Few doubt the overall benefits of a healthy diet and regular exercise, but can adhering to a salubrious lifestyle keep the brain sharp? There has been a trend afoot saying "yes," but two new studies published in JAMA on August 25 found no cognitive benefit in older people who started exercising or taking supplements. Cognitive changes were secondary measures for each of these large studies. One study, led by Jeff Williamson at Wake Forest University in Winston-Salem, North Carolina, reported that older, sedentary adults who engaged in physical activity for two years saw no differences in cognitive function compared to others who took health education classes. The other study, led by Emily Chew of the National Institutes of Health in Bethesda, Maryland, reported no cognitive benefit for seniors who took omega-3 fatty acids and/or antioxidants for four years. The researchers and commentators highlighted several reasons why the studies fell flat, ranging from the frailty and older age of people in the cohorts to the simple fact that these interventions don’t improve cognition. In the end, researchers were left to stress that regardless of whether staying fit sharpens the brain, the numerous other bonuses of a healthy lifestyle make it well worth the effort.
Several observational studies support the idea that physical activity staves off cognitive decline (see Jul 2011 news; May 2012 news). However, results from randomized controlled trials (RCTs) have been mixed, perhaps due to factors including differences in the length and intensity of the interventions, and to varying levels of social stimulation achieved by activities in control groups, which could affect cognition (see Sep 2008 news; Apr 2013 news; Jul 2014 conference news). The most recent plug for exercise came at this year’s AAIC meeting, when Laura Baker of Wake Forest University presented data from a trial of 65 people with mild cognitive impairment and high blood sugar. In this cohort, which is particularly at risk for dementia, six months of moderate exercise boosted executive performance (see Aug 2015 conference news).
In the JAMA study, first author Kaycee Sink of Wake Forest drew on cognitive data from a much larger trial. The Lifestyle Interventions and Independence for Elders (LIFE) study tests whether a two-year moderate exercise routine would prevent loss of mobility in cognitively normal sedentary adults. Its more than 1,600 participants, aged 70-89, scored low on physical fitness tests at baseline, but all could walk at least a quarter mile without incident. In addition to tracking physical condition and mobility, the researchers employed a battery of neuropsychological tests to measure memory, executive function, and attention at baseline and two years later.
Half of the participants exercised moderately five to six times a week. They took part in a twice-weekly group exercise program of 30 minutes of walking followed by 20 minutes of strength and flexibility training, and they were asked to exercise on their own three to four days per week. An active control group took a weekly interactive health education class, which included a few minutes of stretching. The researchers found that the exercise and control groups fared roughly the same, having remarkably stable cognitive scores between baseline and two years. Exceptions to this were people over the age of 80 and those who scored particularly low on the physical fitness test from the get-go. For these older or frailer people, exercise did improve scores on executive function compared to the active control group.
Why did this cohort of sedentary adults obtain no cognitive benefit, while previous smaller trials indicated that physical activity boosts cognition? Baker thought that the physical activity may not have been intense enough. Not only were the activities themselves mild in nature, but sedentary adults may have had a difficult time moving enough to achieve an aerobic workout, she said.
Accelerometry data from 545 participants supports this idea. This subset wore accelerometers for one week at baseline and at the end of the trial. The gadgets were programmed to pick up only movement of moderate or greater intensity (thus excluding activities like a slow stroll, stretching, or strength training). While the participants in the intervention group self-reported an increase in physical activity of 130 minutes per week, accelerometer readings at the beginning and end of the trial were similar, suggesting the intervention group did not in fact increase their dose of moderate- or greater-intensity exercise. In the control group, however, accelerometers recorded 40 minutes per week less exercise by the end of the trial, revealing that without a physical-activity intervention, people become even more sedentary over time. Baker said that participants in her study were about a decade younger and not selected based on lack of mobility, so they may have achieved a more intense aerobic workout.
Sink and Baker agreed that the low-to-moderate exercise was probably more strenuous for the older, less-fit volunteers, giving them a more intense aerobic workout, which may explain their boost in executive function.
While acknowledging that the trial tested low-intensity exercise, Sink said that the social stimulation in the active control group could have prevented age-related cognitive decline just as much as the exercise did in the intervention group. Indeed, both groups remained relatively cognitively stable throughout the trial, and similarly small fractions (12 to 13 percent) of each developed mild cognitive impairment or dementia. However, given that this cohort was not enriched for people at risk for cognitive decline, it is difficult to say how much they would have declined with no intervention at all, Sink said. Nicola Lautenschlager of the University of Melbourne in Australia saw the stable cognition in both groups as a silver lining. “This negative result could still translate into positive findings in that any cognitively stimulating activity in older age could potentially improve cognition,” she wrote. She added that the promising results of exercise in the older group also support the message that it is never too late to benefit from a change in lifestyle.
