BOSTON—Combined results from a pair of six-month, randomized trials indicate that aerobic exercise improves executive function to a significantly greater degree than do stretching and tone exercises in patients with mild cognitive impairment (MCI) or mild insulin resistance, Laura Baker, PhD, reported at the 2013 Alzheimer’s Association International Conference. The benefits were greatest in carriers of the APOE ε4 allele.
But the reason behind this improved function remains something of a mystery, said Dr. Baker, Associate Professor, Wake Forest School of Medicine in Winston-Salem, North Carolina. “In APOE ε4–negative participants, the mechanism is probably improved insulin sensitivity. But in the APOE ε4–positive patients, it seems to be some other mechanism that we don’t understand.”
Exercise modulates the risk of cognitive decline in several ways, according to Dr. Baker. “It has a diversified portfolio of targets,” she said. “Exercise exerts benefits on inflammation, improves the integrity of both macro- and microvessels, has a beneficial effect on physical and psychologic stress, and modulates inflammation, all of which have been shown to have potent effects on amyloid burden.”
These findings over the years have “set the stage nicely for clinical trials,” said Dr. Baker. “But what’s the right exposure? Who are the best responders? And what is the clinical significance of the changes? Do they translate into any improvement in quality of life?”
Two Physical Activity Trials
To answer some of these questions, Dr. Baker and her colleagues conducted two randomized, physical activity trials. The researchers recruited 67 participants: 33 subjects in a study of exercise in adults with MCI and 34 subjects with impaired insulin sensitivity who were in a similar study.
The two studies examined different aspects of the relationship between cognitive and metabolic health, Dr. Baker said. “Mild metabolic disease leads to vascular dysfunction and poor glucose tolerance, which puts a person at an increased risk of MCI and Alzheimer’s dementia.”
Both studies were six months long and randomized participants to 45-minute sessions of either a stretching and toning program or aerobic exercise, conducted four times a week. Both were held at local YMCAs and supervised by trained staff.
For the duration of the stretching program, the target heart rate was less than 35% of the maximum; the exercises also included balance and yoga. The aerobic program aimed for a heart rate of 70% to 80% of the maximum rate. It consisted of increasingly difficult workouts on a treadmill, stationary bike, or elliptical trainer. Adherence was very good, Dr. Baker said, with 93% of the subjects in each study completing the protocol.
Each trial had the same end points: tests of executive function (a composite of trail-making, word fluency, symbol-digit, and visual working memory) and short-term memory (story recall, list learning, and delayed matching).
The participants had a mean age of 68.5; altogether, 46 were randomized to the aerobic program and 21 to the stretching program. Subjects were out of shape, with a mean VO2 peak of 22 mL/kg per minute, which is considered below average for that age, said Dr. Baker. They were not an obese group overall, but they had a high body fat percentage of about 38%.
In the MCI study, the mean Mini-Mental State Examination score was 27. In the metabolic dysfunction study, the mean fasting glucose was 100 pg/dL, and the mean fasting insulin was 11.47 mU/mL.
Significant Gains After Aerobic Exercise
At the end of the studies, the aerobic exercise groups had made significant gains in their cardiorespiratory fitness, as measured by improvements in the VO2 peak, the treadmill incline, and the time that they could exercise. These measures were unchanged from baseline in the stretching group. The VO2 peak changes were not significantly associated with executive function.
The exercise groups in both studies also experienced significant gains on the composite measure of executive function, Dr. Baker said. They had an increase of about two points from baseline, compared with a decline of about three points from baseline in the stretching group. The gains were similar whether the subjects had MCI or insulin resistance.
All subjects in both studies also underwent oral glucose tolerance testing at baseline and again at their last visit to identify changes in insulin resistance. Measures of fasting glucose, fasting insulin, insulin resistance, and glucose disposal during metabolic clamp improved significantly in the exercise groups, with no difference by patient group or by APOE ε4 status.
A subanalysis that controlled for insulin sensitivity examined exercise’s contribution to the changes in executive function among the 52 individuals who were APOE ε4–negative and the 15 who were APOE ε4–positive. “With the change in insulin sensitivity out of the picture, the exercise-related cognitive benefit was greater for APOE ε4–positive adults,” she said.