# Exercise as it relates to Disease/Cognitive effect of aerobic exercise in older adults with Alzheimer’s disease

This is a critical appraisal of the 2021 article, "Cognitive Effects of Aerobic Exercise in Alzheimer’s Disease: A Pilot Randomized Controlled Trial" by Fang Yu, David M Vock, Lin Zhang, Dereck Salisbury, Nathaniel W Nelson, Lisa S Chow, Glenn Smith, Terry R Barclay, Maurice Dysken, and Jean F Wyman. This critical appraisal was conducted by a student at the University of Canberra.

## What is the background to this research?

An estimated 459000 Australian's are currently living with dementia, with this number predicted to more than double by 2058. The estimated cost for caring for people with dementia in Australia as of 2016 was $14.25 billion. Alzheimer's disease (AD) is the most common form of dementia, accounting for up to 80% of all cases.AD is an irreversible neurodegenerative brain disease. Early symptoms include mild cognitive impairment and memory loss. These symptoms progressively worsen and cause decreased independence until ultimately resulting in severe physical and mental impairment which requires full-time care.
The article details a pilot randomised controlled trial and its findings on the effects of aerobic exercise on the cognition of AD patients. Previous studies on the relationship between aerobic exercise and AD show's a positive effect on modulation of biomarkers and systems related to AD. Previous research has also shown aerobic exercise to help in the prevention of AD, however the findings from randomised control trials (RCT) on the effectiveness of aerobic exercise in treating those with AD have been inconsistent. Generated on existing knowledge, the researchers for the trial hypothesised that the treatment group (aerobic exercise) will show a slower decline in global compared the natural expected decline.

## Where is the research from?

Screening, testing and data collection for this study was conducted at the University of Minnesota between 2014 and 2020. The study was published in the Journal of Alzheimer's Disease in 2021. The article credits 10 researchers for the study, nine of which had previous published work on the relationship between AD and exercise. This includes several similar RCT studies exploring aerobic exercise as a treatment for AD as well as a systematic review on the topic. The authors all had nothing to disclose in the articles conflict of interest statement.

## What kind of research was this?

The study was a pilot RCT with 96 participants. The participants were all older adults living with AD. Similar RCT have been conducted however results have been inconsistent due to the methodological difference such as inclusion criteria, exercise modality and load. Meta-analysis studies on the topic conclude that aerobic exercise appears to delay the decline in cognitive function however more RCT with objective measurements are needed to confirm these findings. The purpose of this trial was test to a new methodology that a full scale RCT could adopt in the future.

## What did the research involve?
### Participants

* 96 participants (53 male, 43 female), mean age: 77.4±6.8 years.
* Inclusion criteria: Minnesota local 66+ year olds with AD verified by providers and clinician experts per 2011 diagnostics criteria; who had Mini-Mental State Examination and Clinical Dementia Rating of 15–26 and 0.5–2 respectively; had taken AD medication longer than one month if prescribed; received provider clearance for exercise safety and spoke English.
* Exclusion criteria: resting heart rate <50 or >100 beats per minute, neurologic disorders (other than AD), psychiatric disorders (e.g., schizophrenia), alcohol or chemical dependency, risked harm from exercise, new symptoms or diseases that had not been evaluated by providers, abnormal findings from the cycler-ergometer test or magnetic resonance imaging.

### Setting

* In-person screening, data collections, and cycle-ergometer tests was conducted at the Univerisity of Minnesota
* The exercise intervention took place at a YMCA gym or senior community, before additional exercise sites were added in year 3.

### Method

* Participants were randomly assigned at a 2:1 ration to the treatment group and the control group respectively.
* Treatment group participants completed a six-month cycling intervention that involved participants cycling three times a week. Participants cycled at 50–75% of their heart rate reserve (HRR) or to 9–15 on the Borg Ratings of Perceived Exertion (RPE). Participants cycled for between 20-50 minutes a session. The intensity and length of each session increased linearly until participants were cycling at 75% of their HRR or 15 RPE and for 50 minutes, which occurred in week 10. Each session included a five-minute warm-up and cool-down. Participants were under interventionist supervision and heart rate was monitored continuously throughout each session.
* The control group completed a stretching and range of motion program. Like the treatment group, control group participants had three sessions a week and gradually increased the duration of each session starting at 20 minutes in week one and increasing to 50 minutes by week 10. The program mostly consisted of seated movements and static stretches at <20% HHR or <9 RPE.
* Participants were tested on a battery of cognitive function tests prior to the beginning of the intervention and again after 3, 6, 9, and 12 months post the intervention commencing. The primary outcome was global cognition, which was measured using the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog). Secondary outcomes were episodic memory, executive function, attention, processing speed, and language. These were measured using the AD Centers’ Uniform Data Set neuropsychological test battery as well as alternative instrument, if available, to reduce the practise effect.

