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Physical Activity Moderates Amyloid-Beta Burden in Clinically Normal Older Adults

Article In Brief

Targeting physical activity and vascular risk factors may have additive beneficial effects on delaying the progression of Alzheimer's disease, a new study suggests.

Even a moderate level of physical activity, along with control of vascular risk factors, appears to delay and diminish cognitive decline in individuals with a high amyloid-beta (Abeta) burden, according to a longitudinal study of people at risk for Alzheimer's in the July 16 online edition of JAMA Neurology.

The two variables—physical activity and systemic vascular risk—appear to be independent of each other, and additive with respect to cognitive decline. Moreover, their effects were quantifiable in terms of diminished brain volume loss over time.

Researchers and those who reviewed the study for Neurology Today agree the study offers important longitudinal confirmation of the importance of physical activity in mitigating the risk of amyloid-related cognitive decline and Alzheimer's disease (AD) and provides critical counselling information clinicians can share with their patients.

“The take-home message is that greater physical activity in people with a high amyloid burden may be protective against cognitive decline,” said corresponding author Jasmeer P. Chhatwal, MD, PhD, assistant professor of neurology at Harvard Medical School.

“Importantly, this potential protective effect was seen at a fairly modest level of regular activity—eight or nine thousand daily steps as measured by a pedometer. People may think they have to go to Herculean efforts to increase their activity, but these data suggest that they don't have to run a marathon to potentially see a benefit. Notably, the effect of physical activity appears to be separate and additive with the potentially protective effects of lowering vascular risk. Finally, we saw evidence that physical activity was associated with slower brain volume loss over time, which is also a very tangible outcome.”

Study Design, Findings

Data came from 182 participants in the Harvard Aging Brain Study, a longitudinal examination of cognitive aging and preclinical AD led by Reisa A. Sperling, MD, and Keith A. Johnson, MD. The lead author of the paper was Jennifer Rabin, PhD, of the University of Toronto, Sunnybrook Research Institute.

Participants were followed for up to eight years and were required to have baseline measurements of amyloid-beta using positron emission tomography, and baseline medical data to quantify vascular risk. Structural brain imaging using MRI was carried out at baseline, year three and year five.

Investigators measured physical activity at baseline using a waistband-mounted pedometer. Participants were asked to wear the pedometer on their waist for seven consecutive days during waking hours. Mean steps per day was used as the primary measure of daily physical activity.

The main outcome was cognition, as measured annually with the Preclinical Alzheimer Cognitive Composite (PACC), which includes the Mini-Mental State Examination, Wechsler Adult Intelligence Scale–Revised Digit Symbol Coding, Wechsler Memory Scale–Revised Logical Memory delayed recall, and the Free and Cued Selective Reminding Test.

The researchers found that greater baseline engagement in physical activity was associated with slower amyloid-related cognitive decline and gray matter volume loss: that is, the effect of physical activity on slowing the rate of cognitive decline as measured by PACC and on brain volume loss was clearest in those with elevated amyloid burden. Moreover, the effect of physical activity on cognitive decline was independent of how well a subject's vascular risk factors were controlled.

Additionally, MRI demonstrated the effect of physical activity on specific brain regions: greater engagement in physical activity was associated with slower amyloid-related cortical thinning in medial temporal (entorhinal cortex), insula, lateral temporal, and medial parietal regions.

Dr. Chhatwal added that in time the significant effects of lifestyle and vascular control may augment the effect of pharmacological agents aimed at amyloid-related tau deposition in the brain. “We believe the effects [of physical and activity and vascular risk factor control] seen here may be additive with the potential beneficial effects of disease modifying agents targeting amyloid and tau, when they become available,” he said. “Late onset Alzheimer's is really multifactorial, so it makes sense that the most effective treatment approaches may be multifactorial too.”

Expert Commentary

Experts who reviewed the report for Neurology Today said the study is convincing confirmation of the value of physical activity in delaying cognitive decline, and firm evidence clinicians can offer in guidance to their patient.

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“People may think they have to go to Herculean efforts to increase their activity, but these data suggest that they dont have to run a marathon to potentially see a benefit. Notably, the effect of physical activity appears to be separate and additive with the potentially protective effects of lowering vascular risk. Finally, we saw evidence that physical activity was associated with slower brain volume loss over time, which is also a very tangible outcome.”—DR. JASMEER P. CHHATWAL

“This is really important translational research that clinicians can apply to care for their patients at risk,” said Richard S. Isaacson, MD, FAAN, director of the Alzheimer's Prevention Clinic at Weill Cornell Medicine and NewYork-Presbyterian, and trustee of the McKnight Brain Research Foundation. “Too many physicians feel that there is nothing their patients can do to reduce Alzheimer's risk. But they need to step back and realize that the science has changed.

“There is a lot of controversy in the field about whether amyloid is the cause of Alzheimer's, but there is greater agreement that it is a marker of disease severity,” Dr. Isaacson said. “A consensus is emerging that physical activity can minimize or attenuate not just amyloid-related cognitive decline but volume loss in parts of the brain related to Alzheimer's. The exercise effect is additive with control of vascular risk factors.

“The totality of evidence is overwhelming,” he told Neurology Today. “Physical activity and vascular risk factor modification are the cornerstone of any evidence-based Alzheimer's risk reduction plan.”

Yaacov Stern, PhD, chief of cognitive neuroscience in the department of neurology at Columbia University, agreed. “What is nice about this report is that the authors had a measure of amyloid burden at baseline, so we have an underlying indicator of Alzheimer's pathology,” he said. “Then they were able to get an actual measure of physical activity at baseline and follow the subjects longitudinally. We get a specific picture of neurodegeneration over time and a good characterization of the nature of protection that physical activity provides for the brain over time.”

Dr. Stern noted that a significant body of research is emerging looking at the effects of lifestyle, genetics and environment on the aging brain, with a focus on two properties—brain maintenance and cognitive reserve—by which these effects may be protective of the brain over time or help individuals cope better with brain changes. (Dr. Stern is chair of the Collaboratory on Reserve and Resilience, a three-year collaboration among several research institutions, supported by the National Institute of Aging, focused on age-related and disease related cognitive decline; reserveandresilience.com.).

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“What is nice about this report is that the authors had a measure of amyloid burden at baseline, so we have an underlying indicator of Alzheimers pathology. Then they were able to get an actual measure of physical activity at baseline and follow the subjects longitudinally. We get a specific picture of neurodegeneration over time and a good characterization of the nature of protection that physical activity provides for the brain over time.”—DR. YAAKOV STERN

He emphasized the importance of both attention to vascular risk factors and physical activity. “These are two separate variables that influence brain health over time,” he said. “It's very useful for patients to know that life experiences can help maintain the brain in a health state. The direct evidence in this study is that those with higher physical activity had less volume loss.”

Disclosures

Drs. Chhatwal and Isaacson had no disclosures. Dr. Stern has consulted for Axovant.

Link Up for More Information

• Rabin JS, Klein H, Kirn DR, et al. Associations of physical activity and β-Amyloid with longitudinal cognition and neurodegeneration in clinically normal older adults https://jamanetwork.com/journals/jamaneurology/fullarticle/2738357. JAMA Neurol 2019; Epub 2019 Jul 16.