How these exergames improve cognition is unclear, but two other studies suggest how the exercise component might work. Even without a virtual aid, exercise modulates the negative effects of the ApoE4 allele, report a team led by Denise Head at Washington University, St. Louis, Missouri. In the January 9 Archives of Neurology, they detail how sedentary ApoE4 gene carriers deposit more amyloid than those who exercise. Yet another study hints that autophagy is key. In the January 27 Nature, Beth Levine, University of Texas Southwestern Medical Center, Dallas, and colleagues report that exercise stimulates this recycling process—which rids cells of unwanted components—and that autophagy-deficient mice don't get the long-term muscle benefits of exercise. Some researchers wonder if exercise might also improve brain cell autophagy—which has been linked to Alzheimer’s and other neurodegenerative diseases.

A Virtual Brain Boost
Mounting evidence suggests exercise protects the aging brain, but according to the Centers for Disease Control and Prevention, less than 15 percent of elderly make exercise a part of their daily routine. What would make exercise more appealing to older adults? Anderson-Hanley and colleagues hypothesized that people would exercise more if they could make a game of it. In a cluster randomized control trial at eight different assisted living facilities, they asked 79 cognitively normal people over the age of 55 to ride identical recumbent bikes. Controls (n = 41) spent three months riding a plain old recumbent bike, but ”exergamers” (n = 38) rode a bike outfitted with a virtual display and gaming software. Games simulated a 3D tour, varied terrain, and a "ghost" competitor. Sixty-three people completed the study with at least three rides per week that averaged 33-35 minutes.

In terms of frequency of rides, energy expended, and speed, the exergamers and controls were not significantly different—so the study did not find evidence for increased motivation among exergamers. To the team's surprise, however, exergamers showed greater cognitive bang for their buck. They scored higher than non-gamers on tests of executive function, namely, the Color Trails 2-1, the Stroop C, and Digit Span Backwards tests, and fewer exergamers converted to MCI (three gamers versus nine controls). “This is a preliminary study with a small sample size, so we would encourage caution not to over-interpret the figures, but take them as an indicator that more research is warranted," Anderson-Hanley told ARF. In addition, the benefit of the simultaneous physical and mental exercise was greater than the expected additive effects of the two separately.

"It seems there's something special about this interactive synergistic mental and physical exercise," said Anderson-Hanley. "We hope that this will encourage older adults to pursue exercise, particularly this type, which is actually fun to do and may, for the same effort, yield added cognitive benefit." She and her team have already applied for an NIA grant to look at the benefits of cybercycling in a much larger sample of people who already have MCI. They also plan to explore whether cycling while doing unrelated mental exercises, such as completing a crossword puzzle or reading a book, would confer the same benefits. Cognitive training had had only moderate benefit in previous studies (see ARF related news story).

Deborah Barnes, University of California, San Francisco, pointed out that the two exercise groups started at baseline with different scores of executive function. "That made me much more skeptical of the findings—you'd like to see them starting at the same place, and then ending up at a different one," she said. Anderson-Hanley pointed out that the baseline difference was not statistically significant and was accounted for in the statistical analyses.

Regardless, said Barnes, if an exercise is enjoyable, people are more likely to stick with it. This type of exercise could be attractive to older populations because it is fun and can be done at home, with minimal risk of falling or need to venture out.

Gaming is a hot topic in the field right now, said Thomas Prohaska, University of Illinois at Chicago. More studies on the benefits of these virtual reality activities for older adults is likely to surface soon, he added. He warned that people should not put too much stock in one study, and that replication and longitudinal studies are needed. However, he said such virtual reality games may be akin to cognitively challenging activities like dancing—one has to coordinate with an outside stimulus or complete sequences of movements. "What effect does this have on the cognitive ability of the person? We need to understand better how and why these work," he said.

An ApoE4 Interaction
According to the WashU study, exercise may modulate the negative effects of the ApoE4 allele. Previous studies reported ApoE4 carriers deposit more amyloid than non-carriers (see ARF related news story on Reiman et al., 2009), and they are at greater risk for early cognitive decline (see ARF related news story on Caselli et al., 2009). Since people who are physically active are at reduced risk for cognitive decline (see ARF related news story on Middleton et al., 2011), Head and colleagues wondered if exercise would modulate ApoE4's negative effects.

The team recruited 201 cognitively normal adults aged 45-88 from the Knight Alzheimer's Disease Research Center at WashU, and determined each subject's ApoE genotype. A previously validated survey assessed how much running, walking, and jogging each person had done in the past 10 years (see Bowles et al., 2004). Participants were then grouped into low- or high-exercise engagement groups based on whether or not they fulfilled the American Heart Association-recommended 30 minutes of moderate exercise five days per week. Some volunteers (165) gave cerebral spinal fluid (CSF) samples, and 163 underwent positron emission tomography with the amyloid ligand Pittsburgh Compound B (PIB-PET).

