WASHINGTON, DC—For the first time, a randomized study has demonstrated that vigorous physical exercise not only improves cognition in patients with mild cognitive impairment (MCI), but also moves Alzheimer’s disease biomarkers in the right direction.

Six months after subjects with MCI began aerobic exercise, their scores on a composite measure of cognition increased significantly. In addition, hypometabolic brain regions associated with Alzheimer’s disease symptoms were reperfused, and levels of phosphorylated tau—a marker of neuronal injury—in CSF significantly decreased, said Laura Baker, PhD, of Wake Forest University in Winston-Salem, North Carolina. Dr. Baker presented results from the trial at the 2015 Alzheimer’s Association International Conference.

An Intervention With Multiple Targets

The finding of reduced tau is especially intriguing, said Dr. Baker. The biggest improvements occurred in subjects older than 70 whose tau levels were elevated due to age. “I hope that we are moving toward being able to demonstrate that regular, moderate aerobic exercise can attenuate the effects of both aging and Alzheimer’s [disease],” she said. “This is a potential intervention that combats two diseases if we regard aging as a disease process.”

Aerobic exercise is easy to institute, inexpensive to continue, and confers numerous physical and mental benefits, Dr. Baker said.

“Like other lifestyle interventions, exercise targets multiple health-restoring biological processes. It’s not just one molecule affecting one part of our chemistry, but multiple targets. These kinds of interventions with diversified target portfolios may be our most potent means to prevent and slow Alzheimer’s [disease].”

Dr. Baker and her colleagues conducted a six-month exercise trial with 71 sedentary adults who had MCI and prediabetes (hemoglobin A1c of 5.7% to 6.4%). The researchers randomized the subjects, ages 55 to 89, to either a control program of thrice-weekly stretching or to an exercise program of thrice-weekly aerobic exercise for 45 to 60 minutes. Most subjects used a treadmill, but other forms of exercise were also allowed, including stationary bikes and approved group classes.

The intervention group aimed to maintain an exertion level of 70% to 80% of their maximum heart rate, while the control group exercised at below 35% of their maximum heart rate. Both interventions were carried out under the supervision of a study researcher. Importantly, both groups received the benefit of leaving their house several times a week and experiencing social interactions at the gym, Dr. Baker said.

At baseline and six months, all participants completed cognitive testing (verbal recall and tests of executive function), a 400-meter timed walking test, glucose tolerance test, body fat assessment, and blood and CSF collection. Forty participants also underwent structural and functional brain MRI.

For their analysis, Dr. Baker stratified participants by those younger than 7 and those older than 70. The investigators also controlled for age and education.

Biomarker Data

There were no reductions in CSF tau in either age group in the stretching cohort. However, in the exercise cohort, both age groups experienced significant declines in CSF tau. Tau levels in the older group decreased by 10 pg/mL. “In fact, the greatest drops in tau occurred among the folks who were starting with the highest levels,” Dr. Baker said.

The researchers also found a trend, albeit nonsignificant, for a positive change in CSF amyloid-beta-42 among the intervention group. “In the stretching group, we expected to see continuation of disease, and this was reflected in the CSF amyloid levels, which increased over six months. In the aerobic group, this increase appeared to be attenuated.”

Changes in Key Brain Regions

Whole brain blood flow also improved significantly in the exercise group and was driven by increased flow in regions associated with aging and Alzheimer’s: the superior frontal cortex, posterior cingulate, and cingulate gyrus.

“In all three regions, blood flow was increased bilaterally, and these increases were similar,” said Dr. Baker. “This [finding] was encouraging and suggests that changes related to aging and Alzheimer’s [disease] benefited. Typically, the signature profile of aging is reduced flow in the superior frontal region, and the profile for Alzheimer’s [disease] is reduced flow in the posterior cingulate and cingulate gyrus. These are exactly the regions that were boosted by exercise.”

The cognitive measure was a compilation of several tests of executive function. “Independent of age and APOE ε4 status, we saw significantly improved performance.”

Dr. Baker said that she is eager to follow up with her cohort and find out not only how many participants have independently continued to exercise, but to retest them and see if the effects were transient or imparted some lasting benefit. She also plans to initiate an 18-month phase III trial of the two interventions at 15 sites throughout the United States. “We really hope these results will help us move this work forward,” she said.

—Michele G. Sullivan

Aerobic Exercise Benefits Patients With Mild Cognitive Impairment