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 newsMay 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 newsApr 2013 newsJul 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 newsDangour 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., 2004Kang 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


  1. It is unfortunate that the trial has the same design that nearly every U.S. trial of dietary supplements to date has had—participants were not selected who had low levels of the nutrients in question. They may all have had very healthy diets that provided sufficient levels of the nutrients of interest. There is also limited presentation of analyses in the publication that considered dietary intake levels so that the reader can judge how likely the trial was to even be able to test whether the supplements are effective in persons with low intake. The epidemiological studies that have found protective associations did not find protective benefits at very high levels of intake obtained through supplements. Rather, the contrast was moderate intake levels from food being protective of cognitive decline versus people with low dietary intake levels. This trial does not test this. The trial findings cannot be generalized to those in the population who have marginal to low nutrient intake of the nutrients in question. 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.

  2. I see several issues related to the AREDS2 trial that weaken the generalizability of this type of study's negative conclusions.

    The authors point to cardiovascular disease as one likely cause of cognitive decline in the overall population. For example, they note more cognitive decline in subjects with vascular or heart disease (CVD). It looks like roughly 40 to 45 percent of the study population is on statins. It is not much of a leap to suggest that statin use is likely higher in the CVD population. Protection against CVD is one of the best-established health benefits of fish oil—strong enough to win American Heart Association recommendations to supplement. However, the available data show that omega-3 protected from CVD in earlier studies prior to widespread statin use, but more recent trials have been negative because the majority population now uses statins. That is, omega-3 shows no added benefit over statins in controlling CVD—with the important exception of sudden cardiac death! So, one factor in the negative outcome is the distinct possibility that statin use was sufficiently protective against CVD-related risk of cognitive decline that 1 gram of fish oil had no added benefit. That would be similar to several recent CVD fish oil trials.

    The other big factor likely to reduce cognitive scores in subjects with an average age of about 72 years would be ApoE4-related AD risk, which accounts for nearly 80 percent of the AD in a population under 80 years. Given the epidemiology and ADCS DHA clinical trial data suggesting that DHA is ineffective in ApoE4 carriers (but possibly effective in non-carriers), one might expect a lack of efficacy against early AD-related decline in a population of average age 72. It would be better to look at risk of decline in subjects over 80 where ApoE3 predominates.

    The third issue with this trial is that it treats a general population in which one-third of the subjects in both groups have relatively high dietary omega-3 intake. As Martha Morris has pointed out, there is not much point in testing dietary supplements on those in the upper percentiles of intake that appear to be protective. This study didn't seem to measure the blood levels but one can assume that many randomized subjects had adequate baseline dietary intake.

    Sink et al. show a possible effect of physical activity on executive function, which the authors say is most sensitive to exercise. The group they chose to study is impaired and the level of exercise is necessarily less aerobic than what one might require to achieve a fitness level in many participants. However, the biggest issue is that the ApoE4 carriers are less than 80 percent of the sample, because the authors have not enriched for those at risk for AD. Preclinical data, including unpublished data from our lab, suggest that ApoE4 risk is mitigated by exercise. If you look at the Wisconsin Registry for Alzheimer Prevention data presented by Stepanie Schulz at AAIC 2015, you see that exercise benefited AD biomarkers, such as PiB, in ApoE4 carriers (see Aug 2015 conference news). You can see the biomarker benefits in the whole group, but it is the ApoE4 group that drives it (see Okonkwo et al., 2014). The Lifestyle study has older participants and is 80 percent non-ApoE4 and doesn't see an exercise benefit.    

    I would say flip the study groups to have a better chance to get positive trials. Select for younger people who carry on ApoE4 risk allele in the exercise trials, and select for older non-E4 for testing the omega-3/antioxidant supplements.


    . Physical activity attenuates age-related biomarker alterations in preclinical AD. Neurology. 2014 Nov 4;83(19):1753-60. Epub 2014 Oct 8 PubMed.

  3. I am familiar with this trial, as it was coordinated through my institution. I moved to Wake Forest from the University of Washington as the trial was in close-out phase and have never participated in trial conduct, data analysis, interpretation, or manuscript prep (i.e., I have no conflicts of interest to report). There are differences between this study and our PACE study that was recently featured in Alzforum, which likely account for disparate findings:

    Dose of exercise is by far the most likely reason for differences: On average, a “dose” of aerobic exercise was much less than that attained by other studies of structured exercise. The authors acknowledge that the intensity of prescribed exercise may have been insufficient. They used accelerometry data to identify “moderate” levels of physical activity, using >760 counts of activity per minute as a threshold. Others (e.g., Sasaki et al., 2011) have used much higher values to identify the lower limit of what might be considered "moderate" physical activity (e.g., >2,689 counts per minute). Furthermore, the LIFE trial emphasized “physical activity,” not necessarily activity that was aerobic. Our work specifically examines the cognitive and AD-modifying effects of aerobic exercise. It may be that although all types of exercise are beneficial for the body and mind in one way or another, high-intensity aerobic exercise may be essential to improve cognition and slow progression of AD pathology.

