Exercise and Alzheimer's disease: Current perspectives

As the population ages, the number of people in Ireland living with dementia is projected to rise from an estimated 55,000 in 2016, to 77,000 by 2026.¹ To help ensure our ageing society lives productive lives, research into treating, preventing and managing conditions such as Alzheimer’s disease and other forms of age-related neuro-degenerative diseases is an urgent public health priority. 

Today, the longevity-related prevalence of neurodegenerative diseases, especially dementia, and the current absence of a cure are among the top prominent societal health-related challenges.² Current pharmacological treatment for Alzheimer’s disease is symptomatic and can only temporarily stabilise the illness. New, potential disease-modifying treatment strategies have not yet demonstrated clinically relevant effects, highlighting the need for continued research into non-pharmacological treatments and interventions that address modifiable risk factors.³

Exercise and its role in dementia prevention is at the forefront of the research agenda in Alzheimer’s disease. An emerging area of research is now examining whether physical exercise can slow the progression or improve symptoms in people with prodromal or symptomatic Alzheimer’s disease. This review will examine the evidence for exercise interventions in people with mild cognitive impairment and Alzheimer’s disease.

Physical activity in healthy older adults

In recent years, convincing evidence has shown that regular physical activity can reduce the risk of cognitive decline, AD and other dementias.^4,5 A systematic meta-analysis of prospective studies  examined the association between physical activity levels and risk of cognitive decline in healthy subjects (33,816 non-demented subjects) and found high levels of physical activity reduced the risk of future cognitive decline by 38% (hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.54–0.70; P < 0.00001).⁶ Analysis of low and moderate physical activity also showed significant protection (reduced risk 35%) against cognitive impairment (HR 0.65, 95% CI 0.57– 0.75; P < 0.00001). 

In older adults identified at risk of cognitive decline, moderate physical exercise was shown to improve cognitive function.⁷ The Irish Longitudinal Study on Ageing (TILDA) examined physical activity levels in 8,172 adults aged 50 years and older and found two-thirds of this population reported low or moderate levels of physical activity, while only one-third reported high levels of activity.⁸ It was also found that low physical activity is almost twice as prevalent in those aged 75 years and older. These findings are in agreement with the Healthy Ireland Survey which found that physical activity decreases with age, with only 15% of those aged 65 and over considered highly active.⁹

From examining the figures relating to physical activity in Ireland, it can be concluded that the majority of older Irish adults are not meeting World Health Organization international activity guidelines that recommend at least 150 minutes of moderate intensity aerobic physical activity throughout the week (performed in bouts of at least 10 minutes) and muscle strengthening activities (two or more days per week) for a 20-30% lower risk of dementia.^10,11

Exercise and brain function

It is has long been established that exercise has a positive effect on a number of physiological functions and more recently the impact on brain health and cognitive function have been explored. There is converging evidence from both animal and human studies that regular physical exercise acts as a promoter of brain health, mediating neural homeostasis and counteracting the effects of brain ageing.¹² Potential mechanisms to account for the exercise-cognitive relationship include favourable effects on neuronal survivability and function, neuro-inflammation, vascular health, neuroendocrine response to stress, and brain amyloid burden. In healthy subjects, the beneficial effects of physical exercise is supported by studies showing increased memory performance and at the same time increased whole-brain and hippocampal volumes,¹³ as well as increased activity in neural networks.¹⁴

Exercise in mild cognitive impairment

Mild cognitive impairment is considered an intermediate stage between the cognitive change associated with normal ageing and dementia.¹⁵ Mild cognitive impairment may represent a clinical prodrome to Alzheimer’s disease and other dementias, with 10-15% of people with mild cognitive impairment progressing to dementia per year.¹⁶ No pharmacological interventions have been shown to slow the rate of cognitive decline in this patient population. Exercise, if implemented at the earliest possible stage of the neurodegenerative process, may alter the disease trajectory and help slow the rate of cognitive decline.¹²

The first of a number of randomised controlled trials  using rigorous controlled methodology to examine the role of exercise in mild cognitive impairment was published by Baker et al in 2010.¹⁷ Participants were randomised to a high intensity aerobic exercise or stretching control group. The aerobic group performed supervised exercise at 75-85% of heart rate reserve for 45-60 minutes per day, four days per week for six months. The control group carried out supervised stretching activities according to the same schedule. Findings indicated that a high intensity aerobic intervention had sex-specific effects on executive control processes for older women at high risk of cognitive decline. 

