25 Jul 2019

Physical activity not only benefits the heart and the body, it may also shield the brain from the damaging effects of Aβ. That’s according to findings presented at the Alzheimer’s Association International Conference, held July 14–18 in Los Angeles. Active people in their 70s were less likely to suffer the cognitive and neurodegenerative consequences of Aβ deposition than their more sedentary peers, said Jennifer Rabin, Massachusetts General Hospital in Charlestown. Good vascular health also held Aβ-related damage in check, although it appeared to do so independently of physical activity, she said. The study, led by Jasmeer Chhatwal at MGH, was published July 16 in JAMA Neurology.

Sport in the 50s associated with less plaque 25 years later.

In the 70s, physical activity associated with less cognitive decline and brain atrophy in people with Aβ deposition.

Activity and good vascular health may independently protect against amyloid.

“This important study adds considerable weight to the growing amount of evidence indicating the importance of maintaining a physically active lifestyle for reducing the risk of cognitive decline and neurodegeneration,” commented Kirk Erickson, University of Pittsburgh.

Numerous observational studies suggest that physically active people are at lower risk for cognitive decline, dementia, and/or neurodegeneration (Jan 2019 news; Apr 2019 news; Mar 2018 news; Blondell et al., 2014).

This was borne out by several studies of large cohorts presented at this year’s AAIC. Researchers led by Katherine Bangen at the University of California, San Diego, reported that among 2,337 50-year-olds in the Framingham Offspring study, those who exercised less were more likely to become cognitively impaired seven years later. Tianya Hou, working with Dorina Cadar at University College London, reported that among 7,807 participants 50 and older in the English Longitudinal Study of Ageing, those who reported greater physical activity had slower cognitive decline and better maintained executive function over the ensuing eight years. In her talk, Cadar reported that in the same cohort, high physical activity reduced the risk of dementia over 12 years by 40 percent. Likewise, Priya Palta, Columbia University, New York, reported that in the Atherosclerosis Risk in Communities (ARIC) study, people who pursued moderate to high physical activity in midlife had 12 percent less cognitive decline over 14 years and about a 40 percent reduced incidence of dementia than their sedentary peers (Palta et al., 2019).

Wanqing Wu, Huashan Hospital, Shanghai, reported that among 1,370 50-plus-year-olds in the Shanghai Aging Study, those who exercised at a moderate to vigorous level were 45 percent less likely to get dementia over the next five years. Richard Mayeux’s lab, also at Columbia, reported that maintaining physical activity across the lifespan may be important for maximum benefit. First author Yian Gu’s analysis of 1,288 adults in the Washington/Hamilton Heights-Inwood Columbia Aging Project suggests that those who had exercised vigorously since their teenage years were 60 percent less likely to develop dementia. All is not lost for late starters. Participants who reported low physical activity between ages 12–25, but high activity after age 50, were still half as likely to get dementia as those who reported never being physically active.

How does exercise protect the brain? Earlier studies have implicated lower levels of brain amyloid, less hypometabolism and atrophy (Liang et al., 2010; Brown et al., 2012; Okonkwo et al., 2014). This, too, was borne out by presentations in Los Angeles. Katsuyuki Miura and colleagues from Shiga University, Japan, found that among 680 men in the Shiga Epidemiological Study of Subclinical Atherosclerosis, those 60 and older who walked a lot, as assessed by pedometer over seven days at baseline, had less brain atrophy five years later. The benefit appeared limited to the prefrontal cortex and left entorhinal cortex. Marta Milà-Alomà, Barcelonaβeta Brain Research Center, Spain, reported that in the ALFA+ cohort, who have family histories of AD and extensive biomarker data, physical activity came with reduced amyloid burden, as judged by CSF Aβ42. Among 257 cognitively normal volunteers, 26 percent of the physically active fell below the 1,098 pg/mL threshold versus 47 percent of the inactive group.

Even so, few studies have examined how physical activity modulates the relationships between Aβ deposition, brain volume, and cognitive decline.

Rabin and colleagues addressed this in the Harvard Aging Brain Study (HABS). They followed 182 cognitively normal participants who averaged 73 years of age at baseline. Each had worn a waistband pedometer for one week during waking hours, to measure the number of steps they were taking in a typical day. Also at baseline, the participants underwent Aβ-PET and MRI scans, took cognitive tests, and were assessed for vascular risk factors. Annual cognitive tests and MRI scans were then taken over an average of six and 4.5 years, respectively.

