Regular Exercise May Slow Progression to Alzheimer's

Pauline Anderson

September 19, 2019

Regular aerobic exercise appears to delay hippocampal atrophy in older amyloid-positive patients with amnestic mild cognitive impairment (aMCI), new research suggests.

The single-blind, proof-of-concept study also showed that patients who were previously sedentary and who participated in an aerobic exercise program experienced improvements in memory and executive function, although they still experienced progressive overall brain atrophy and amyloid beta (Aβ) deposition.

Control persons in the study who performed stretching exercises also experienced cognitive benefits.

Dr Rong Zhang

The findings suggest that aerobic workouts may slow the effects of Alzheimer disease (AD) if introduced in the early stages, study author Rong Zhang, PhD, professor, Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, told Medscape Medical News.

Zhang wants clinicians to encourage patients at risk for AD, including those who have memory complaints or a family history of AD, to "safely" perform moderate to vigorous aerobic exercise for a minimum of 30 minutes three to five times a week.

"That's the best suggestion based on the data I have right now," he said.

The study was published online August 8 in the Journal of Alzheimer's Disease.

Fitness and Brain Health

Numerous studies have linked fitness with brain health. A 2018 study showed that individuals who had lower fitness levels experienced faster deterioration of vital nerve fibers in white matter. In addition, animal research has correlated exercise with slowed hippocampal atrophy.

These previous findings prompted Zhang and his team to investigate further. He pointed out that a "key" unanswered question is "what happens to the brain of aMCI patients if they engage in aerobic exercise."

The study included 70 participants (mean age, 65 years). Most were white, and 61% were women. Study participants did not engage regularly in exercise, had memory problems, as indicated by the global Clinical Dementia Rating scale, and had been diagnosed with aMCI.

Participants were randomly assigned to participate in either aerobic exercise training (AET) or a stretching and toning (SAT) program.

In the AET group, each participant's program was based the individual's fitness level. The program started with three 25- to 30-minute exercise sessions per week at an intensity of 75% to 85% of maximal baseline heart rate. The dose and intensity of the exercise program progressively increased as participants adapted to their workouts.

The frequency and duration of the SAT exercises were the same as for AET, but the heart rate in the SAT group was kept below 50% of maximum during each session. During the course of the study, participants used low-resistance exercise bands to improve muscle strength.

Participants monitored their heart rate and kept a training log. Each month, they visited the clinic to download heart rate data and review their progress with an exercise physiologist.

At baseline and at the end of the study, 59% of participants underwent MRI, and 52% underwent positron-emission tomography scanning. The mean cortical 18F-florbetapir uptake (standardized uptake value ratio [SUVR]) was higher for the SAT group than the AET group.

Among those who underwent brain imaging, 85.0% in the AET group and 86.4% in the SAT group were amyloid positive. About 27.8% of the AET group and 38.9% of the SAT group were APOE4 carriers.

Less Atrophy

One of the study's primary outcome measures was the California Verbal Learning Test, Second Edition (CVLT-II), a 16-item list-learning task that measures verbal learning and episodic memory.

Another primary outcome was the Delis-Kaplan Executive Function System (D-KEFS), which comprises several individual verbal and nonverbal executive function measures.

Secondary outcomes, which focused on amyloid-positive patients, included global brain and hippocampal volumes and mean cortical and precuneus Aβ plaque deposition.

Researchers also assessed peak oxygen uptake (VO2), the gold-standard measure of cardiorespiratory fitness.

Of the 70 participants, 31% withdrew from the study. This relatively high attrition rate may have biased outcome measures, the authors note.

Over 12 months, both study groups improved slightly but significantly relative to baseline on the total CVLT-II score and on the D-KEFS trail making, color-word inhibition, and category fluency scores.

These improvements likely reflect more than just a practice effect, said Zhang. He pointed out that all participants had memory impairment that affected their ability to learn.

In both groups, global brain and hippocampal volumes decreased (P < .001 compared to baseline) and precuneous SUVR increased (P = 0.024 compared to baseline).