Following on from this landmark study, a broad range of exercise intervention studies have demonstrated that cognitive benefit can be achieved with varying exercise modalities (primarily aerobic training and more recently resistance type training) in populations with mild cognitive impairment.^17,18,19,20 Several meta-analyses have reported that increased activity levels in those with known cognitive impairment are associated with improvements in a number of cognitive processes, including attention, processing speed and executive function.^21,22 A number of meta-analyses that examined the effects of isolated aerobic training on cognition in individuals with mild cognitive impairment found significant improvement in global cognitive scores, with one meta-analysis also reporting a weak, but significant effect on memory.^23,24

While evidence to date indicates that exercise may be of cognitive benefit to this patient population, exactly what exercise prescription (frequency, intensity, time and type) and which particular cognitive domains are malleable to exercise intervention remains uncertain. However, when considering the evidence in its entirety, aerobic type exercise of moderate to high intensity appears to produce the greatest cognitive benefit in mild cognitive impairment although it can take a sustained period of up to six months of exercise training for cognitive benefit to become evident.^18,25,26

Exercise in Alzheimer’s disease

Until recently, little evidence existed for the role of physical exercise in people with Alzheimer’s. While it is now thought that exercise or regular physical activity might play a role in both protecting the brain from Alzheimer’s and other dementias, it may also have a role in helping people to live better with the disease. 

Previously published exercise intervention studies in Alzheimer’s disease have demonstrated inconsistent findings.^27,28,29 Many studies were performed in moderate to severe stages of the disease with the physical activity interventions being investigated often not supervised or monitored. The most recent Cochrane review³⁶ of physical activity for people with dementia concluded that some promising evidence suggests that exercise programmes may improve the ability to perform activities of daily living in people with dementia, but no conclusive evidence supported the benefits of exercise on cognition, neuropsychiatric symptoms or depression in dementia. Overall, the quality of studies included in the review was reported as very low, highlighting an ongoing need for further large, randomised trials of exercise in people with Alzheimer’s disease and dementia.

Whether physical exercise could improve symptoms in people with Alzheimer’s disease, or beneficially impact the brain changes caused by the disease, has been the focus of a number of RCTs in more recent years. At the 2015 Alzheimer’s Association International Conference, Hasselbalch et al from the Danish Dementia Research Centre reported results from the Danish ADEX study.³⁰ In the ADEX study, 200 people with mild to moderate Alzheimer’s disease were randomly assigned to either a supervised aerobic exercise programme (60-minute high intensity exercise sessions three times a week for 16 weeks supervised by experienced physiotherapists) or a control group. The primary outcome measure was change in cognitive performance estimated by the Symbol-Digit Modalities Test (SMDT). Secondary outcomes were neuropsychiatric and depressive symptoms, activities of daily living, quality of life and other cognitive measures. No significant difference was found between the intervention and control group on the primary outcome, but there was a significant difference in neuropsychiatric symptoms in favour of the intervention group. In a per protocol analysis (defined as attendance > 80% and exercise intensity > 70% of maximal heart rate), there was a significant effect on the primary outcome in favour of the intervention group, suggesting a dose-response relationship between moderate to high intensity exercise and cognition. In addition, people who participated in the exercise programme improved in physical fitness, physical function, dual-task performance and exercise self-efficacy. This study offered preliminary findings that high intensity aerobic exercise can postpone decline in cognition and reduce neuropsychiatric symptoms in patients with Alzheimer’s disease. 

Preliminary results from a community-based RCT, the Alzheimer’s Disease Exercise Program Trial (ADEPT), indicate that participants who were randomised to six months aerobic exercise (150 minutes a week) showed reduced hippocampal atrophy rate on neuroimaging compared to those in the control arm, suggesting that aerobic exercise may moderate neurodegenerative processes in early Alzheimer’s disease.³¹ The full findings have yet to be published.