The participants averaged nearly 6,000 steps per day, a modest level of activity that did not necessarily include structured exercise, according to Chhatwal. The researchers found no relationship between physical activity and Aβ burden—as measured by the distribution volume ratio across a composite of frontal, lateral temporal and parietal, and retrosplenial regions—at baseline. As expected, more-active people had lower vascular risk.

The researchers also found that Aβ burden at baseline correlated with decline on Preclinical Alzheimer’s Cognitive Composite (PACC) in the following years. Baseline physical activity appeared to dramatically lessen that Aβ-related cognitive decline. In fact, among people with the highest Aβ burden—defined as a DVR above 1.9—those who had walked more than 8,300 steps per day did not decline on the PACC, while those who walked less than 2,900 dropped by about 1.25 standard deviations. People with the lowest Aβ burden, below 1.1 DVR, also did not decline regardless of their baseline physical activity.

The researchers observed similar trends for gray-matter brain volume. Though brain shrinkage occurred across the cohort, baseline Aβ burden correlated with a steeper drop in volume, and physical activity attenuated that effect. In particular, those who were more active had less Aβ-related cortical thinning in the entorhinal cortex, insula, lateral temporal, and medial parietal regions, all of which typically shrink over the course of AD. However, unlike some previous studies, they found no association between physical activity and hippocampal volume.

Chhatwal told Alzforum that although physical activity staved off brain atrophy in people with high Aβ deposition, that protection accounted for only about 20 percent of the cognitive benefits. He proposed that exercise improves the integrity of neural networks involved in memory, and improves circadian rhythms, both of which likely also contribute to the cognitive benefit.

Rabin also reported less cognitive decline and less brain atrophy in Aβ-positives who had low vascular risk. Chhatwal was surprised to find that vascular health and physical activity independently associated with these beneficial outcomes. This could suggest that physical activity protects neurons from Aβ-mediated damage by means other than improving vascular health, for example by boosting neurotrophic factors or strengthening neural circuitry. However, other researchers cautioned that it may be extremely difficult to disentangle the contributions of physical activity and vascular health.

Together, the findings support the idea that better physical fitness and better cardiovascular health can fend off Aβ-mediated degeneration, Chhatwal said.

This is borne out in the ARIC study. Also at AAIC, Palta reported that physical activity associated with less Aβ accumulation in the brain. She noted that prior studies on this association have been equivocal, perhaps because most examined few people over short intervals. In a subset of the ARIC cohort, Palta studied 326 participants who had florbetapir scans between 2011 and 2013, 25 years after the volunteers had entered ARIC. Each had described the duration and frequency of their four most common leisure activities during the year before their baseline assessment and also over the year before their brain scan. Palta and colleagues used the Compendium of Physical Activities to assign a metabolic equivalent (MET) to each activity (Ainsworth et al., 2000).

Mid-life METs per week correlated inversely with whole-brain florbetapir standard uptake value ratios (SUVRs). ARIC used an SUVR of 1.2 as a cutoff for amyloid positivity. Those below the cutoff reported a mean MET per week of 381 minutes, while those above only mustered an average of 270 minutes. Calculated as an odds ratio, those who were physically active in midlife and met 2018 physical activity guidelines (Piercy et al., 2018) were about 17 to 30 percent less likely to have brain amyloid. Though those ORs were not statistically significant, Palta said the trend was consistent. Late-life physical activity did not correlate with amyloid, likely because the two were measured within a year of each other.

Rabin’s findings add to the preponderance of evidence in the field that physical fitness and vascular health strengthen the brain’s resilience against all manner of insults, including Aβ, commented Eric Larson of Kaiser Permanente Washington Health Research Institute in Seattle. He added that improvements in overall health, including diet, exercise, and social connections, likely all help mitigate the risk of AD and related diseases.

Teresa Liu-Ambrose of the University of British Columbia in Vancouver agreed. “What is not known in this study is whether the level of physical activity observed at baseline was maintained by the individuals over time,” she added. “Understanding the relationship of physical activity levels over time in relation to changes in cognitive and brain outcomes is important. It may identify critical periods of prevention or intervention.”

Chhatwal acknowledged some study limitations, including the brief, one-week measurement of physical activity. The waistband pedometers available at the time had a short battery life, which limited the number of days they could be worn, and also did not measure the intensity of physical activity, he said. The researchers are now using modern wrist accelerometers, which give a more detailed accounting of activity and intensity over longer periods of time. He said future studies will include those data, as well as longitudinal measurements of both Aβ and tau deposition.—Jessica Shugart and Tom Fagan