May/June 2019

Alzheimer’s & Dementia: Exercise and Dementia — Does Physical Activity Provide Cognitive Benefits?
By Jamie Santa Cruz 
Today’s Geriatric Medicine
Vol. 12 No. 3 P. 6

The World Health Organization recommends regular physical exercise—both aerobic and strength training—for older individuals as a means of reducing cognitive decline.1 However, studies on the effects of exercise on cognitive function in individuals with dementia have produced mixed results. While some research indicates a positive effect, other studies have failed to find clear benefits. Thus, the question remains: Is exercise actually effective at slowing down cognitive decline in individuals with dementia?

Evidence in Favor: Cognitive Benefits in Dementia
Repeated randomized controlled trials have found that various types of exercise programs produce cognitive benefits in dementia over a three- to four-month period. For example, one trial of 40 community-dwelling adults with mild to moderate dementia examined the impact of a four-month home-based exercise intervention consisting of strength and balance training exercises plus daily walking. Those in the exercise group showed improved scores on the Mini-Mental State Examination (MMSE) over baseline as compared with controls.2 Similarly, a Belgian trial of 25 patients with moderate to severe dementia found that a program of daily physical exercises supported by music produced significant improvements in cognition on both the MMSE and the fluency subtest of the Amsterdam Dementia Screening Test 6 compared with controls.3 Multiple other trials have produced similar results.4-7

A weakness of most randomized controlled trials showing a cognitive benefit of exercise in dementia is that the study populations have been small. One 2016 trial, however, tested a moderate- to high-intensity exercise intervention in a larger sample: 200 community-dwelling patients with mild Alzheimer’s disease (AD). Participants were randomized to either a supervised exercise group (one-hour sessions three times per week for four months) or to a control group. The study found no effect on cognition in the exercise group as a whole; however, in an exploratory analysis, the researchers found a possible beneficial impact on cognition among those who were most consistent in attending exercise sessions and who exercised at the greatest intensity, suggesting a dose-response relationship between exercise and cognition.8

Evidence Against: No Cognitive Benefits in Dementia
Although a range of studies suggest that exercise has a benefit for dementia treatment, other studies have found no such benefit. Such was the case, for example, with a 2017 Swedish trial of nearly 200 individuals with dementia in a nursing home setting. Participants were randomized either to a four-month high-intensity exercise intervention or to a seated attention control activity. The exercise intervention had no benefit for either global cognition or executive function over control, relative to baseline measures. This was true regardless of the sex of the participants, their forms of dementia, and their cognitive levels at baseline.9

In the case of the Swedish trial, the researchers hypothesized that the lack of benefit could be due to the fact that the exercise intervention focused on strength training rather than aerobic exercise. But a 2018 randomized control trial from British researchers produced no better results with aerobic exercise. In this large, carefully designed trial of almost 500 participants with mild to moderate dementia, participants were assigned to either an exercise group (which included both aerobic exercise and strength training) or to a usual-care group. Not only did exercise fail to produce cognitive benefits, but those in the exercise group actually demonstrated slightly worse cognition at the end of 12 months than did those in the usual care group.10

Mixed Results From Meta-Analyses and Systematic Reviews
The mixed results in individual randomized trials mirror the contradictory findings of several recent meta-analyses and systematic reviews.

Specifically, a 2015 systematic review of 17 randomized controlled trials found only very limited benefits of exercise in dementia—namely, researchers concluded that exercise programs may improve ability to do activities of daily living in dementia, but that exercise provides no benefits for cognition, neuropsychiatric symptoms, or depression.11

By contrast, however, two other recent meta-analyses reached the opposite conclusion and have affirmed the benefits of exercise—especially aerobic exercise—for cognition in dementia. The first of these meta-analyses, published in 2016, found that exercise has a positive benefit on cognition in both AD and other dementias and that both high-frequency and low-frequency exercise programs are beneficial.12

The second meta-analysis with a positive result, published in 2018, included 19 randomized controlled trials involving patients with AD as well as those at high risk of AD. This meta-analysis found that exercise interventions appear to slow cognitive decline in both groups—in those who have AD as well as in those at risk of the disease.13

Resolving the Inconsistencies
To make sense of the inconsistencies, a first point of note is that the research on exercise and its impact on cognition in dementia is still in its infancy. “There are a relatively small amount of studies that examine this relationship and there are still many unknowns due to limitations of the current literature,” says Gregory Panza, MS, an exercise physiologist at Connecticut’s Hartford Hospital and lead author of the 2018 meta-analysis referenced previously that found a positive benefit of aerobic exercise on cognition in dementia.

