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Alzheimer's disease (AD) is a form of dementia that currently affects millions of people in North America alone. Its increasing prevalence, lack of cure, and course of progress makes AD an important area of research. In AD, massive loss of neurons affects several regions of the brain, including the hippocampus and prefrontal cortex. This neurodegeneration is due to the buildup of tau protein tangles and β-amyloid plaques that disrupts neuron communication, resulting in symptoms that involve memory loss and cognitive decline. Alzheimer’s is a chronic disease that develops over a long period of time. The majority of cases are not simply due to genetics but are sporadic and can be influenced by several risk factors including some environmental factors and lifestyle choices. An individual’s diet choices, their use of cannabis, their cognitive reserve, and their life events have all been found to play a role in either prolonging or advancing the onset of Alzheimer’s disease. With no known cure these risk factors have become important in early intervention for delaying the pathogenesis of Alzheimer’s.
Table of Contents
1.1 Effect of Diet
Many lifestyle choices and diet habits have been found to act as either protective factors or promoting factors for Alzheimer’s disease. These include the amount of fatty foods consumed, cholesterol levels, specific vitamin intake, and the general diet followed by an individual.
1.1a Promoting factors
There are several diet choices linked with Alzheimer disease that have been found to promote the onset of the disease. High fat diets are one of these disease promoting factors that cause dietary inflammation. Fatty diets promote the accumulation of lipoprotein complexes resulting in a pro-inflammatory response which is one of the major causes of neurodegeneration. High cholesterol has also been linked with AD, and hypercholesterolemia is considered to be an early risk factor for the disease, especially when it begins in early life. High levels of low density lipoproteins (LDL) have the strongest link with AD and some cholesterol reducing drugs have been found to prolong disease onset. Studies have also shown that rabbits fed a high cholesterol diet had an increase in β-amyloid deposition after only one month. This can be explained by the role cholesterol plays in the intracellular processing of amyloid precursor proteins (APP) as well as its role in regulating γ-secretase. This is a protease that cleaves APP into β-amyloid, one of the main proteins involved in the plaque formations of AD patients. Hypercholesterolemia is promoting the onset of AD in many ways, not only does it induce neuroinflammation and the formation of plaques but it also causes oxidative stress and impaired mitochondrial functioning in the brain. This is an important area of research since these are modifiable risk factors that may lead to the potential prevention of Alzheimer’s disease.
1.1.b Protective factors
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Some dietary habits are protective factors for Alzheimer’s disease. These factors have been found to prolong the onset of the disease and are frequently linked with individuals who are unaffected by Alzheimer’s disease. The Mediterranean diet is known to decrease the risk of AD as well as prolong the onset by slowing the process of cognitive decline. Many components of this diet are believed to play a role in the disease pathogenesis. The Mediterranean diet consists of a high intake of fish along with fruits and vegetables, all of which are antioxidant foods containing flavonoids, vitamin C, vitamin E, or carotenoids. Fish has been shown to lower blood pressure and decrease the level of fats found in the blood. On the other hand, the antioxidants reduce oxidative stress , inflammation, and clots. Studies have found that individuals who carefully follow the Mediterranean diet have significantly lower levels of interleukin-6 (Il-6) as well as other inflammatory markers. Both neuroinflammation and oxidative stress are strongly linked with Alzheimer’s disease which explains the beneficial effects of this diet. Something as simple as watching your eating habits can therefore have a large effect on your risk of AD and other diseases that are linked with Alzheimer’s, including diabetes, hypertension and impaired lipoprotein metabolism.
1.2 Type 2 Diabetes and Alzheimer's
Almost fifty percent of individuals suffering with AD have obesity, type 2 diabetes, or are simply insulin resistant and . These diseases are caused by poor diets that result in decreased insulin production and sensitivity which are both needed for proper brain functioning. It is also well known that individuals with Type 2 Diabetes are at twice the risk of later developing AD.
