions (see Jun 2014 newsDec 2014 conference news).

As in the PACE-2 study, exercise classes will be held at YMCAs. Baker’s team is working with YMCA leaders to develop a standardized program for supervised exercise that could be implemented across the country. Cognitively impaired people have special needs and cannot simply join a regular exercise class, researchers agreed. If the results from this trial are positive, ideally the intervention would be covered by Medicare for seniors with cognitive issues, Baker said.

Will people actually take such an exercise class? “We all know exercise is good for us, yet as a country, we still don’t exercise,” Baker noted. However, her experience in the PACE trials indicates that cognitive benefits motivate people more strongly than physical ones. “If you provide people who have cognitive impairment with scientific evidence that physical activity might slow their decline, they start exercising immediately,” she told Alzforum.—Madolyn Bowman Rogers


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News Citations

  1. Can Exercise Slow the Progression of Alzheimer’s Pathology?
  2. Exercise and the Brain: More Support for Protective Effects
  3. DC: Ways to Slow Brain Aging: Exercise, Estrogen, and Sleep?
  4. Work Up a Sweat to Stay Sharp, Randomized Trial Suggests
  5. Research Brief: To Preserve Your Gray Matter, Take a Hike
  6. Get Moving—Walking Enlarges Hippocampus, Preserves Memory in Seniors
  7. Healthy Lives, Healthy Minds: Is it Really True?
  8. Test Battery Picks Up Cognitive Decline in Normal Populations
  9. Try This at Home: Cognitive Testing in the Age of Prevention Trials?

Paper Citations

  1. . Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Arch Neurol. 2010 Jan;67(1):71-9. PubMed.
  2. . Vascular dementia. Semin Clin Neuropsychiatry. 2003 Jan;8(1):37-45. PubMed.

External Citations

  1. AlzRisk analysis
  2. Phase 2 PACE-2 study
  3. PROMOTE study
  4. Phase 3 ADEX study
  5. NIH Cognitive Toolbox

Further Reading