ARTICLE IN BRIEF
Investigators reported that dementia patients who participated in a four-month high-intensity exercise program actually experienced a small but statistically significant worsening of cognition. Independent experts said certain study limitations may have impacted the findings.
Four months of moderate- to high-intensity exercise in people with dementia resulted in no cognitive benefits, a large randomized trial commissioned by the United Kingdom's National Institute for Health Research found.
The researchers randomized 392 people with mild to moderate dementia to aerobic and strength training, and 165 to usual care. The primary outcome was their score on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) at 12 months.
Surprisingly, the study actually found a small but statistically significant worsening of cognition in people randomized to the exercise group. By 12 months, their mean ADAS-cog score had increased to 25.2, compared to 23.8 in the usual-care arm. The adjusted between-group difference was −1.4 (95% CI −2.6 to −0.2, p=0.03), although the authors noted that the difference was small and of uncertain clinical relevance.
Although fitness improved in the exercise group, as measured by performance on a test of six-minute walking distance, there was no improvement in activities of daily living or on any other secondary outcome, the study authors reported in the May 16 edition of the British Medical Journal. Nor did any differences emerge on preplanned subgroup analyses by dementia type (Alzheimer's disease or other), severity of cognitive impairment, sex, or mobility level.
The study authors, led by investigators at Oxford University, concluded, based on the results of this paper, that they could not recommend high-intensity exercise to patients with dementia. “There is the possibility,” the paper stated, “that the intervention could worsen cognition.”
In an interview with Neurology Today, the principal study investigator of the study said she was disappointed but not entirely surprised by the study's finding of no cognitive benefit to exercise in patients with dementia.
“I personally was not surprised that a slowing of cognitive decline did not occur,” said Sarah “Sallie” Lamb, PhD, Kadoorie Professor of Trauma Rehabilitation at the University of Oxford and professor of rehabilitation at the Warwick Clinical Trials Unit, University of Warwick. “But I certainly didn't anticipate any worsening. And I would have anticipated that the improvement in physical fitness would have resulted in improved functioning in daily life — how quickly you can walk upstairs, how confident you feel walking down the block.”
STUDY DESIGN, FINDINGS
The trial was conducted in response to a “Prime Minister's Challenge” launched by the UK government in an effort to seek a cure for, or alleviation of, dementia symptoms. Prior randomized trials of exercise in people with dementia had reached conflicting results. One systematic review, by the Cochrane Database of Systematic Reviews, found that exercise could improve physical but not cognitive or neuropsychiatric symptoms, while another found that aerobic exercise did in fact positively effect cognitive impairment.
Seeking to sort the out the matter, the Dementia and Physical Activity (DAPA) trial screened 2,929 people across England between February of 2013 and June of 2015. The 494 eligible patients had to have had a clinically confirmed diagnosis of mild to moderate dementia in accordance with DSM-IV and a standardized Mini-Mental State Examination score of greater than 10; they also had to be able to sit on a chair and walk 10 feet without assistance, and live in the community either alone or with others. People with acute, unstable physical or terminal illness that would make participation in the exercise program unsafe were excluded.
Participants in the exercise arm were prescribed aerobic and strength exercises tailored to their fitness and health status. They then attended supervised group sessions lasting 60 to 90 minutes in a gym twice a week for four months, and were asked to do home exercises for an additional hour each week.
At four months, the exercise group had participated in 1,697 face-to-face training sessions. The amount of weight lifted, and the duration of higher-intensity aerobic activity, both improved, and the distance walked in six minutes improved by 59 feet (95% CI 38 to 80; p<0.001).
Twenty-five adverse events occurred in the exercise arm, including four that were serious and clearly related to the exercise (one hospitalization for exercise-induced angina, two injurious falls, and one case of significantly worsening hip pain). No adverse events were reported in the usual-care group.
But no hint of benefit was seen in either cognition or activities of daily living, based on measurements at six or 12 months post-randomization (that is, two or eight months after completion of the four-month exercise training).
The mean ADAS-cog score at six months in the usual-care group was 22.4, compared to 22.9 in the exercise group, a non-significant difference of -0.6 (95% CI -1.6 to 0.4). At 12 months, the difference had become significant, in favor of the usual-care group: 23.8 vs. 25.2 (CI -2.6 to – 0.2). Similarly small but significant negative effects were seen for the exercise group on the language, memory, and praxis subscales of the ADAS-cog score.
US neurologists familiar with the paper said they saw no reason, for now, to change clinical recommendations.
“The totality of evidence is still overwhelming that physical exercise is the best thing that a person can do to reduce the risk of developing Alzheimer's disease,” said Richard Isaacson, MD, director of the Alzheimer's Prevention Clinic at the Weill Cornell Memory Disorders Program. “Maybe it's not enough when somebody has already progressed to having dementia. But we'll need more studies to be sure.”
Dr. Isaacson said the DAPA trial was well designed and conducted. “The exercise intervention was very robust,” he said. “It was adequately powered to move the needle. But the needle didn't move. Was it the exercise program that wasn't sufficient? Was it the duration? Was it the ADAS-cog tool? That's really not the best scale in the world. But long story short, given everything they did, the intervention wasn't successful. That's surprising.”
Sudha Seshadri, MD, FAAN, director of the Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases and Robert R. Barker Distinguished University Professor of Neurology at the University of Texas Health Sciences Center in San Antonio, said that her studies have found that the benefits of exercise accrue after decades, not months.
“The effects of exercise are really long-term, so perhaps the duration of the intervention was too short,” said Dr. Seshadri, who is also a senior investigator of the longitudinal Framingham Heart Study.
“My personal hunch, based on some of the initial data from Framingham, is that even a low level of exercise is valuable compared to a sedentary lifestyle,” Dr. Seshadri said. “If I were designing the next study, I would use the results of this study as an indication for the need to include an arm with less vigorous exercise. I would not give up in this area.”
David S. Knopman, MD, FAAN, professor of neurology at Mayo Clinic in Rochester, MN, agreed that the trial was well done but perhaps not long enough to see an effect.
“This trial examined only cognition and activities of daily living as outcomes,” he said. “It didn't look at emotional health, and it didn't look at cardiovascular consequences. The fact that it didn't help cognition after such a short duration of therapy isn't that surprising.”
An analysis of data from the Mayo Clinic Study of Aging, published earlier this year in the Journal of Alzheimer's Disease, prospectively studied a cohort of 280 people. Those who had engaged in midlife, moderate-intensity activity had a significantly decreased risk of incident dementia (HR?=?0.64; 95% CI, 0.41-0.98) by the age of 70.
“Those people who engaged in physical activity in both midlife and late life combined were the ones who had the most significantly decreased risk,” said the first author of that study, Janina Krell-Roesch, PhD, assistant professor of neurology at Mayo Clinic in Phoenix, AZ. “The most beneficial activity was moderate intensity. We have even argued that engaging in vigorous activity when you're older may not be good for you. Just engaging in light or moderate-level activity would be more than sufficient.”
That view was seconded by Dr. Lamb. “My take-home message is that the body of evidence says that gentle physical activity is good for you,” she said. “We tested a high-intensity protocol, equivalent to a drug. If patients are thinking of starting an exercise program, my advice is to begin with something gentle, to have a safe level they can enjoy.”