Elderly person holding a ball with doctor

Alzheimer’s disease (AD) accounts for approximately 70% of dementia cases worldwide (1). With global demographics trending towards an increasingly aged global population, AD diagnoses are on the rise as well. In 2010 there were 35.6 million cases of AD, however by 2030 there are projected to be 65.7 million cases of AD around the globe (1). There are currently no pharmaceutical treatments capable of altering the disease course of AD, highlighting the importance of finding alternative modes of treatment that could potentially relieve the symptoms associated with AD (1). Over the last decade, exercise has been explored as a potential method for preventing and/or slowing the progression of AD (2). Regular exercise is an attractive treatment option because it is low-cost, low-risk and widely available (3). Through its effects on the vascular system and hippocampus, regular lifetime exercise appears to have a positive effect on an individual’s risk for and severity of dementia.

The cognitive benefits of exercise have been well-established in normally-aging adults. After undergoing three months of a regular physical training program, previously inactive adults demonstrated superior brain function, cognition and cardiovascular fitness compared to controls (4). Regular exercise throughout an individual’s lifetime may also prevent the development of dementia in the elderly years. In a long-term study investigating perceived fitness throughout adult life, people who rated their midlife fitness as poor were four times more likely to develop dementia in old age (5). Furthermore, higher levels of cardiorespiratory fitness, which often accompanies regular exercise, are associated with greater brain volume, reduced brain atrophy, reduced risk of dementia and slower dementia progression (3).

The benefits of exercise that have been established in the normally-aging population are mirrored in AD and dementia-sufferers. A meta-analysis examining the effect of exercise in dementia patients found that physical exercise has an overall positive effect on these individuals, including their quality of daily living (1). The exact method by which exercise affects dementia is not yet known, however some researchers subscribe to the cardiorespiratory fitness hypothesis, which posits that increased fitness underlies improvements in cognition, and that improvements from baseline physical fitness levels are essential for an individual to experience the cognitive benefits of exercise (3). This hypothesis is supported by data linking improved cardiorespiratory fitness to increased bilateral hippocampal volume, decreased neuropsychiatric symptoms and better scores on cognition and daily functioning tests (3, 2). 

Despite the demonstrated benefits of exercise, there are some caveats in the ability of exercise to positively impact AD and dementia progression. A study on community-dwelling AD patients found that the benefits of exercise may only surface when the patient engages in frequent, high-intensity exercise (6). The same study also found that short-term exercise programs may not be sufficient for impacting daily living, and that improvements in day to day functioning may only be seen in long-term regular exercisers (6). It is therefore crucial for patients to maintain a regular workout regimen when using exercise as a method of alleviating the progression of dementia.

Despite the documented positive effects of exercise on dementia, researchers are still in the process of clarifying the biological processes by which exercise impacts dementia. One frequently cited theory is that regular exercise may act via the vascular system to improve cognition. Cerebral blood flow (CBF) is reduced by approximately 40% in AD patients compared to controls (7). The lower levels of CBF observed in AD patients are hypothesized to arise from reduced glucose metabolism levels resulting from less neural activation (8, 9). Reduced CBF in normally-aging individuals correlates with routine age-related declines in cognition, indicating that further CBF reductions in AD patients may contribute to their particularly rapid cognitive decline (9). A study including both AD patients and normally-aging individuals observed a correlation between reduced CBF and lower cognitive skills test scores (8). This observation lends support to the theory that lower CBF levels are related to AD severity (8). Exercise has been demonstrated to increase CBF, offering a potential mechanism by which exercise may alleviate the symptoms of AD (10).

Normal aging is also associated with reduced hippocampal volume and the corresponding memory impairments that accompany this reduction (10). One year of moderate exercise training has been found to increase bilateral hippocampal volume, indicating that exercise may act to preserve cognition via the hippocampus (10). Furthermore, in middle aged mice, five weeks of treadmill running was shown to increase the quantity and survival odds of neural progenitor cells in the hippocampus (11). Exercise may specifically benefit the hippocampal health of individuals diagnosed with AD, given that another study in mice found that nine months of voluntary exercise reduced tau buildup in the hippocampus (12). The accumulation of tau in the brain is a well-documented consequence of AD, indicating that exercise may not only act on general aspects of cognitive health but on AD-specific pathologies as well.

It is important to note that exercise is not an instantly-acting therapy and is likely most effective when utilized consistently throughout an individual’s lifetime. Some studies have found that beginning exercise therapies once AD has progressed to a severe stage is ineffective (7). These studies have suggested that exercise may be effective at preventing the progression of AD but not reversing it, suggesting that the benefits of exercise may only be observed in AD patients when the regimen is started early enough (7). This is supported by the previously mentioned observation that individuals with greater midlife physical fitness are less likely to develop dementia in their elderly years (5). An effective way of implementing these findings into a clinical setting could be the implementation of physical exercise programs for all adults who do not feel that they possess high physical fitness. This strategy is supported by the fact that individuals with higher baseline fitness levels experience less hippocampal volume loss in the elder years (10). 