## What were the basic results?
#### Global cognition

Note: Higher ADAS-Cog equals poorer global cognition
The ADAS-Cog score for the cycling group increased by 1.0±4.6 after six months. This is significantly less than the natural expected 3.2±6.3 increase (p = 0.001), supporting the studies primary hypothesis. The ADAS-Cog score for the stretching group increased by 0.1±4.1 after six months. After 12-month, the change in ADAS-Cog was 2.4±5.2 for cycling and 2.2±5.7 for stretching. The between-group difference in score changes was not statistically significant at 6 or 12 months.

#### Other outcomes

No other testing results were significantly different between groups at 6 or 12 months.

## What conclusions can we take from this research?

Based on this studies' findings, aerobic exercise does have a positive effect on slowing the decline of global cognition in AD patients. There was however no significant between the treatment and control group. This may be due to several confiding factors such as the Hawthorne effect, social interaction effect, poorer health and baseline cognition for treatment group, and lack of power to given to detect the difference.
Future studies have supported the notion that aerobic exercise has a positive effect on AD patients' cognitive function. It is important to note however the importance of exercise modality and load in determining the effectiveness of the treatment.

## Practical advice

Although further research needs to be done on the topic, it does appear from this and other research that aerobic exercise does have a positive impact on the cognitive function of AD patients, and sequentially on their quality of life. It is important however to consider if there is any risks involved with exercise by consulting with practitioners. Individual circumstances need to be considered and exercise routines modified to suit. Greater scale RCT with refined methodologies are necessary to establish the best practise for utilizing aerobic exercise in the treatment of AD.