Baker added that the low levels of cognitive impairment in this cohort could have made small improvements difficult to see. Unlike her study, in which participants started off with MCI and high blood glucose, the LIFE cohort was cognitively normal at baseline. The members were also highly educated, which could mean they had a hefty cognitive reserve. Gregory Cole of the University of California, Los Angeles, commented that only about 18 percent of the cohort harbored an ApoE4 allele, which indicates that this group was at low risk for AD. Previous studies reported that exercise exerts its strongest effects on AD biomarkers in ApoE4 carriers (see Aug 2015 conference news). A cohort of younger ApoE4 carriers thus would have been more likely to reveal cognitive benefits of exercise, he wrote.
Supplements Are No Saviors
The second JAMA study sought to tease out cognitive effects from the other side of the lifestyle coin, and looked at how supplementation with omega-3 fatty acids and/or antioxidants fared in terms of cognition. Observational studies support the idea that diets high in omega-3 long-chain polyunsaturated fatty acids (LCPUFAs), most abundantly found in fish, protect cognition (see Dangour et al., 2009). Docosahexaenoic acid (DHA), a component of such fatty acids, supports brain cells, and people with AD have low serum concentrations of the compound (see Tully et al., 2003). However, randomized clinical trials of DHA have been negative, showing the supplement does not slow cognitive decline (see Nov 2010 news; Dangour et al., 2010). Antioxidants such as vitamins C, E, and beta-carotene have been tarred with the same brush—observational studies support their cognitive benefits while trials said otherwise (see Jama et al., 1996; Grodstein et al., 2003; Yaffe et al., 2004; Kang et al., 2006). One small RCT of 49 older women reported that a combination of DHA and lutein, an antioxidant thought to protect the eye from damaging UV rays, improved memory and learning (see Johnson et al., 2008).
To cut through this confusion, Bernstein and colleagues measured cognition in the Age-Related Eye Disease Study 2 (AREDS2), a multicenter trial designed to measure the effects of long-chain polyunsaturated fatty acids (DHA and eicosapentaenoic acid) and/or antioxidants lutein and zeaxanthin on the development of age-related macular degeneration (AMD). The subjects had intermediate symptoms of the disease in both eyes or advanced disease in one eye. In addition to annual eye exams, more than 3,500 participants, averaging 72.7 years of age, underwent cognitive tests at baseline, and again two and four years later. Patients adhered well to treatment, according to annual pill counts, with more than 80 percent of them taking at least 75 percent of their prescribed dose. A subset of more than 500 people underwent serum testing for the nutrients, which revealed a more than twofold increase in serum concentrations of the supplements they were assigned.
Alas, neither the omega-3s (350mg DHA+650mg EPA), the antioxidants (10mg lutein+2mg zeaxanthin), nor a combination of the two slowed cognitive decline, as measured by telephone-administered tests, which included a modified version of the mini mental state exam (MMSE) and measures of verbal fluency, processing speed, and memory. Cognition declined over time across all groups, and people with a history of cardiovascular disease, hypertension, stroke, or lower education tended to decline faster. First author Emily Chew of the National Institutes of Health in Bethesda, Maryland, told Alzforum the results did not surprise her, given previous negative results of other RCTs.
Cole speculated that the widespread statin use, which reportedly reduces cardiovascular risk for cognitive decline, could have overshadowed any cognitive benefits of DHA. Chew noted that the relationship between statins and cognitive decline is tenuous, and that patients without cardiovascular disease also failed to benefit from supplement use.
Another influential factor could have been that participants in the trial already consumed sufficient levels of omega-3 fatty acids through their diet. A majority of the trial participants were highly educated, suggesting they may have been more likely to consume a healthy diet to begin with, the authors said. However, the researchers did not include baseline nutrition or diet as a measure in the study, an omission that clouds interpretation of the results, commented Martha Morris of Rush University in Chicago. “The trial findings cannot be generalized to those in the population who have marginal to low nutrient intake of the nutrients in question,” she wrote. “For example, based on a number of epidemiological studies, the protective level of benefit of fish is one serving per week and that for green leafy vegetables (rich in lutein) is about one serving per day. If most people in this trial consumed these servings then one would of course not expect to see a positive result.” The protective influence of diet jibes with recent results from the PREDIMED trial, in which a Mediterranean diet heavy in fruits, vegetables, whole grains, and fish, improved cognitive function (see Valls-Pedret et al., 2015). Chew also stressed the importance of consuming a balanced, heart-healthy diet, rather than relying on certain supplements.
In an accompanying editorial, Sudeep Gill and Dallas Seitz of Queen’s University in Kingston, Ontario, emphasized that maintaining a healthy lifestyle throughout life, rather than just in its final stages, may be the best way to head off cognitive decline. Regardless of its effects on cognition, eating and exercising right, even when started in old age, comes with a bevy of other health rewards worth reaping.—Jessica Shugart
- Exercise and the Brain: More Support for Protective Effects
- Research Brief: Total Activity, Not Just Exercise, Keeps Mind Sharp
- Work Up a Sweat to Stay Sharp, Randomized Trial Suggests
- Exercising Brain or Body: Both Seem to Help a Bit
- Healthy Lives, Healthy Minds: Is it Really True?
- Exercise Boosts Cognition In Symptomatic Disease
- Can Exercise Slow the Progression of Alzheimer’s Pathology?
- Paper Alert: Negative DHA Trial Fuels Soul-Searching in AD Field
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