As the elderly population in Canada continues to grow,

the elderly population in Canada continues to grow, so does the incidence of
many age-related health problems. Alzheimer’s disease (AD) is among these, one
of immense importance. AD is a chronic neurodegenerative disease characterized
by memory loss and gradual cognitive impairment beyond what is expected from
normal aging. It is one of the most common forms of dementia, having a
prevalence of 60-70% of all dementia cases1.

is still much to learn about this disease as the exact biological cause is
still not known. However, there are several hypotheses to how the damage is
caused in the brain leading to the cognitive impairment. The primary hypothesis
is on the accumulation of amyloid-beta and Tau proteins, which are thought to
form plaques and tangles in the brain2-3. It is unclear to the exact
roles that these play in the disease; however, they are found in significant
amounts in autopsies of people with AD. It is believed that these plaques and
tangles can block communication signals between neurons, thus leading to neurodegeneration
or death of neurons. This is what is believed to cause the memory loss, and the
other symptoms of Alzheimer’s disease.

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Canada alone, 564,000 people live with dementia with the numbers growing every
year. It is estimated that by 2031, the numbers will almost double, affecting
up to 937,000 Canadians4. The growing effect of the disease has not
only affected the people with the disease but also put and huge financial drain
on the Canadian health care system and the thousands of caregivers. In 2016
alone, the combined costs of treatment and care are estimated to be up to $10.4
billion4. A large proportion of the cost is toward pharmacological
treatments. The search continues to find a cure for Alzheimer’s as there
currently exists none that can stop or reverse the progression of the disease.
Research has been focusing on multiple viable treatment options to relieve
signs and symptoms, one of the more popular focus being pharmacological. However
additional to the problem with economic cost, medicational treatments commonly
have multiple unpleasant and unwanted side effects. Thus this gives incentives
for research to move outside of the medicinal regime and look at different
non-traditional routes such as prescription of a certain amount of Physical Exercise

there is a staggering growth of research studies looking into exercise as a
viable treatment. As seen in Figure 1, the number of publications on PubMed on
the topic of “Exercise and Alzheimer’s disease” has been growing exponentially,
research on this topic has almost doubled in the past 10 years. There have been
almost 300 publications on this topic in 2017 alone. This just emphasizes that
more and more resources are used to look into this non-traditional treatment as
an option for treating AD.





1: Publications on Alzheimer’s and Exercise over the Years

PE has been long proven to help with both mental and physical health of people
of all ages and health status5. It does not have the unpleasant
side-effects like many common pharmacological options and may prove to be quite
a viable option of treatment for AD. Previous data from several studies, both
animal and epidemiologic, has shown that physical exercise has improved the
quality of life of people living with Alzheimer’s and even improved the quality
of life of their family and caregivers. Though several studies were conducted
in this area, there is a lack of consensus regarding to exact mechanisms to how
exercise helps with cognitive impairment in people with AD. It is also unclear
to how much physical activity, what kind, and at what intensity is optimal to
decrease the cognitive decline and improve the lives of people affected with AD.
The goal of this research paper is to conduct a literature review to look at both
basic science research and epidemiological research to synthesise data on the
possible mechanisms of how physical activity improves cognitive abilities in
people with Alzheimer’s disease and to summarize the results of the clinical
studies to create a guideline/recommendation for physical activity in people
with AD.

Mechanisms of interaction between
physical exercise and cognitive decline in Alzheimer’s:

exercise has been shown to reduce amyloid-beta amounts in transgenic mice6.
Results such as these are exciting as they offer a simple relationship between
a cause and the effect of reducing Alzheimer’s plaques in the brain. There is
consensus that exercise can reduce the symptoms and determents of AD but
unfortunately, the underlying reasons why exercise may provide a biological
causality for plaque clearance is unknown. However, there are several hypotheses
of the inverse relationship of the two. Figure 2 shows a chart summary of the several
hypotheses of potential mechanisms that are going to be further discussed this
research paper.


2: Summary of Mechanisms

Exercise and Growth Factors:

plausible hypothesis is that exercise has a positive effect on activating
growth factors such as insulin-like growth factor 1 (IGF-1), vascular
endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF).
The exact pathways of activating these growth factors through PE is unclear,
however studies have shown promising positive correlations between the two.

