Taking just over 5000 steps daily could curb progression of preclinical Alzheimer’s disease (AD) by slowing the accumulation of tau protein in the brain, new data showed, possibly offering a more attainable activity goal for sedentary older adults.

Tau accumulation and cognition plateaued with 5001-7500 steps per day, but even modest activity at 3001-5000 steps daily was associated with notable slowing of tau accumulation and cognitive decline in those with existing early AD pathology.

Researchers leading the Harvard Aging Brain Study (HABS) had previously reported that higher daily step counts were linked to slower cognitive decline among cognitively normal adults with elevated brain amyloid-beta, but it was unclear whether this might be related to changes in amyloid-beta or tau over time or if more moderate activity would offer the same benefit.

“In the current study with a larger HABS cohort with longer follow-up, we were able to clarify that the association with cognitive decline was not explained by differences in amyloid accumulation,” first author Wai-Ying Wendy Yau, MD, with Massachusetts General Brigham and Harvard Medical School, Boston, told Medscape Medical News.

“Instead, for a given amount of elevated amyloid burden, higher step counts were associated with slower accumulation of tau — the protein most closely linked to memory loss in AD — which largely explained the relationship with slower cognitive decline,” Yau said.

The study was published online on November 3 in Nature Medicine.

Unique Study

Physical inactivity is a well-established risk factor for AD, but its relationship with progression of AD pathology remains unclear. “Most previous studies linking physical activity to AD risk relied on clinical symptoms rather than direct measures of amyloid or tau in the brain,” Yau explained.

Yau and colleagues followed for up to 14 years 296 older adults from the long-running HABS project who were cognitively unimpaired at baseline. Participants wore pedometers to record daily steps and underwent annual cognitive testing along with regular amyloid and tau PET brain scans.

They divided participants into four step-count groups: inactive (≤ 3000 steps/d); low activity (3001-5000 steps/d); moderate activity (5001-7500 steps/d); and active (≥ 7501 steps/d).

Even modest activity levels made a measurable difference over time. Compared with inactive individuals, cognitive decline was lower by 40%, 54%, and 51% across increasing physical activity levels.

Similar results were seen in terms of functional decline. Compared with inactivity, there was 34%, 45%, and 51% slower functional decline across increasing physical activity levels.

Gains plateaued around 7500 steps per day, suggesting that moderate activity may be enough to confer meaningful benefit, the researchers said.

Of note, the associations between physical activity and cognition and function were not related to differences in cross-sectional or longitudinal amyloid-beta pathology.

Instead, in a subset of 172 individuals with longitudinal tau PET, a “new and concordant” association emerged between higher physical activity and slower tau accumulation in the brain, “which significantly mediated the relationships with slower cognitive and functional decline,” the researchers wrote.

While clinical trials are needed to establish cause and effect, the findings are “very encouraging and add to growing evidence that physical activity is an important factor in healthy aging including for brain and cognitive health,” Yau said.

Important Data With Caveats

Several outside experts weighed in on the findings in a statement from the UK nonprofit Science Media Centre.

Masud Husain, DPhil, BMBCh, FMedSci, professor of neurology and cognitive neuroscience, University of Oxford, Oxford, England, noted that the study had a relatively small cohort and was not designed as a clinical trial to measure the effects of exercise.

“These limitations mean that we have to be cautious in our interpretation of the findings,” Husain commented.

However, he added, “The strength of this research is the combination of serial highly specialized scans that measure amyloid and tau deposition in the brain, with cognitive assessments and baseline step count. This is unique.”

Tara Spires-Jones, PhD, director of the Centre for Discovery Brain Sciences at The University of Edinburgh, Edinburgh, Scotland, noted that, “So far, trials indicate that exercise is good for cardiovascular function and has small benefits for cognitive function. On balance the data in the field indicate that keeping physically active is good for your brain but is not a guarantee of preventing or slowing dementia.”

Charles Marshall, PhD, professor of clinical neurology, Queen Mary University of London, London, England, agreed.

“With this type of observational study, it is always hard to be sure whether the physical activity is actually the thing causing the observed difference. The authors do a good job of trying to disentangle this, but we cannot be certain whether the people doing more exercise are healthier in other ways, nor whether the development of Alzheimer’s disease changes are influencing activity levels (reverse causality),” Marshall commented.

It's also unclear whether the findings are due to physical activity in later life or if cognitive benefits come after decades of regular physical activity, he said.

“Nevertheless, this study does add to a wealth of evidence suggesting that regular physical activity is good for your brain as well as all of the other physical benefits it brings, and I would have no hesitation in encouraging people to aim for a daily step goal,” Marshall said.

This study was supported by the National Institutes of Health and a Doris Duke Charitable Foundation Clinical Scientist Development Award. The study authors, Husain, Spires-Jones, Marshall, and Julia Dudley had no conflicts of interest.