As expected, those in the high-exercise group exhibited higher CSF Aβ42 levels and lower PIB binding than low-exercisers. Likewise, those who were ApoE4 negative had high CSF Aβ42 and low PIB binding relative to carriers. The team also found an interaction between exercise and ApoE4 in terms of PIB binding. Low-exercise/ApoE4 carriers had higher PIB binding than carriers in the high-exercise group. The team didn't find the same interaction for CSF Aβ42 levels, though there was a trend in that direction. The reason the two datasets did not converge is unclear, said Head, but may be because PIB and CSF Aβ levels measure two slightly different aspects of amyloid, Head said.

People who were ApoE4 positive and in the high-exercise group had about the same level of amyloid as non-carriers in the low-exercise group. However, Head cautioned that since the data are cross-sectional, she cannot determine the direction of causality, i.e., rather than more exercise leading to less amyloid deposition, more amyloid could have led to less exercise. Nevertheless, the study hints that "engaging in exercise may be particularly beneficial for people who are at genetic risk for Alzheimer's disease," she said. The field needs further longitudinal studies to probe the interaction, she added. This finding is consistent with some other cross-sectional studies that suggest a sedentary lifestyle plus an ApoE4 genotype puts people at greater risk for Alzheimer's, said Barnes. However, "I'm not sure we want to make clinical recommendations for people based on their E4 status," she said. Guidelines from the American College of Medical Genetics and the National Society of Genetic Counselors do not recommend people be given their ApoE4 status (see ARF related news story), in part because the results are not diagnostic. Really, everyone should exercise regardless of their status, Barnes said.

Exercise Stimulates Autophagy
Yesterday’s Nature paper may suggest a molecular reason for exercise's beneficial effects. Levine and colleagues found that physical exertion induced autophagy—the critical process by which cells break down unneeded or unwanted cell components—in mouse skeletal muscle. Autophagy is depressed in Alzheimer's disease (see Nixon et al., 2011), and its stimulation reportedly improves cognition in mouse models of tauopathy and amyloidogenesis (see ARF related news story).

First author Congong He and colleagues bred mice incapable of stimulus-induced autophagy, which, unlike resting-state autophagy, is ramped up during times of starvation or stress. During acute exercise, the mutant mice could not run as far and metabolized glucose less efficiently than controls. Over the long term, the mutants lacked protection against the impaired glucose tolerance that comes with a high-fat diet. This exciting finding seems almost obvious after thinking about it, said Philipp Jaeger, University of California, San Diego, who was not involved in the study. Starvation is a known trigger for autophagy, he said, so locally induced starvation brought on by exercise seems somewhat obvious. "Why didn't we look at this earlier?" he asked. "The big question is, What is going on in the brain?" he added.

Though it was not mentioned in the paper, a peek inside the brains of these mice indicated that exercise ramps up autophagy there as well, said Levine. "Based on what we know about the protective effects of autophagy in neurodegenerative disease, and our preliminary findings that exercise does induce autophagy in brain, I think it's reasonable to hypothesize that exercise-induced autophagy might, at least in part, explain the protective effects of exercise," she said. "One could look in the brains of these mice to see whether exercise is beneficial for adult neurogenesis, and whether there are effects on amyloid deposition, for example, in Alzheimer's mice," suggested Tony Wyss-Coray, Stanford School of Medicine, California.

Levine plans to collaborate with other groups to find out if autophagy is necessary for the neuroprotective effects of exercise in animal models of neurodegenerative diseases.—Gwyneth Dickey Zakaib.

References:
Anderson-Hanley C, Arciero PJ, Brickman AM, Nimon JP, Okuma N, Westen SC, Merz ME, Pence BD, Woods JA, Kramer AF, Zimmerman EA. Exergaming and Older Adult Cognition: A Cluster Randomized Clinical Trial. Am J Prev Med. 2012 February. Abstract

Head D, Bugg JM, Goate AM, Fagan AM, Mintun MA, Benzinger T, Holtzman DM, Morris JC. Exercise Engagement as a Moderator of the Effects of APOE Genotype on Amyloid Deposition. Arch Neurol., 2012 Jan 9. Abstract

He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z, An Z, Loh J, Fisher J, Sun Q, Korsmeyer S, Packer M, May HI, Hill JA, Virgin HW, Gilpin C, Guanghua X, Bassel-Duby R, Scherer PE, Levine B. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature. 2012 January 26. Abstract