Not only are there a limited number of studies, but many of those that are available have been small and of relatively poor methodological quality. In fact, the authors of the 2015 systematic review that found no cognitive benefits of exercise in dementia explicitly noted that there was considerable unexplained heterogeneity in the analysis, and that the quality of the evidence was “very low.”11

With respect to meta-analyses in particular, Panza, a doctoral candidate in the department of kinesiology and the Human Performance Laboratory at the University of Connecticut, notes a major weakness of several analyses that have found a lack of impact of exercise on cognition: Namely, they have included mixed samples of people with multiple types of dementia (AD, vascular dementia, and other types of dementia) and analyzed them all together as one sample, rather than examining each group separately. “This is an issue because there are several physiological differences among the different types, and as a result, exercise may be affecting each type of dementia differently,” Panza says. Additionally, previous meta-analyses usually have failed to examine moderators such as age and gender. It’s important to examine moderators, he says, “because it gives you valuable information on which variables may be influencing the impact that the exercise is having on cognitive function.”

To address these limitations of previous research, Panza and his coauthors adhered to high-quality methodological reporting standards in their own 2018 meta-analysis, suggesting that their group’s finding of a positive cognitive benefit of exercise in dementia may carry more weight than the negative findings of some previous analyses. In their study, Panza and his colleagues also conducted within-group analyses (in which they compared cognitive changes both before and after the intervention for both the exercise and control groups), rather than merely conducting a between-group analysis as had previous meta-analyses. The within-group analysis allowed the group to take into account the cognitive decline that occurs naturally with untreated disease in the control group, and this analysis revealed the novel finding that exercise could improve cognition among controls. Overall, then, the Panza’s meta-analysis offers important support to the hypothesis that exercise can indeed slow cognitive decline in dementia.

Exercise in Midlife Protects Against Dementia
In addition to the evidence about the effect of exercise on cognition in individuals who already have dementia, there’s also a body of research on the effects of mid- to late-life exercise on future risk of cognitive impairment.14 For instance, in a longitudinal study of women spanning 44 years, high levels of physical fitness were associated with a significantly reduced risk of dementia several decades later as compared with medium levels of physical fitness; in fact, high levels of physical fitness delayed onset of dementia by 9.5 years compared with medium fitness.15

Some research suggests that exercise may have especially significant benefits for individuals at highest genetic risk for dementia. A 2014 study, for instance, examined a group of 97 cognitively normal adults and compared how high vs low levels of physical activity correlated with each group’s hippocampal volume over the following 18 months. Researchers found that exercise had no apparent impact on hippocampal volume in those without genetic risk. But in those at genetic risk (that is, carriers of the APOE-E4 allele), low levels of physical activity were associated with a decline in hippocampal volume. This same group of less-active, higher-risk individuals was also more likely to show both cognitive and functional decline over the study period.16

According to Stephen Rao, PhD, Ralph and Luci Schey Endowed Chair at the Cleveland Clinic Lou Ruvo Center for Brain Health, a main mechanism by which exercise is thought to affect dementia risk is by affecting inflammation. “What exercise seems to be doing is reducing the amount of inflammation that ultimately is a very important factor in the progression of the disease. The disease is going on for 10 to 15 years prior to its diagnosis. So anything you can do to alter processes like inflammation can make a big dent in the rate of progression of the disease.”

To be clear, not all research shows a protective benefit of exercise against dementia: One 2018 systematic review and meta-analysis found that randomized controlled trials on exercise for dementia prevention are limited, but that the existing evidence does not show any significant effect of exercise in terms of reducing dementia risk.17

However, several other meta-analyses have come to the opposite conclusion. A 2011 meta-analysis of 15 prospective studies that included a total of more than 33,000 subjects without dementia concluded that all levels of physical exercise, from low to high, offer a significant and consistent protective effect (-35% or greater) against cognitive decline.18 Similarly, a 2016 meta-analysis of 10 high-quality prospective observational cohort studies found that those who were more active had a 35% to 40% lower chance of developing AD than did those who were less active.19

Implications for Providers
According to Panza, there are still significant gaps in the research on exercise and dementia, and there’s a need for considerably more research using neuroimaging and molecular markers to examine the neuropsychological, electrophysiological, and pathophysiological effects that exercise has on dementia. Still, he recommends exercise—especially aerobic exercise—as a valuable treatment option for those who have dementia or are at risk. “Not only is there evidence that exercise can delay the onset of Alzheimer’s disease but the physical benefits of exercise may also help their patients keep their independence longer.”

