By Nicole Strossman, Biochemistry & Molecular Biology, ‘17
“I chose to write this review for my UWP 104F after reading about potential treatments for Alzheimer’s Disease. As this is a disease that affects such a wide variety of people, and currently has no cure, I wanted to educate myself about the developments regarding it. Although the potential treatments are still under investigation, they provide hope for people affected by a currently incurable disease.”
Alzheimer’s Disease (AD) is a terminal neurodegenerative disorder characterized by cognitive decline. As the most common cause of dementia, AD affects over 24 million people worldwide, and this number is only expected to increase due to greater life expectancies (1). Although this disease affects a great number of people, there is currently much that remains unknown about it, particularly the causes and potential treatments. While there seems to be a consensus among researchers and clinicians that the disease is characterized by neurofibrillary tangles and beta-amyloid plaque accumulation in the brain, their causes and implications are still under investigation (2-5). Furthermore, although old age is identified as posing the greatest risk for disease development, it appears that other factors, such as genetic mutations, oxidative stress, diet, and certain medical conditions, may also play a role (5,6).
The purpose of this literature review is to examine how oxidative stress, particularly due to deficiencies in vitamins D and E and diabetes mellitus (DM), may lead to the development of AD, and to evaluate the implications that these findings may have on further research. This paper will first address these risk factors for the disease, and will then discuss how knowledge about them can potentially lead to targets for treatment.
Oxidative Stress as a Cause of AD
Although old age is known to be the most common cause of AD, it appears that other factors may also be responsible for the cognitive decline that leads to the development of the disease. Oxidative stress has been implicated as one of these factors, as the accumulation of free radical species induces damage in vital macromolecules, such as DNA, proteins, and lipids (2,7). Though the mechanism is not fully understood, this seems to induce inflammatory reactions from the brain, leading to damage and the formation of beta-amyloid plaques (8). While oxidative stress has a multitude of causes, there are three in particular that may be positively correlated with the risk for AD: vitamin D deficiency, vitamin E deficiency, and diabetes mellitus.
Vitamin D Deficiency
Vitamin D has been shown to have a protective effect against cognitive decline in the brain, as it appears to prevent neurodegeneration due to its antioxidant effects5. Thus, it is not surprising that individuals who are deficient in vitamin D have been found to have an increased risk of developing AD (5,6). This link was shown to hold true in a study of 1,658 U.S. adults who initially did not have any form of dementia6. The researchers followed up with the study participants after an average of 5.6 years and found that 102 of them had developed AD, and that there was a positive correlation with vitamin D deficiency (6). Another study conducted in Italy showed the same results: vitamin D deficiency was responsible for a larger number of participants developing AD after a 6 year follow up (5).
Similarly, a different study found AD risk to be greater in northern regions compared to southern in Italy, New Zealand, and Chile (9). While this trend initially did not seem to relate to vitamin D deficiency, it was noted that people in the northern regions were more likely to be deficient in the vitamin, thus further demonstrating its role in AD development (9).
While these studies provide evidence that individuals lacking in vitamin D have an increased risk of AD, there may be other influences present that could be affecting the risk. Additionally, most studies only examine elderly individuals with this particular deficiency, so it is unknown if insufficient amounts of the vitamin throughout life is the issue, or whether a short-term deficiency later in life is enough to increase the risk (6,9). However, the correlation between AD and vitamin D does seem to support that oxidative stress may cause the disease (5,6,9).
Vitamin E Deficiency
Like vitamin D, a lack of vitamin E also seems to pose a greater risk for development of AD (3,10-12). Vitamin E refers to eight different compounds, four tocopherols and four tocotrienols, all of which appear to promote antioxidation in the body (16). Deficiencies in the tocopherols, especially alpha- and gamma-tocopherol, may have a link to AD. Lack of alpha-tocopherol seems to result in nerve cell damage and death, as this deficiency has been found to cause less branching of the dendrites in Purkinje fibers, significantly decreasing communication throughout the brain (3,10,12). Additionally, deficiencies of both alpha- and gamma-tocopherol may lead to neuroinflammation due to oxidative stress, further enhancing cognitive decline and, consequently, AD (3,8,10,12).