1.2a Insulin and the Brain
|Insulin in the Brain|
|Figure 1. Correia S.C. et al. 2011.|
Insulin plays a protective role in the brain and enhances both memory and plasticity. Alzheimer’s patients have an insulin deficiency and decreased insulin signaling which explains the strong link between Type 2 diabetes and Alzheimer’s disease. Insulin regulates the metabolism of β-amyloid and Tau protein phosphorylation to maintain them at appropriate levels in the brain. When insulin is low or the signalling has become resistant it can cause the accumulation of β-amyloid and tau hyperphosphorylation which results in the formation of plaques. Insulin is not only important for the inhibition of Tau phosphorylation but also promotes its transport into axons by binding it to microtubules. Without proper insulin these Tau neurofibrillary tangles will accumulate in the brain causing damage. Insulin degrading enzymes are also important since they degrade β-amyloid. Individuals who are not responsive to insulin will have less of these insulin degrading enzymes available to breakdown the β-amyloid that is accumulating. Insulin clearly plays an important role in the brain which explains why its deregulation can result in cognitive decline and why insulin resistance is an extremely common feature in the brain of AD patients.
1.2b Intranasal insulin therapy
Research and clinical trials have been exploring the use of insulin as a possible treatment for the prevention of Alzheimer’s disease  and . Replacing the missing insulin in Alzheimer’s patients may alleviate some of the disease’s symptoms as well as delay its pathogenesis. Intranasal insulin is a noninvasive nasal spray that allows for direct delivery of insulin to the brain, bypassing the blood-brain barrier (BBB). A clinical trial showing the positive effect of this treatment was done using 2 groups, a placebo treated group and an insulin treated group. After 8 weeks of treatments the insulin treated individuals performed a memory recall task showing improvement in learning and memory processes associated with the hippocampus, an area of high insulin receptor density. Starting mid-spring 2013 there will be larger clinical trials beginning in hopes of finding more positive results with insulin treatments for AD.
2.1 Effects of cannabis
|Cannabis and Alzheimer's Disease|
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Recent discoveries have shown that cannabinoids play an important role in Alzheimer’s disease. They are constantly finding medical benefits associated with cannabis and they have now found it to play a role in many age-related processes including neuroinflammation, neurogenesis, and memory. It is therefore believed that cannabis users may have delayed the pathogenesis of AD and protected themselves from the onset of the disease. These findings could be important for future prevention treatments in AD as well as symptom mediation for patients. Cannabis administration is currently being tested on transgenic APP mice with hopes of future cohort studies on chronic cannabis users.
2.1a Neuroinflammation and Microglia
|Anti-inflammatory effects of cannabis on transgenic APP mice|
|Figure 5. Martín-Moreno A.M. et al. 2012.|
Cannabinoids generally interact with both the CB1 receptors found on all neural cell types throughout the brain and the CB2 receptors that are mainly found on microglial cells, the phagocytic immune cells of the central nervous system. The release of pro-inflammatory cytokines and the activation of microglia as well as other neuroinflammatory processes are associated with AD. Neuroinflammation in Alzheimer’s is caused by the activation of microglial cells around the plaques and is associated with many negative symptoms involving cognition and memory impairment. The use of anti-inflammatory drugs has been found to decrease symptom severity in patients and long term uses of these drugs have prevented the onset of the disease. Cannabis is a known anti-inflammatory which explains its positive effects on the Alzheimer brain. Experiments done on transgenic APP mice have shown that the oral administration of synthetic cannabinoids through drinking water prevented the microglial activation that is associated with AD. They first cultured and stained microglial cells to monitor cell density in the AD induced transgenic mice compared to the wild type mice. Their results showed that the APP injected mice had a greater density by 53%, which shows the role of neuroinflammation in Alzheimer’s. The mice were then treated with the oral cannabinoid agonists and showed a significant decrease in microglial cell density along with a decrease in other cytokines and pro-inflammatory factors like COX-2, and TNF-α. Cannabinoids can therefore act to counteract the microglial activation in AD and decrease inflammation in the brain allowing for a possible treatment of Alzheimer’s.