AD, cells in the hippocampus, which are integral to learning and memory,
undergo neuronal atrophy. The BDNF family of signaling molecules are elusive
for their roles in neuron regulation, growth, and especially memory formation7.
In patients with Alzheimer’s disease, there is a down-regulation of the genes
that produce BDNF in the hippocampus7. Simply, researchers have
found that exercise increases the levels of BDNF produced in the brain for
later cell signaling during body repair7. This may counterbalance
the loss of BDNF and memory function from Alzheimer’s disease. BDNF also activates
tropomyosin-related kinase B (trkB) receptors on oligodendrocyte precursor
cells8-9. This promotes the formation of new oligodendrocytes to initiate
the myelination process in nerve cells. Though increased myelination, signal
transmission efficiency is improved between nerve cells which can lead to
better memory functions in the hypothalamus8-9.

like BDNF, are also found in lower than normal levels in the AD brain and the reduction
in the expression level of this growth factor has been associated with AD neuropathology.
There is also evidence IGF-1 has a potential protective effect against AD11-13.Thus
by increasing cerebral IGF-1 levels through PE, the AD brain will be
potentially subjected to less neuropathology.

is quite difficult to measure in humans; however, rat studies have shown improves
hippocampal neurogenesis through PE14. By inducing both BDNF and
growth factor expression in the brain, PE can significantly enhance
neuroplasticity and neurogenesis, and therefore lead to increased hippocampal

Improvement of Vascular Function:

one-third of the AD cases are complicated with vascular pathologies leading to
a synergistic effect on cognitive decline16-17. Therefore, another viable
hypothesis that is considered by many researchers is that PE causes an
improvement in cerebral vascular functioning and perfusion in the brain; this
means that there is an increase in cerebral blood flow to supply to the neurons
leading to improved neurogenesis in certain brain areas. Both animal and human
studies have shown that there is a significant increase in brain perfusion and
angiogenesis within just few weeks of aerobic training17.

beneficial effects on cerebral blood flow have been associated with the reduction
of cerebrovascular and endothelial dysfunction pathophysiology in people with
AD. This effect is due predicted to be due to the activation of nitric oxide
(NO) which is derived from endothelial NO synthase (eNOS). NO plays a pivotal
role in vascular tone, blood pressure, and vascular homeostasis18-19.
AD pathology causes a deterioration of NO homeostasis leading to hypoxia Thus
by increasing NO, vascular reserves in the brain will improve leading to maintenance
of neuronal plasticity. Moreover, Vascular endothelial growth factor (VEGF) is
upregulated with exercise20-21. VEGF
production is triggered by hypoxia which happens during aerobic activities such
as PE17. These vascular growth factors can act on the endothelial
cells lining the wall of the blood vessels in the brain triggering them to
divide and produce new blood vessels resulting in better perfusion20-22.
Through either two of the mechanisms mentioned, brain perfusion will increase
having the potential to decrease certain AD pathologies related to vascular

Plaque Deposition and Neuroinflammation:

key characteristic of AD is the formation of amyloid-beta plaques in the
cerebral cortex and hippocampus. Several research has shown reduction of plaque
deposition in AD mice who undergo aerobic exercise23-24. This in
itself can help improve pathologies in individuals with Alzheimer’s.

is usually a protective response; however, unmanaged and prolonged inflammation
can lead to multiple complications and pathologies, and most importantly,
increased redox stress upon cells. In people with AD, there is an increased
amount of amyloid-beta deposits which are able to activate astrocytes which
turn will release of proinflammatory mediators including TNF-a, and interleukin
IL-1b25. Since the amyloid-beta aggregates and cannot be cleared,
proinflammatory mediators will be constantly expressed leading to prolonged
inflammation in the brain which can have detrimental effects causing neural
atrophy. If inflammation is somehow reduced in the brain, less damage will be
caused by the amyloid-beta deposits45.

hypothesized mechanism is that exercise is believed to decrease the amount of
inflammation in the brain. One possibility is that exercise increases clearance
of amyloid-beta, consequentially, there will be less amyloid-beta to enter the
astrocytes and therefore less proinflammatory mediators being released25.
Evidence for the reduction of cerebral inflammation is found in a transgenic
Alzheimer’s mouse models sedentary mice had a higher hippocampal expression of
proinflammatory interleukins IL-1b and TNF-a, and reduced levels of anti-inflammatory
markers such as interferon-gamma (IFN-g) and chemokine ligand 3. When the AD
mice were put through an exercise regime of swimming, they were shown to have a
lower periphery expression of inflammatory markers than sedentary mice26-27.

Clinical Applications of PE in people
with Alzheimer’s:

basic science research showed quite consistent results; however, the
experiments were all done in a controlled setting. For more applicable
evidence, I reviewed several clinical trials that used PE as a treatment for
Alzheimer’s disease. Looking into several prospective studies, there has been
quite consistent evidence that increase PE had beneficial outcomes for people
with Alzheimer’s. Hernández et al. conducted a systematic review in this topic
including 15 different RCTs28. Thirteen of the included studies had
positive results and they were able to conclude that the practice of physical
exercise could present significant results for the improved functionality and
performance of daily life activities, improvement in functional capacity
components (flexibility, agility, balance, strength), and improvement in certain
cognitive components such as sustained attention, visual memory, and frontal
cognitive function in people with mild to severe AD. The clinical studies looked
at different kinds of outcomes including: physical function, cognitive functions,
career burden, self-care and mobility. For
this research paper, I will mainly be focusing on the outcome of improvements
on cognitive functions.