Promoting physical activity in older adults

The Irish National Dementia Strategy recommends engaging those with known cognitive impairment in public health promotion strategies and addressing physical inactivity as a modifiable risk factor. Some experts believe supervised exercise classes should become part of the standard of care for people with cognitive problems, as patients may not be equipped with the necessary knowledge and tools to exercise at the correct frequency and intensity without the guidance of an exercise professional. This begs the question, when prescribing exercise to those with a diagnosis or ‘at risk’ of cognitive impairment, how best to engage people to bring about meaningful health behaviour change? If exercise is established as an evidenced-based intervention for prevention of dementia, public health and community programmes will need to be funded to provide the access and resources for people at risk and those with symptomatic disease. 

In 2016, two reports entitled National Physical Activity Plan for Ireland³² and the Royal College of Physicians of Ireland’s Physical Activity: a prescription for a wonder drug³³ were published. Both reports feed into national and international health strategies that have an overarching aim to make Ireland more physically active as a nation. 

Related to these strategies, the National Exercise Referral Framework was also published recently.³⁴ This new framework recognises exercise as an effective targeted intervention in many chronic diseases, including dementia, and would give general practitioners in Ireland the opportunity to refer patients to structured supervised exercise programmes. The feasibility of the proposed framework as a national model and the sustainability of the funding model still need to be established prior to roll out.

Conclusions

Exercise has demonstrated some positive findings in recent RCTs and must be considered a plausible treatment strategy for mild cognitive impairment, Alzheimer’s disease and other dementias. A considerable amount of attention was garnered by the recent findings of the FINGER study,³⁵ a large double-blind RCT that demonstrated a multi-domain intervention (diet, exercise, cognitive training, vascular risk monitoring) could improve or maintain cognitive functioning in at-risk older people from the general population. This adds strong support to a multi-modal approach to prevention strategies for Alzheimer’s disease, but understanding the effect of each intervention in isolation first needs to be established. 

The findings from recent studies discussed in this clinical review suggest that exercise can impact Alzheimer’s-related changes in the brain at all stages of the disease. There is a growing body of evidence that suggests exercise may boost cognition and reduce neuropsychiatric symptoms, even in symptomatic disease. For aerobic exercise in particular, the field is standardising methods and focusing on the most appropriate dose of exercise to prescribe. It appears that the duration and intensity of an exercise intervention are crucial to determining its cognitive effect. 

From the evidence gathered, it is imperative that the appropriate exercise prescription dose (a high intensity and up to six months in duration) is achieved to elicit a cognitive response in a mild cognitive impairment or Alzheimer’s disease patient population.