For medical professionals hoping to implement exercise regimens for patients already diagnosed with AD, it is clear that early diagnosis is critical to the effectiveness of these programs. Esurgi is currently developing the Eye AD: a device designed to diagnose AD in its early stages via the detection of abnormal eye movements. Would you find the Eye AD helpful in diagnosing AD in its early stages?

Sources:

1. Groot, C., Hooghiemstra, A., Raijmakers, P., Berckel, B. V., Scheltens, P., Scherder, E., . . . Ossenkoppele, R. (2016). The effect of physical activity on cognitive function in patients with dementia: A meta-analysis of randomized control trials. Ageing Research Reviews, 25, 13-23. doi:10.1016/j.arr.2015.11.005

2. Sobol, N. A., Dall, C. H., Høgh, P., Hoffmann, K., Frederiksen, K. S., Vogel, A., . . . Beyer, N. (2018). Change in Fitness and the Relation to Change in Cognition and Neuropsychiatric Symptoms After Aerobic Exercise in Patients with Mild Alzheimer’s Disease. Journal of Alzheimer’s Disease, 65(1), 137-145. doi:10.3233/jad-180253

3. Morris, J. K., Vidoni, E. D., Johnson, D. K., Van Sciver, A., Mahnken, J. D., Honea, R. A., … & Burns, J. M. (2017). Aerobic exercise for Alzheimer’s disease: A randomized controlled pilot trial. PloS one, 12(2), e0170547.

4. Chapman, S. B., Aslan, S., Spence, J. S., Defina, L. F., Keebler, M. W., Didehbani, N., & Lu, H. (2013). Shorter term aerobic exercise improves brain, cognition, and cardiovascular fitness in aging. Frontiers in Aging Neuroscience, 5. doi:10.3389/fnagi.2013.00075

5. Kulmala, J., Solomon, A., Kåreholt, I., Ngandu, T., Rantanen, T., Laatikainen, T., … & Kivipelto, M. (2014). Association between mid‐to late life physical fitness and dementia: evidence from the CAIDE study. Journal of internal medicine, 276(3), 296-307.

6. Hoffmann, K., Sobol, N. A., Frederiksen, K. S., Beyer, N., Vogel, A., Vestergaard, K., … & Jacobsen, S. (2016). Moderate-to-high intensity physical exercise in patients with Alzheimer’s disease: a randomized controlled trial. Journal of Alzheimer’s Disease, 50(2), 443-453.

7. van der Kleij, L. A., Petersen, E. T., Siebner, H. R., Hendrikse, J., Frederiksen, K. S., Sobol, N. A., … & Garde, E. (2018). The effect of physical exercise on cerebral blood flow in Alzheimer’s disease. NeuroImage: Clinical, 20, 650-654.

8. Binnewijzend, M. A., Kuijer, J. P., Benedictus, M. R., van der Flier, W. M., Wink, A. M., Wattjes, M. P., … & Barkhof, F. (2013). Cerebral blood flow measured with 3D pseudocontinuous arterial spin-labeling MR imaging in Alzheimer disease and mild cognitive impairment: a marker for disease severity. Radiology, 267(1), 221-230.

9. Davenport, M. H., Hogan, D. B., Eskes, G. A., Longman, R. S., & Poulin, M. J. (2012). Cerebrovascular reserve: the link between fitness and cognitive function?. Exercise and sport sciences reviews, 40(3), 153-158.

10. Erickson, K. I., Voss, M. W., Prakash, R. S., Basak, C., Szabo, A., Chaddock, L., … & Wojcicki, T. R. (2011). Exercise training increases size of hippocampus and improves memory. Proceedings of the National Academy of Sciences, 108(7), 3017-3022.

11. Wu, C. W., Chang, Y. T., Yu, L., Chen, H. I., Jen, C. J., Wu, S. Y., … & Kuo, Y. M. (2008). Exercise enhances the proliferation of neural stem cells and neurite growth and survival of neuronal progenitor cells in dentate gyrus of middle-aged mice. Journal of applied physiology, 105(5), 1585-1594.

12. Belarbi, K., Burnouf, S., Fernandez-Gomez, F. J., Laurent, C., Lestavel, S., Figeac, M., … & Grosjean, M. E. (2011). Beneficial effects of exercise in a transgenic mouse model of Alzheimer’s disease-like Tau pathology. Neurobiology of disease, 43(2), 486-494.

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