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Can Walking Protect Cognition in Amyloid-Positive Older Adults?

Data from an observational cohort suggest a benefit, but cannot support claims about causality.


BOSTON—Walking appears to moderate cognitive decline in people with elevated levels of amyloid in the brain, according to a four-year observational study described at the Clinical Trials on Alzheimer’s Disease conference.

Among a group of cognitively normal older adults with beta-amyloid brain plaques, those who walked the most had significantly less decline in memory and thinking than those who walked little, said Dylan Kirn, MPH. Walking did not affect any biomarkers of Alzheimer’s disease, such as brain glucose utilization, amyloid accumulation, or hippocampal volume, but it was associated with significantly better cognitive scores on a composite measure of memory over time.

Dylan Kirn, MPH

“We should be careful in interpreting these data, because this is an observational cohort, and we cannot make claims regarding causality or the mechanism by which physical activity may be influencing cognitive decline,” said Mr. Kirn, Clinical Research Project Manager at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital in Boston. “But I find these results interesting and novel, and I think they support further investigation.”

The Harvard Aging Brain Study

The research is part of the ongoing Harvard Aging Brain Study, which is a longitudinal investigation of cognitively normal elderly individuals that seeks to identify the earliest changes in molecular, functional, and structural imaging markers that signal a transition from normal cognition to progressive cognitive decline and preclinical Alzheimer’s disease. The walking study included 255 subjects with a mean age of 73. Participants were highly educated, with a mean of 16 years’ schooling. About 24% of the population was amyloid-positive on PET imaging. All patients were cognitively normal, with a Clinical Dementia Rating scale score of 0. Activity was measured at baseline with a pedometer, which was worn for seven consecutive days; only people who walked at least 100 steps per day were included in the analysis.

In addition to amyloid PET imaging, subjects underwent an 18F-fluorodeoxyglucose (FDG) PET scan to assess brain glucose utilization, and MRI to measure hippocampal volume changes and white matter hyperintensities (WMHs). Changes in all of these biomarkers can herald the onset of Alzheimer’s disease.

The study’s primary outcome was the relationship between physical activity, as measured by number of walking steps per day, and changes on the Preclinical Alzheimer’s Cognitive Composite (PACC) test. This relatively new cognitive scale is gaining increasing use in clinical trials. The PACC is a composite of the Digit Symbol Substitution Test score from the Wechsler Adult Intelligence Scale–Revised, the Mini-Mental State Examination, the Total Recall score from the Free and Cued Selective Reminding Test, and the Delayed Recall score on the Logical Memory IIa subtest of the Wechsler Memory Scale. It correlates well with amyloid accumulation in the brain, said Mr. Kirn.

The cohort was followed for as long as six years (median follow-up, four years), and PACC scores were calculated annually. The investigators examined the relationship between walking at baseline and PACC decline during the study period in two multivariate models. One model controlled for age, sex, and years of education, and the second controlled for those variables plus cortical WMHs, bilateral hippocampal volume (HV), and FDG PET in brain regions typically affected by Alzheimer’s disease.

The investigators sorted physical activity into tertiles by the average number of steps per day over the seven-day measuring period. The middle tertile was the mean (ie, 5,616 steps/day), the top tertile was one standard deviation above the mean (ie, 8,482 steps/day), and the bottom tertile was one standard deviation below the mean (ie, 2,751 steps/day). Amyloid-positive patients were further categorized as having high or low brain amyloid load.

No Relationship Between Activity and Biomarkers

The researchers found no significant relationships between any of the biomarkers and any level of physical activity in either of the analyses, said Mr. Kirn. When looking at the time-linked changes in the PACC, however, they found significant differences. Subjects who walked at least the mean number of steps per day were much more likely to maintain a stable cognitive score, while those who walked the fewest steps declined by about a quarter of a point on the PACC. The difference in decline between the high-activity and low-activity subjects was statistically significant, even when the investigators controlled for amyloid burden and other Alzheimer’s disease biomarkers.

The level of physical activity at baseline was a particularly strong predictor of cognitive health among amyloid-positive subjects. Those in the high-activity group maintained a steady score on the PACC. Those in the mean activity group declined slightly, and those in the low activity group showed a sharp decline, losing almost a full point on the PACC by the end of follow-up.

In the amyloid-negative group, the researchers found no association between cognition and activity. PACC scores improved for all groups during the study period, which probably reflects a practice effect, said Mr. Kirn.

“We observed that physical activity was significantly predictive of cognitive decline in high-amyloid participants, but not in low-amyloid participants,” he said. “Individuals with high amyloid and low physical activity at baseline had the steepest decline in cognition over time. But in those with high amyloid and high physical activity at baseline, we did not see a tremendous amount of decline.”

The study suggests that pedometers may help stratify patients for clinical trials or assess cognitive risk in elderly subjects. “Most studies that have looked at physical activity and dementia use a self-reported activity level, so the results have been varied,” said Mr. Kirn. “These findings support consideration of objectively measured physical activity in clinical research, and perhaps in stratification for risk of cognitive decline.”

—Michele G. Sullivan

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