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New research bolsters evidence that people with early signs of Alzheimer’s can take steps to slow the devastating neurologic disease — literal steps. Researchers tracked nearly 300 older adults who had no cognitive impairment at the start of the study, measuring their memory and problem-solving skills, among other abilities, for up to 14 years. They also scanned their brains to monitor the build-up of beta-amyloid and tau, toxic proteins linked to disease progression. Advertisement The scientists found that patients who started with high levels of beta-amyloid, an early biological sign of Alzheimer’s, declined less if they were more physically active. Low or moderate levels of physical activity in this group, the authors reported, could slow cognitive decline by half compared with inactive individuals. That effect plateaued at around 5,000 to 7,500 steps a day. But exercise didn’t slow the buildup of beta-amyloid, the target of current therapies aimed at restraining cognitive loss. Physical activity was instead linked with a slower buildup of tau, which scientists increasingly believe plays a more direct role than amyloid in cell damage and death. The findings, published in the journal Nature Medicine, build on previous evidence that exercise can delay and slow dementia by proposing a mechanism for this phenomenon: reduced accumulation of tau. The paper also suggests that the oft-cited goal of 10,000 steps a day, which may be difficult to achieve for some older adults, might not be necessary for cognitive benefits. Advertisement Because the results come from an observational study, they do not prove that exercise causes the observed benefits. But the authors argue their findings can be used to design clinical trials that could offer more definitive evidence. “We’re all working on better treatments, better drugs, but we can’t underestimate the value in these lifestyle factors that people can implement on their own to protect their brain health,” said Wendy Yau, a neurologist at Mass General Brigham and the study’s first author. Nearly 7 million people live with Alzheimer’s in the U.S., and that’s projected to double by 2060. The disease is among the 10 leading causes of death in the U.S., according to the Centers for Disease Control and Prevention. While there are two approved drugs for the condition — Leqembi, developed by Biogen and its partner Eisai, and Eli Lilly’s Kisunla — there’s intense interest in further slowing or preventing the fatal disease’s progression, particularly before symptoms appear. “I think the preclinical population is one that’s been getting and is going to continue to get more and more attention,” said Carolyn Fredericks, a Yale neurologist not involved in the study who said its findings offer an intriguing, testable hypothesis. “Looking at the efficacy of these kinds of lifestyle measures in this [presymptomatic] period makes so much sense, and very few people have done it.” There is growing evidence that physical activity is a modifiable risk factor for Alzheimer’s. Earlier this year, researchers published results from a randomized trial showing that older adults at risk of cognitive decline benefited from a set of lifestyle interventions that included regular exercise, nutrition, and health coaching. But much of this clinical evidence comes from self-reported activity levels, which aren’t always reliable. Previous studies have also offered little insight into the precise mechanism behind exercise’s benefits, though mouse experiments have suggested that exercise might reprogram brain cells. Advertisement In the new paper, a research team led out of Mass General Brigham looked to shed new light on the topic through the Harvard Aging Brain Study, an observational study launched in 2009 to find early changes related to cognitive decline. The authors analyzed older adults who used a step-counter to track their daily activity during a one-week period. Study subjects, who were followed for nine years at the median, then had their cognition assessed each year with a pair of tests: Preclinical Alzheimer’s Cognitive Composite (PACC) and Clinical Dementia Rating Sum of Boxes (CDR-SB), the latter a commonly used metric in Alzheimer’s trials. They also had their beta-amyloid and tau levels measured via position emission tomography, or PET. Researchers found that increased physical activity correlated with slower decline as measured by PACC5 and CDR-SB, consistent with previous findings from this group. This correlation, however, was only significant in participants with high levels of beta-amyloid at the study’s outset, a group that included 88 participants. The authors then looked at beta-amyloid and tau in the brains of roughly 240 and 170 patients who were imaged for these proteins, respectively. They found that while exercise didn’t affect beta-amyloid levels, physical activity was linked with a slower buildup of tau in the inferior temporal cortex, a region that controls object and facial recognition. High levels of tau there often foreshadow the spread of toxic tangles throughout the brain. But interpreting that result is tricky, cautioned David Knopman, a Mayo Clinic neurologist and Alzheimer’s expert who was not involved in the work. Knopman pointed out that while participants may have less tau because they exercised, the opposite could be true — they may have exercised more because they had less tau, as the protein can affect motivation and behavior. “What I’m saying actually is not that I doubt what they [did]. I just have a nagging anxiety that the causality runs in the other direction,” he said. “I can’t prove they’re wrong, and they can’t prove they’re right.” Advertisement That’s a point the authors acknowledge in the study, though they argue that several observations suggest that exercise is driving the change in tau, including the fact that there was no association between physical activity and cognition at the study’s start. To understand how exercise’s effects varied by activity level, the authors broke up the cohort into subgroups based on whether they were inactive (less than 3,000 steps a day) or whether their activity levels were low (3,001 to 5,000), moderate (5,001 to 7,500), or high (7,501 and up). The researchers found that low activity was associated with substantial benefits compared with the inactive group, an effect that seemed to level off, with similar benefits between the moderate and high activity groups. The scientific team found that while it took around seven years for inactive participants to show signs of impaired cognition, it took roughly 10 to 14 years for those with low to moderate activity to show signs of impairment. “I think this is a really well-done study that has parameters in there which we were missing before,” said Christianne Wrann, a neuroscientist at Massachusetts General Hospital who has studied the relationship between exercise and Alzheimer’s. “No one is suggesting that you can cure Alzheimer’s disease just purely by exercising. If that would work, everyone would be doing that, but I think it does suggest that there’s a significant effect.” The study doesn’t answer what Yau calls the “million-dollar question”: How regular exercise leads to reduced tau buildup. But she notes there are several possibilities, including an exercise-induced increase in brain blood flow that helps the body clear waste. The paper’s authors are now looking to see how changes in activity over time impact cognitive decline, as the present study only evaluated participants’ activity over a one-week period at the study’s outset. Researchers are also using wearable devices to gather additional data from participants, including exercise intensity, to better understand what kind of activity maximizes cognitive benefits.