The mean cortical SUVR did not change after 12 months. These results did not alter after adjusting for the baseline group difference in mean cortical SUVR.

For those in the AET group, peak VO2 significantly improved by about 10% compared with the SAT group (P = .010).

Among amyloid-positive patients, those in the AET group demonstrated less hippocampal volume reduction compared with the SAT group (P = .030).

Impact on Tau?

The finding regarding hippocampal volume is important, said Zhang, because tau tangles initially occur in the hippocampal area, and less hippocampal atrophy in these patients may mitigate the rate of tau accumulation. Research suggests that for AD to develop, an interaction between amyloid and tau must occur.

"It appears that aerobic exercise might have some impact on that interaction," said Zhang.

He would like to find out if this is the case, and he plans to conduct a larger, longer study. "What I really want to see is a clinical endpoint, like reducing Alzheimer's disease or dementia," he said.

The lack of a "real" placebo group is a "major limitation" of the study, said Zhang. He explained the challenges of designing a control group for an exercise study and said it would be unethical to recruit sedentary patients into a study and then encourage them to remain sedentary.

Another limitation was that APOE genotype analysis was performed only in a subset of participants, which limits the statistical power to analyze the interaction effect of APOE genotype and treatment on outcome measures.

Previous research suggests that AET-related improvement of cognitive performance is attenuated in APOE4 carriers.

"Therefore, our findings could have been influenced by the APOE4 status and need confirmation by the future studies with a larger sample size," the authors write.

Several physiologic mechanisms may help explain how aerobic exercise boosts cognitive function. These include improved cerebral perfusion and white matter fiber integrity and increased release of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF).

During physical exercise, skeletal muscle contractions can upregulate hippocampal BDNF expression and may lead to adult hippocampal neurogenesis, the authors.

Overall, 11 adverse events occurred. These included four cases of arrhythmia during VO2 testing, as well as cases foot, ankle, and knee pain, which occurred while patients were on the treadmill. The numbers of adverse events were similar for each group.

Stepping Stone

Commenting on the findings for Medscape Medical News, Richard Isaacson, MD, director of the Alzheimer's Prevention Clinic at New York–Presbyterian/Weill Cornell Medicine, said the study is a "stepping stone" to the types of trials that can more definitively prove that exercise and other lifestyle interventions "really move the needle" against Alzheimer pathology.

"The most important aspect of this study is that the exercise group specifically delayed atrophy of the hippocampus in patients with the earliest symptomatic stage of Alzheimer's disease," he said.

From the totality of evidence, most clinicians now believe that exercise has some protective effect on brain health, but relatively few have thought that exercise would affect people with MCI, said Isaacson.

"This study brings us one step closer toward teasing out the effects of exercise in people with biomarker-defined Alzheimer's vs people who have memory loss not due to Alzheimer's specifically," he said.

On average, Isaacson and his colleagues now recommend 21 interventions for patients in their Alzheimer's Prevention Clinic. "But based on the current evidence, personally tailored exercise programs are likely the single most powerful evidence-based driver of change," Isaacson said.

"A Great First Step"

Also commenting for Medscape Medical News, Rebecca Edelmayer, PhD, director of scientific engagement, Alzheimer's Association, agreed that the study, although small, is "a really great first step."

"We have seen throughout the literature in the field that exercise and other types of nonpharmacological interventions may be a way we could impact the brain's biology, but we need to build the evidence for that," said Edelmayer.

The Alzheimer's Association has launched the 2-year US POINTER study, which will monitor the effects of a structured exercise regime, as well as the effects of improved nutrition, social and cognitive stimulation, and better management of overall health.

It will include more than 2000 participants aged 60 to 79 years who have health risk factors and are at high risk for cognitive decline. It will include imaging and genetic testing as well as assessment of other biomarkers.

The study was funded by the National Institutes of Health. The authors have disclosed no relevant financial relationships.

J Alzheimers Dis. Published online August 8, 2019. Abstract

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