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Walking has beneficial cognitive effects in amyloid-positive older adults


Key clinical point: Walking was associated with preserved cognition over a median of 4 years in cognitively normal, amyloid-positive subjects.

Major finding: Subjects with high amyloid burden who walked the least declined by almost 1 point on the PACC score; high-amyloid subjects who walked the most stayed at their baseline score.

Data source: A prospective, observational study comprising 255 elderly subjects with normal cognition.

Disclosures: The presenter had no financial disclosures.



– Walking appears to moderate cognitive decline in people with elevated brain amyloid, a 4-year observational study has determined.

Among a group of cognitively normal older adults with beta-amyloid brain plaques, those who walked the most experienced significantly less decline in memory and thinking than those who didn’t walk much, Dylan Kirn reported at the Clinical Trials on Alzheimer’s Disease conference. Walking didn’t affect any of the hallmark 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.

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

Dylan Kirn
Dylan Kirn
The project is part of the ongoing Harvard Aging Brain Study, which is a longitudinal study 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. Mr. Kirn is the clinical research manager for the study.

The walking study comprised 255 subjects with a mean age of 73 years. They were highly educated, with a mean of 16 years’ schooling. About 24% were amyloid-positive by PET imaging. All were cognitively normal, with a Clinical Dementia Rating scale score of 0. Activity was established at baseline with a pedometer, which was worn for 7 consecutive days; only those who walked at least 100 steps per day were included in the analysis.

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

The 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 an increasingly popular item 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 Exam, the Total Recall score from the Free and Cued Selective Reminding Test, and the Delayed Recall score on the Logical Memory IIa sub-test from the Wechsler Memory Scale. It correlates well with amyloid accumulation in the brain, Mr. Kirn said.

The cohort was followed for up to 6 years (median of 4), and PACC scores were calculated annually. The investigators looked at the relationship between walking at baseline and PACC decline over the study period in two multivariate models: One controlling for age, sex, and years of education, and the second for those variables plus the biomarkers of cortical WMHs, bilateral hippocampal volume (HV), and FDG-PET in brain regions typically affected by Alzheimer’s.

Physical activity was divided into tertiles by the average number of steps per day over the 7-day measuring period: Mean (5,616 steps), one standard deviation above mean (high; 8,482 steps), and one standard deviation below mean (low, 2,751 steps). Amyloid-positive patients were further divided into those with high brain amyloid load and those with low amyloid brain load.

There were no significant relationships between any of the biomarkers and any level of physical activity in either of the analyses, Mr. Kirn said. However, when looking at the time-linked changes in the PACC, significant differences did emerge. 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 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 the other hallmark Alzheimer’s 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, there was no association between cognition and activity. All the groups improved their PACC scores over the study period, probably reflecting a practice effect, Mr. Kirn said.

Finally, he split the amyloid-positive group into subjects with low and high brain amyloid levels. “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 didn’t see a tremendous amount of decline.”

The study suggests that pedometers may have a place in stratifying patients for clinical trials, or assessing 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,” Mr. Kirn said. “These findings support consideration of objectively measured physical activity in clinical research, and perhaps in stratification for risk of cognitive decline.”

He had no financial disclosures.

On Twitter @Alz_Gal

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