References

1. Pierce M, Cahill S, O’Shea E. Prevalence and Projections of Dementia in Ireland, 2011–2046. Dublin, Ireland: Trinity College Dublin. 2014
2. Kirton J. A Summit of Significant Success: Prospects for the G8 Leaders at Lough Erne. G8 Research Group June. 2013;12:2013
3. Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Annals of internal medicine. 2008;148(5):379-97
4. Hamer M, Chida Y. Physical activity and risk of neurodegenerative disease: a systematic review of prospective evidence. Psychol Med  2009;39(01):3-11
5. Heyn P, Abreu BC, Ottenbacher KJ. The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Arch Phys Med Rehabil 2004; 85(10):1694-704
6. Sofi F, Valecchi D, Bacci D et al. Physical activity and risk of cognitive decline: a meta-analysis of prospective studies. J Internal Med  2011; 269(1):107-17
7. Lautenschlager NT, Cox KL, Flicker L et al. Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: A randomized trial. JAMA 2008; 300(9):1027-37
8. Cronin H, O’Regan C, Kenny RA. Physical and behavioural health of older Irish adults. Fifty Plus in Ireland 2011. 2011:73
9. Ipsos M. Healthy Ireland Survey. Dublin: The Stationery Office. 2015
10. Physical activity guidelines advisory committee report, 2008. Washington, DC: US Department of Health and Human Services. 2008;2008:A1-H14
11. WHO. Global recommendations on physical activity for health. 2010
12. Ahlskog JE, Geda YE, Graff-Radford NR, Petersen RC. Physical exercise as a preventive or disease-modifying treatment of dementia and brain aging. Mayo Clinic Proceedings. 2011;86(9):876-84
13. Erickson KI, Voss MW, Prakash RS et al. Exercise training increases size of hippocampus and improves memory. Proceedings of the National Academy of Sciences. 2011;108(7):3017-22
14. Colcombe SJ, Kramer AF, McAuley E, Erickson KI, Scalf P. Neurocognitive aging and cardiovascular fitness: recent findings and future directions. J Molecular neuroscience: MN. 2004; 24(1):9-14
15. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Int Med 2004; 256(3):183-94
16. Farias ST, Mungas D, Reed BR, Harvey D, DeCarli C. Progression of mild cognitive impairment to dementia in clinic-vs community-based cohorts. Arch Neurol 2009; 66(9):1151-7
17. Baker LD, Frank LL, Foster-Schubert K et al. Effects of aerobic exercise on mild cognitive impairment: A controlled trial. Arch Neurol 2010;67(1):71-9
18. Nagamatsu LS, Chan A, Davis JC et al. Physical activity improves verbal and spatial memory in older adults with probable mild cognitive impairment: 6-month randomized controlled trial. J Aging Research 2013 
19. Nascimento CMC et al. Regular multimodal aerobic exercise reduces pro-inflammatory cytokines and improves BDNF peripheral levels and executive functions in elderly MCI individuals with different BDNF VAL66MET genotypes. Alzheimer’s and Dementia 2015; 11(7):P323
20. Suzuki T, Shimada H, Makizako H et al. A randomized controlled trial of multicomponent exercise in older adults with mild cognitive impairment. PLoS One. 2013;8(4):e61483
21. Smith PJ, Blumenthal JA, Hoffman BM et al. Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized controlled trials. Psychosom Med 2010;72(3):239-52
22. Öhman H et al. Effect of Physical Exercise on Cognitive Performance in Older Adults with Mild Cognitive Impairment or Dementia: A Systematic Review. Dement Geriatr Cogn 2014; 38(5-6):347-65
23. Zheng G, Xia R, Zhou W, Tao J, Chen L. Aerobic exercise ameliorates cognitive function in older adults with mild cognitive impairment: a systematic review and meta-analysis of randomised controlled trials. British Journal of Sports medicine. 2016:bjsports-2015-095699
24. Gates N, Fiatarone Singh MA, Sachdev PS, Valenzuela M. The effect of exercise training on cognitive function in older adults with mild cognitive impairment: a meta-analysis of randomized controlled trials. Am J Geriatr Psychiatry. 2013;21(11):1086-97
25. Baker LD, Frank LL et al. Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Arch Neurol 2010; 67(1):71-9
26. De Gobbi Porto FH, Coutinho AMN et al. Effects of aerobic training on cognition and brain glucose metabolism in subjects with mild cognitive impairment. Journal of Alzheimer’s Disease. 2015;46(3):747-60
27. Yágüez L, Shaw KN, Morris R, Matthews D. The effects on cognitive functions of a movement‐based intervention in patients with Alzheimer’s type dementia: a pilot study. International journal of geriatric psychiatry 2011; 26(2):173-81
28. 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 2010; 29(2):109-14
29. Cheng ST, Chow PK, Song YQ et al. Mental and physical activities delay cognitive decline in older persons with dementia. Am J Geriatr Psychiatry 2014; 22(1):63-74
30. Hoffmann K, Sobol NA, Frederiksen KS, Hasselbalch SG et al. Moderate-to-high intensity physical exercise in patients with Alzheimer’s disease: A Randomized Controlled Trial. J Alzheimer’s Disease 2015; 50(2):443-53
31. Honea RA, Vidoni ED et al. Aerobic exercise reduces hippocampal atrophy in individuals with early Alzheimer’s disease. Alzheimer’s & Dementia: J Alzheimer’s Association 2014; 10(4):P303
32. National Physical Activity Plan for Ireland - Get Ireland Active! 2016
33. Ireland RCoPo. Physical Activity: A prescription for a wonder drug 2016
34. Woods C, McCaffrey N, Furlong B et al. National Exercise Referral Framework 2016
35. Ngandu T, Lehtisalo J, Solomon A et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet 2015; 385(9984):2255-63