    LIFE participants were physically frail, by definition, and so were very different than people we enrolled in our exercise studies. Physical frailty likely impacted the adults’ ability to exercise at higher intensity, which brings us back to dose. On the other hand, Sink et al. found that the adults who scored more poorly at enrollment of tests of physical function (more frail) improved more on tests of executive function (Fig. 2c). It is possible that for these folks who have more difficulties mobilizing, any exercise was challenging and therefore their “dose” may have been a bit higher, relatively, than for those who are able to move about with more ease. Although this statement appears to contradict what I said earlier, the overall statement remains true: Reaching exercise doses that confer cognitive benefits would likely be more difficult for these individuals in the LIFE cohort.

    The LIFE study tells us that low-dose exercise can be beneficial for physical function and help reduce physical frailty, which is very important since so many older adults are physically compromised. The LIFE study also tells us, though, that in order to see cognitive benefits, the “dial” controlling intensity of aerobic exercise has to be turned up.

    Finally, as the authors pointed out, the LIFE cohort was predominantly cognitively normal (12-13 percent MCI/dementia after 24 months), whereas our previous studies included only adults at high risk for cognitive decline.


    . Validation and comparison of ActiGraph activity monitors. J Sci Med Sport. 2011 Sep;14(5):411-6. Epub 2011 May 25 PubMed.

  4. Dr. Baker points out several good reasons why the results from the LIFE study differ from the PACE study that were recently featured on Alzforum. There are two other reasons why the LIFE study is unique from most other studies of physical activity on cognition, including PACE. The first is that our participants were much older than those typically enrolled in physical activity/exercise interventions. Our mean age was 80, compared to 65 in PACE. This 15-year difference in age is important and could help explain why our participants may have still achieved “moderate” levels of physical activity in spite of our seemingly low accelerometer definition of moderate activity of >760 counts/min. Dr. Baker notes that moderate activity has been defined as accelerometer counts that are greater than 2,690/min. But the cited study (Sasaki et al., 2011) based this definition on young (mean age 27 years), healthy participants and thus it may not be an appropriate definition of moderate activity for older adults. Indeed, a recent article by Zisko et al. highlights the importance of taking age and cardiorespiratory fitness into account when defining activity levels, especially for the elderly. Due to declining VO2 max, many elderly cannot reach the moderate/vigorous activity levels set for younger adults. Using objectively measured VO2 max, they determined that moderate intensity activity for a population of 70- to 77-year-olds corresponded to 669-4048 counts/min depending on gender and fitness level. Our definition of >760 counts/min for moderate activity is consistent with Zisko‘s results given the age and frailty of our population.

    The second important factor to remember when interpreting the results of the LIFE study in the context of other physical activity interventions is that, unlike many studies, we did not use a “stretching control.”  Because cognitive outcomes were not the primary outcome of LIFE (mobility disability was), the control group consisted of cognitively and socially engaging health-education seminars.  Both cognitively and socially engaging activities have been shown to be beneficial to cognition.  Thus, in LIFE, we may have diminished our ability to show that physical activity is superior to a control condition in cognitive outcomes because our control condition likely also benefited cognition.


    . New relative intensity ambulatory accelerometer thresholds for elderly men and women: the Generation 100 study. BMC Geriatr. 2015 Aug 4;15:97. PubMed.

    . Validation and comparison of ActiGraph activity monitors. J Sci Med Sport. 2011 Sep;14(5):411-6. Epub 2011 May 25 PubMed.

  5. I strongly endorse Martha Clare Morris' comments. It is about time that trials of nutrients do not get funded (or published) unless the baseline level of the nutrient concerned (or, second-best, its intake) is measured. In addition, of course, the final level of the nutrient should be reported. In this way, we will know if the population under study included a significant proportion with poor nutrient status and if the treatment corrected this. The treatment outcomes can then be assessed by stratification of the population for baseline nutrient level. In the Chew trial, as the authors stated "the study was conducted in a select population of well-nourished and highly educated persons." The omega-3 fatty acid levels were not measured in this trial, so we have no idea if any of them had insufficient levels to protect their brain.