2.1b Memory and neurogenesis
|Novel object recognition memory test|
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|Effects of cannabinoids on memory in a novel object recognition test|
|Figure 1. Martín-Moreno A.M. et al. 2012.|
Unlike CB2 receptors that are mainly expressed on microglial cells the CB1 receptors are found throughout the brain and are the main cannabinoid receptors in the hippocampus, therefore accounting for the effect cannabinoids have on learning and memory. Studies have shown that the inhibition of endocannabinoid reuptake has resulted in the improvement of memory impairment. The use of cannabinoid administration on transgenic APP mice has also been used to study the long term effects of cannabis on memory function in AD. The main memory test used in these experiments was novel object recognition. The transgenic APP mice could not distinguish between familiar (A) and novel objects (NO) due to the memory loss associated with Alzheimer’s, and therefore looked at both objects for equal amounts of time. Once treated with cannabinoids these mice had similar response times as the wild type mice meaning they showed some memory improvement and went back to looking at the novel object for a longer time period. Another hippocampal dependent memory test used was the Morris water maze which showed similar positive results when using cannabinoid administration. This memory improvement is not only due to the role of cannabis in reducing neuroinflammation but also its role in promoting neurogenesis. Research has shown that cannabinoids play an important role in regulating the neurogenesis that can occur in the hippocampus of the adult brain. Mice lacking CB1 receptors were found to have defective adult neurogenesis which shows the importance of the cannabinoid system. Cannabinoids also act on non-neuronal cells to cause nerve growth factor release for axonal growth. Neuronal damage was also found to be more common in cells lacking cannabinoid receptors showing their influence on neuron survival and protection against the deleterious effects of β-amyloid in AD.
2.1c β-amyloid levels and toxicity
Cannabinoids have been found to play a role in decreasing the levels of β-amyloid in AD. Removal of the peptide is done by increasing its transit time from the brain through either the blood or the cerebrospinal fluid. Both CB1 and CB2 receptors have been found on the choroid plexus of these barriers in rats and studies have shown that the transit time of β-amyloid from one compartment to another was faster in the cannabinoid treated rats. Transgenic AD induced APP mice also showed a positive effect to cannabinoid administration with a 27-30% β-amyloid decrease after treatment. Cannabinoids have not only been found to reduce β-amyloid levels but also protect neurons from the negative effects of oxidative stress and neurodegeneration caused by β-amyloid. Calcium influx is directly influenced by β-amyloid through the activation of voltage gated channels and pore formation. This deregulation of intracellular calcium is a key feature of AD. Cannabinoids acting on the CB1 receptors protect hippocampal neurons through the inhibition of presynaptic calcium influx, preventing the excessive release of glutamate and protecting neurons from excitotoxicity. This is therefore another possible benefit of cannabis use when it comes to prolonging the onset of Alzheimer’s disease as well as improving the lives of patients living with the disease today.
3.1 Effects of Cognitive Reserve and Stress
|Effects of stress on the brain|
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High education and the maintenance of cognitive activity throughout life are both protective factors for AD. Greater cognitive reserve is found in individuals who have complex jobs that keep them mentally active and who have received more years of education. Lower rates of Alzheimer’s disease and a slower onset of cognitive decline are found in individuals who have a greater cognitive reserve. Similarly, there has been a strong link between individuals with lower levels of education and an earlier onset of Alzheimer’s disease. Cognitive reserve does not decrease the formation of β-amyloid plaques in the brain but simply attenuates its effects on memory. This could simply be due to the fact that having a greater cognitive reserve protects them from experiencing the symptoms in the early stages of disease development. It could also be caused by the fact that being more mentally active in leisure and work tasks increases cerebral blood flow, glucose utilization, oxygen metabolism, resistance to endogenous excitatory neurotransmitters, and production of growth factors in the brain. It is therefore important to have an active engagement in cognitive social and leisure activities as we age to keep a healthy brain. The onset of Alzheimer’s disease has also been linked with many psychological factors and some life events. Stress accounts for one of these factors and can have either a promoting or preventative effect on disease onset depending on the length and intensity of the stressful event. Individuals who have suffered from depression or have been under chronic stress or anxiety were found to be more sensitive to the onset of the disease, however acute stress was found to have an opposite effect and prolonged the onset. The link between stress and AD is due to the physiological effects of stress on the body, increasing blood pressure as well as cortisol levels. Cortisol is a hormone that can enter the brain and cause damaging toxic effects by promoting neuronal death when chronically released. This can therefore lead to the onset of Alzheimer’s disease and shows the importance of providing care and therapy for the individuals in our society who suffer from these different psychological factors. There has also been some research done on lifestyle treatments that have been found to improve memory through music and its effects on mood.