In contrast, other research has shown vitamin E levels alone to have no impact on AD risk (2,13). Some studies have reported that there is no significant difference in serum vitamin E levels in patients with and without AD, while others have reported that the difference only occurs in individuals that genetically have a higher risk for AD (13). A few studies have found a correlation between vitamin E deficiency and the ApoE4 gene variant, but research in this area is limited, as many people do not know that they have this mutation. Thus, due to the conflicting evidence on the relationship between vitamin E and AD, more studies are necessary.
Type 2 Diabetes Mellitus (DM)
Hyperglycemia experienced in patients with DM may cause oxidative stress due to the accumulation of superoxides (4,14). This oxidative stress can then manifest in the brain, leading to damage and death of neurons. Therefore, it follows that patients with DM may have an increased risk of developing AD, as demonstrated in various studies (4,15) . In some cases, it appears that the risk for AD doubles in patients with DM (4).
The relationship between AD and DM was further explored in terms of cardiovascular disease. It has been hypothesized that cardiovascular disease increases the risk for AD, but upon further analysis, it appeared that this correlation may be due to the factors that pose risks for cardiovascular disease, such as DM. However, a study testing this hypothesis did not find a significant relationship between AD and DM (15). While it did seem that DM may increase the risk for dementia, there was no increase of plaques or tangles in the brains of diabetic patients, and thus no indication of an increased risk for AD. Consequently, more research in this area is necessary due to the opposing findings.
Since oxidative stress has been identified as a potential cause for AD, treatment options targeting this are currently under investigation. Both vitamin and herbal supplements may be able to prevent or lessen the effects of AD due to their antioxidative effects, and thus are being examined for their efficacy (7,11,16,17).
Vitamins with antioxidant effects, such as vitamin E, have shown success in reducing cognitive decline in some individuals (16). Consuming increased amounts of vitamin E, both through supplements and food sources, may lead to a decreased risk for development of dementia (11,16). In a specific analysis of the components of vitamin E, it appears that the increased presence of alpha- and gamma-tocopherol reduces the progression of mild cognitive impairment to AD, although it is dependent on the dose, which varies based on the person.
However, there is contrasting evidence that vitamin E may not make a difference at all, or that it may actually be harmful (2,16). In a study conducted on 769 individuals, there were no significant differences between the placebo group and the vitamin E supplement group in terms of their development of AD (16). Furthermore, one study found that vitamin E doses above 800 IU/d have been shown to cause death2. However, since other studies cited that doses of 1000 IU/d prevented cognitive decline, more research is necessary in order to fully evaluate the effects of the vitamin.
Additionally, some herbal supplements may also play a role in reducing cognitive decline, as they contain flavonoids that can function as antioxidants (7,17). Pomegranate peel extract as a treatment has been successful in reducing the amount of plaque formation without causing harm to the liver, which is a concern in some herbal supplements (17). Similarly, green tea pills seemed to have a beneficial effect on people with AD, as they reduced oxidative damage in many areas of the body, including nervous tissue (7). While both of these supplements appear to reduce oxidative damage, more clinical trials are necessary, as there currently is not enough evidence to determine their efficacy.
The damage of nerve cells and accumulation of beta-amyloid plaques attributed to oxidative stress has caused clinicians and researchers to investigate the link between oxidative stress and AD (2,7,8). While vitamin D deficiency appears to be linked to AD due to the general neuroprotective effects that the vitamin has, vitamin E deficiency seems to be linked to Purkinje fiber damage and neuronal death (2,3,6,9.10,11,16). Furthermore, the hyperglycemia faced by many individuals with DM may cause accumulation of superoxides in the brain, ultimately leading to damage and death of neurons (4,14). In all three of these conditions, the oxidative stress experienced by the individuals appears to be positively correlated with an increased risk for AD (3-6,9-11,14). However, there are studies that present results that disagree with these trends, highlighting the complexity of this condition and its potential causes (2,13,15).
Consideration of oxidative stress as a cause of AD has led to treatment options specifically targeting these areas. Vitamin E supplements have been given to patients due to their antioxidant effects, and while some trials have reported positive results, others have reported no benefit, or even negative results (2,11,13). In addition, some herbal supplements, such as green tea extract and pomegranate peels, have been shown to reduce oxidative damage and thus delay the effects and reduce the damage of AD (7,17). However, more clinical trials are necessary in order to fully evaluate the benefits of supplements, as there is a limited amount of evidence available.
Overall, the advancements in research of AD leading to the discovery of oxidative damage as a potential cause for the disease have uncovered many possible treatment options. Further research in this area is necessary to identify a potential cure for a disease that affects so many people.
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