    A second problem is that in this healthy elderly group, those taking placebo showed an extremely small degree of cognitive decline in the period studied. How can it be expected that any treatment would slow down what is already a clinically insignificant degree of cognitive decline?

    A third problem with the study is that it was done on people with macular degeneration, which is well known to be associated with elevated levels of plasma homocysteine (Huang et al., 2015). The authors would not have been aware of a recent study that showed that omega-3 fatty acids do not benefit the brain in people with high homocysteine (Jerneren et al., 2015). In the latter report it was shown that a high omega-3 fatty acid status only slows brain atrophy in people with a good B vitamin status, i.e., with low homocysteine.

    I conclude that the Chew trial cannot be used to claim that omega-3 fatty acids are of no benefit for slowing cognitive decline. 


    . Homocysteine and the risk of age-related macular degeneration: a systematic review and meta-analysis. Sci Rep. 2015 Jul 21;5:10585. PubMed.

    . Brain atrophy in cognitively impaired elderly: the importance of long-chain ω-3 fatty acids and B vitamin status in a randomized controlled trial. Am J Clin Nutr. 2015 Jul;102(1):215-21. Epub 2015 Apr 15 PubMed.

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News Citations

  1. Exercise and the Brain: More Support for Protective Effects
  2. Research Brief: Total Activity, Not Just Exercise, Keeps Mind Sharp
  3. Work Up a Sweat to Stay Sharp, Randomized Trial Suggests
  4. Exercising Brain or Body: Both Seem to Help a Bit
  5. Healthy Lives, Healthy Minds: Is it Really True?
  6. Exercise Boosts Cognition In Symptomatic Disease
  7. Can Exercise Slow the Progression of Alzheimer’s Pathology?
  8. Paper Alert: Negative DHA Trial Fuels Soul-Searching in AD Field

Therapeutics Citations

  1. Docosahexaenoic acid (DHA)

Paper Citations

  1. . Fish consumption and cognitive function among older people in the UK: baseline data from the OPAL study. J Nutr Health Aging. 2009 Mar;13(3):198-202. PubMed.
  2. . Low serum cholesteryl ester-docosahexaenoic acid levels in Alzheimer's disease: a case-control study. Br J Nutr. 2003 Apr;89(4):483-9. PubMed.
  3. . Effect of 2-y n-3 long-chain polyunsaturated fatty acid supplementation on cognitive function in older people: a randomized, double-blind, controlled trial. Am J Clin Nutr. 2010 Jun;91(6):1725-32. Epub 2010 Apr 21 PubMed.
  4. . Dietary antioxidants and cognitive function in a population-based sample of older persons. The Rotterdam Study. Am J Epidemiol. 1996 Aug 1;144(3):275-80. PubMed.
  5. . High-dose antioxidant supplements and cognitive function in community-dwelling elderly women. Am J Clin Nutr. 2003 Apr;77(4):975-84. PubMed.
  6. . Impact of antioxidants, zinc, and copper on cognition in the elderly: a randomized, controlled trial. Neurology. 2004 Nov 9;63(9):1705-7. PubMed.
  7. . A randomized trial of vitamin E supplementation and cognitive function in women. Arch Intern Med. 2006 Dec 11-25;166(22):2462-8. PubMed.
  8. . Cognitive findings of an exploratory trial of docosahexaenoic acid and lutein supplementation in older women. Nutr Neurosci. 2008 Apr;11(2):75-83. PubMed.
  9. . Mediterranean Diet and Age-Related Cognitive Decline: A Randomized Clinical Trial. JAMA Intern Med. 2015 Jul;175(7):1094-103. PubMed.

External Citations

  1. Lifestyle Interventions and Independence for Elders
  2. Age-Related Eye Disease Study 2

Further Reading


  1. . Long-term consumption of fish oil partially protects brain tissue from age-related neurodegeneration. Postepy Hig Med Dosw (Online). 2015 Feb 6;69:188-96. PubMed.
  2. . The LIFE Cognition Study: design and baseline characteristics. Clin Interv Aging. 2014;9:1425-36. Epub 2014 Aug 27 PubMed.

Primary Papers

  1. . Effect of a 24-Month Physical Activity Intervention vs Health Education on Cognitive Outcomes in Sedentary Older Adults: The LIFE Randomized Trial. JAMA. 2015 Aug 25;314(8):781-90. PubMed.
  2. . Effect of Omega-3 Fatty Acids, Lutein/Zeaxanthin, or Other Nutrient Supplementation on Cognitive Function: The AREDS2 Randomized Clinical Trial. JAMA. 2015 Aug 25;314(8):791-801. PubMed.