Rao likewise acknowledges the unknowns, but he too affirms that exercise appears to be an important means of reducing dementia risk. “Exercise is key. It’s never too late. Providers should really encourage their patients to exercise, within reason, within their level of fitness.”

— Jamie Santa Cruz is a health and medical journalist based in Parker, Colorado.

References
1. Physical activity and older adults. World Health Organization website. http://www.who.int/dietphysicalactivity/factsheet_olderadults/en. Accessed October 30, 2018.

2. Vreugdenhil A, Cannell J, Davies A, Razay G. A community-based exercise programme to improve functional ability in people with Alzheimer’s disease: a randomized controlled trial. Scand J Caring Sci. 2012;26(1):12-19.

3. Van de Winckel A, Feys H, De Weerdt W, Dom R. Cognitive and behavioural effects of music-based exercises in patients with dementia. Clin Rehabil. 2004;18(3):253-260.

4. Kemoun G, Thibaud M, Roumagne N, et al. Effects of a physical training programme on cognitive function and walking efficiency in elderly persons with dementia. Dement Geriatr Cogn Disord. 2010;29(2):109-114.

5. Arcoverde C, Deslandes A, Moraes H, et al. Treadmill training as an augmentation treatment for Alzheimer’s disease: a pilot randomized controlled study. Arq Neuropsiquiatr. 2014;72(3):190-196.

6. Öhman H, Savikko N, Strandberg TE, et al. Effects of exercise on cognition: The Finnish Alzheimer Disease Exercise Trial: a randomized, controlled trial. J Am Geriatr Soc. 2016;64(4):731-738.

7. Cancela JM, Ayán C, Varela S, Seijo M. Effects of a long-term aerobic exercise intervention on institutionalized patients with dementia. J Sci Med Sport. 2016;19(4):293-298.

8. Hoffmann K, Sobol NA, Frederiksen KS, et al. Moderate-to-high intensity physical exercise in patients with Alzheimer’s disease: a randomized controlled trial. J Alzheimers Dis. 2016;50(2):443-453.

9. Toots A, Littbrand H, Boström G, et al. Effects of exercise on cognitive function in older people with dementia: a randomized controlled trial. J Alzheimers Dis. 2017;60(1):323-332.

10. Lamb SE, Sheehan B, Atherton N, et al. Dementia And Physical Activity (DAPA) trial of moderate to high intensity exercise training for people with dementia: randomised controlled trial. BMJ. 2018;361:k1675.

11. Forbes D, Forbes SC, Blake CM, Thiessen EJ, Forbes S. Exercise programs for people with dementia. Cochrane Database Syst Rev. 2015;(4):CD006489.

12. Groot C, Hooghiemstra AM, Raijmakers PG, et al. The effect of physical activity on cognitive function in patients with dementia: a meta-analysis of randomized control trials. Ageing Res Rev. 2016;25:13-23.

13. Panza GA, Taylor BA, MacDonald HV, et al. Can exercise improve cognitive symptoms of Alzheimer’s disease? J Am Geriatr Soc. 2018;66(3):487-495.

14. Defina LF, Willis BL, Radford NB, et al. The association between midlife cardiorespiratory fitness levels and later-life dementia: a cohort study. Ann Intern Med. 2013;158(3):162-168.

15. Hörder H, Johansson L, Guo X, et al. Midlife cardiovascular fitness and dementia: a 44-year longitudinal population study in women. Neurology. 2018;90(15):e1298-e1305.

16. Smith JC, Nielson KA, Woodard JL, et al. Physical activity reduces hippocampal atrophy in elders at genetic risk for Alzheimer’s disease. Front Aging Neurosci. 2014;6:61.

17. de Souto Barreto P, Demougeot L, Vellas B, Rolland Y. Exercise training for preventing dementia, mild cognitive impairment, and clinically meaningful cognitive decline: a systematic review and meta-analysis. J Gerontol A Biol Sci Med Sci. 2018;73(11):1504-1511.

18. Sofi F, Valecchi D, Bacci D, et al. Physical activity and risk of cognitive decline: a meta-analysis of prospective studies. J Intern Med. 2011;269(1):107-117.

19. Santos-Lozano A, Pareja-Galeano H, Sanchis-Gomar F, et al. Physical activity and Alzheimer disease: a protective association. Mayo Clin Proc. 2016;91(8):999-1020.