several studies I looked at had various ways of measuring cognition and they
also had different conclusions on the benefits of PE. Vreugdenhil et al.
conducted a randomized controlled trial (RCT) on small community of people with
Alzheimer’s. Their findings had a positive result (p<0.001) showing that at 4-months follow-up, the individuals who were randomized to exercise had better improvement in cognition, which was measured by Mini Mental State Examination scores, compared to those in the controlled group29. Öhman H et al. on the other hand, found only partial improvements in cognitive functions; an RCT of 210 individuals with AD was conducted measuring cognitive functions through Clock Drawing Test (CDT), Verbal Fluency (VF), Clinical Dementia Rating (CDR), and Mini-Mental State Examination (MMSE). Groups allocated to the exercise regime was able to significantly improve (p=0.03) than those in the control group at the Clock Drawing Test. A positive effect was only observed in the CDT and was not observed in the other domains of cognition measured30. Morris et al in their RCT concluded that there was no clear effect of intervention (PE) on primary outcome measured including Memory and Executive Function. However they did find a correlation between cardiorespiratory fitness between change in memory performance and bilateral hippocampal volume31. This matches with the findings of a systematic review done by Angevaren et al. where they found that aerobic exercise with an intensity improves cardiorespiratory fitness which can lead to beneficial for cognitive functions in healthy older people32. Though these studies had a variety of different conclusions, it is still pretty consistent that exercise has the potential to aid in cognitive functions. These studies do have their limitations because just like basic science studies, they are in a more controlled setting as the long-term adherence to frequent PE is not measured; the studies with the positive effects also were not able to report if the benefits were sustained after the study concluded.  Moreover, there are very few studies with large sample sizes on this topic. . Finalized Exercise Recommendation: Even with the limitations of both basic science and clinical studies, there is quite convincing evidence that aerobic exercise does help people with Alzheimer's disease. Using the studies that I have read up on, I came up with a recommended exercise recommendation. Recommendations for Exercise: 150 minutes weekly of moderate exercise (add in resistance training for additional benefits) Exercises can include: walking, jogging, biking, swimming, simple exercise programs Start off with low-moderate intensity to promote adherance Physicians should take into account their individual patients to make sure that each of them gets the appropriate exercise regime due to their potential comorbidities. At least 6 months of PE is recommended to see results                   150 minutes weekly of moderate-intense exercise (add in resistance training for additional benefits In multiple studies of RCT's I looked at, a majority of them did show an improvement of by just introducing the intervention of 150 minutes of aerobic exercise per week35-37. They are found to be cognitively protective and associated with increased hippocampal volume plus improved spatial memory. Surprisingly, this is also similar to the recommendation of the WHO, which advises "To improve overall cardiovascular health, we suggest at least 150 minutes per week of moderate exercise or 75 minutes per week of vigorous exercise"38. Aerobic exercise implies training that elevates heart rate and increases Vo2. The studies reviewed used multiple different exercises to achieve this, the most common ones being walking, running, walking and resistance training 29-31,33-34,39.One of the RCTs even used a Home Support Exercise Program which is made for frail elderly people which has been tested for both feasibility and safety29.  All these were able to show effective results in improving cognitive functions in people with Alzheimer's. Start off with low-moderate intensity to promote adherence: We have to take into account practicality as well as many of these clinical studies did not follow-up on patients after their completion and thus it is difficult to tell if the individuals stuck to the regime. By prescribing an initial low-moderate intensity, it promotes practicality and adherence at the beginning of the program40. Moreover, high, intensive aerobic exercises can lead to certain adverse effects such as orthopedic injuries, increase fall risk, and provoke acute coronary syndromes.   At least 6 months of PE is recommended to see results Studies with intervention (PE) lasting 6 months and more had higher chances of improvement in cognitive functions41-42. There is also evidence that short term increase of aerobic exercise did not benefit the individual in several studies43-44. Several studies that only introduced a short-term exercise regime (<12 weeks) not enough to improve cognitive impairment in individuals with Alzheimer's. Thus the exercise can't just be for short-term but a life style change. Physicians should take into account their individual patients to make sure that each of them gets the appropriate exercise regime due to their potential comorbidities. Thus, physicians should help patients select exercise programs compatible with their capabilities and cardiopulmonary status. Thus doctors should assess their patients for risk factors before recommending certain exercise practices. Conclusion: As looked at several pathways and basic science studies, there are convincing evidence that exercise can promote a better cognitive function in people with Alzheimer's. The human research studies had many different conclusions but this may be due to the fact that they all had different measurements to look at cognition functions and the studies themselves have limits due to the small sample sizes. Published systematic reviews of these studies has shown a small but nonetheless significant directional results towards the PE allocated groups. More research is still needed to have a more definitive result with larger sample sizes. A recommendation of ongoing, moderate-intensity physical exercise should still be considered as an option for individuals with Alzheimer's as regular aerobic exercise has multiple potential benefits that are not just limited to improvements in cognitive functions.