## Further information/resources

AD fact sheet
Meta-analysis of RCT

## References

* 1 2 Yu F, Vock DM, Zhang L, Salisbury D, Nelson NW, Chow LS, Smith G, Barclay TR, Dysken M, Wyman JF. Cognitive Effects of Aerobic Exercise in Alzheimer's Disease: A Pilot Randomized Controlled Trial. J Alzheimers Dis. 2021;80(1):233-244. doi: 10.3233/JAD-201100. PMID: 33523004; PMCID: PMC8075384.
* ↑ Sexton, C. E., Anstey, K. J., Baldacci, F., Barnum, C. J., Barron, A. M., Blennow, K., Brodaty, H., Burnham, S., Elahi, F. M., Götz, J., Jeon, Y. H., Koronyo-Hamaoui, M., Landau, S. M., Lautenschlager, N. T., Laws, S. M., Lipnicki, D. M., Lu, H., Masters, C. L., Moyle, W., Nakamura, A., … Carrillo, M. C. (2022). Alzheimer's disease research progress in Australia: The Alzheimer's Association International Conference Satellite Symposium in Sydney. Alzheimer's & dementia : the journal of the Alzheimer's Association, 18(1), 178–190. https://doi.org/10.1002/alz.12380
* ↑ Weller, J., & Budson, A. (2018). Current understanding of Alzheimer's disease diagnosis and treatment. F1000Research, 7, F1000 Faculty Rev-1161. https://doi.org/10.12688/f1000research.14506.1
* ↑ Lane CA, Hardy J, Schott JM. Alzheimer's disease. Eur J Neurol. 2018 Jan;25(1):59-70. doi: 10.1111/ene.13439. Epub 2017 Oct 19. PMID: 28872215.
* ↑ De la Rosa, A., Olaso-Gonzalez, G., Arc-Chagnaud, C., Millan, F., Salvador-Pascual, A., García-Lucerga, C., Blasco-Lafarga, C., Garcia-Dominguez, E., Carretero, A., Correas, A. G., Viña, J., & Gomez-Cabrera, M. C. (2020). Physical exercise in the prevention and treatment of Alzheimer's disease. Journal of sport and health science, 9(5), 394–404. https://doi.org/10.1016/j.jshs.2020.01.004
* ↑ Yu, F., & Kolanowski, A. (2009). Facilitating aerobic exercise training in older adults with Alzheimer's disease. Geriatric nursing (New York, N.Y.), 30(4), 250–259. https://doi.org/10.1016/j.gerinurse.2008.11.001
* ↑ Yu, F., Demorest, S. L., & Vock, D. M. (2015). Testing a modified perceived exertion scale for Alzheimer's disease. PsyCh journal, 4(1), 38–46. https://doi.org/10.1002/pchj.82
* ↑ Li, D., Thomas, R., Tsai, M. Y., Li, L., Vock, D. M., Greimel, S., & Yu, F. (2016). Vascular biomarkers to predict response to exercise in Alzheimer's disease: the study protocol. BMJ open, 6(12), e011054. https://doi.org/10.1136/bmjopen-2016-011054
* 1 2 Yu, F., Salisbury, D., & Mathiason, M. A. (2021). Inter-individual differences in the responses to aerobic exercise in Alzheimer's disease: Findings from the FIT-AD trial. Journal of sport and health science, 10(1), 65–72. https://doi.org/10.1016/j.jshs.2020.05.007
* ↑ Yu, F., Thomas, W., Nelson, N. W., Bronas, U. G., Dysken, M., & Wyman, J. F. (2015). Impact of 6-month aerobic exercise on Alzheimer's symptoms. Journal of applied gerontology : the official journal of the Southern Gerontological Society, 34(4), 484–500. https://doi.org/10.1177/0733464813512895
* 1 2 Yu, F., Bronas, U. G., Konety, S., Nelson, N. W., Dysken, M., Jack, C., Jr, Wyman, J. F., Vock, D., & Smith, G. (2014). Effects of aerobic exercise on cognition and hippocampal volume in Alzheimer's disease: study protocol of a randomized controlled trial (The FIT-AD trial). Trials, 15, 394. https://doi.org/10.1186/1745-6215-15-394
* 1 2 Brasure, M., Desai, P., Davila, H., Nelson, V. A., Calvert, C., Jutkowitz, E., Butler, M., Fink, H. A., Ratner, E., Hemmy, L. S., McCarten, J. R., Barclay, T. R., & Kane, R. L. (2018). Physical Activity Interventions in Preventing Cognitive Decline and Alzheimer-Type Dementia: A Systematic Review. Annals of internal medicine, 168(1), 30–38. https://doi.org/10.7326/M17-1528
* ↑ Panza, G. A., Taylor, B. A., MacDonald, H. V., Johnson, B. T., Zaleski, A. L., Livingston, J., Thompson, P. D., & Pescatello, L. S. (2018). Can Exercise Improve Cognitive Symptoms of Alzheimer's Disease?. Journal of the American Geriatrics Society, 66(3), 487–495. https://doi.org/10.1111/jgs.15241
* ↑ López-Ortiz, S., Valenzuela, P. L., Seisdedos, M. M., Morales, J. S., Vega, T., Castillo-García, A., Nisticò, R., Mercuri, N. B., Lista, S., Lucia, A., & Santos-Lozano, A. (2021). Exercise interventions in Alzheimer's disease: A systematic review and meta-analysis of randomized controlled trials. Ageing research reviews, 72, 101479. https://doi.org/10.1016/j.arr.2021.101479
* 1 2 Liu, W., Zhang, J., Wang, Y., Li, J., Chang, J., & Jia, Q. (2022). Effect of Physical Exercise on Cognitive Function of Alzheimer's Disease Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trial. Frontiers in psychiatry, 13, 927128. https://doi.org/10.3389/fpsyt.2022.927128
* ↑ Yu, F., Nelson, N. W., Savik, K., Wyman, J. F., Dysken, M., & Bronas, U. G. (2013). Affecting cognition and quality of life via aerobic exercise in Alzheimer's disease. Western journal of nursing research, 35(1), 24–38. https://doi.org/10.1177/0193945911420174
* ↑ National Institute on Aging. Alzheimer's Disease Fact Sheet. https://www.nia.nih.gov/health/alzheimers-disease-fact-sheet
* ↑ Journal of Alzheimer's Disease.Cognitive Effects of Aerobic Exercise in Alzheimer’s Disease: A Pilot Randomized Controlled Trial. https://www.j-alz.com/manuscript-disclosures/20-1100r2