Oxidative stress isn’t the only reason why your diet can affect your risk of developing Azlheimer’s. Both diet and lack of exercise are also contributing factors for insulin resistance. Insulin resistance is where the cells of the body respond less to the effects of insulin and therefore glucose uptake is reduced. It can lead to conditions such as hypertension, diabetes and cardiovascular disease; all of which increase the risk of Alzheimer’s. It is estimated that 25-30% of people over the age of 65 have insulin resistance.
What is Insulin?
Insulin is necessary for brain cell function. It facilitates the uptake of glucose by the cells for use in respiration which creates the cell’s energy. The effects of insulin on Alzheimer’s have been investigated using a pilot study into intranasal insulin treatment. Insulin was administered to Alzheimer’s patients daily from a device which sprayed the hormone directly into the nasal passages. Over the four year period, the patients’ cognitive abilities were assessed. Interestingly, recall was improved further in patients receiving a lower dose of insulin but not so in those receiving a higher dose. The researchers emphasise that this was a very small study of only 104 subjects, and so more extensive studies will need to be carried out to understand these effects.
Link to diabetes
Insulin resistance is perhaps mainly associated with diabetes. Sufferers of diabetes have abnormally high blood sugar levels due to either an underproduction of insulin or a resistance of their body cells to the effects of insulin. They are also much more likely to develop Alzheimer’s disease. This provides further evidence from the previously mentioned APL-1 gene that diabetes and Alzheimer’s are linked.
Link to cardiovascular disease
Insulin resistance is also a risk factor for cardiovascular disease, which is one of the main environmental risk factors for Alzheimer’s. Cardiovascular disease affects the blood supply to the brain. If this blood supply is inefficient, there will be a lack of oxygen for the brain cells to carry out respiration.
Link to cholesterol levels
As previously mentioned, high levels of cholesterol are essential for the formation of amyloid plaques, as cholesterol facilitates the release of amyloid beta fragments from the c99 protein. But cholesterol can also contribute to the development of Alzheimer’s disease by its role in causing hypertension. High levels of cholesterol can lead to deposits forming in the arteries called atheromas. These narrow the lumen of the arteries and increase blood pressure. Hypertension is a risk factor for cardiovascular disease, and is also a known risk factor of Alzheimer’s disease. Statins are drugs that control cholesterol levels and are prescribed for the prevention of heart disease. Interestingly, recent experiments into mice found that use of the statins actually improved learning and memory function in mice. More research is needed before we could know if statins can be prescribed for Alzheimer’s, but this study does show evidence for the relationship between heart disease and Alzheimer’s.
The effects of Alcohol and Smoking
Other lifestyle choices are known to affect Alzheimer’s. One advised preventative measure of Alzheimer’s is to consume alcohol in moderation. Excessive alcohol consumption is known to lead to hypertension and insulin resistance. However alcohol also contains antioxidants, so it can be beneficial to drink it in controlled amounts. Smoking is also thought to contribute to Alzheimer’s disease. Although early studies suggested that smoking decreases the risk of Alzheimer’s, this has been widely discredited. Eleven of the controversial studies were found to have been conducted by researchers with connections to the tobacco industry. More current and reliable studies suggest that heavy smoking can increase a person’s susceptibility to Alzheimer’s, and that passive smoking may also have an effect.
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HBO : Documentaries : The Alzheimer’s Project, 2012. The Connection between Insulin and Alzheimer’s
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Environmental factors also significantly influence the development of Alzheimer’s Disease. Although genetic makeup can have a definitive effect in early-onset Alzheimer’s, its influences are more variable in the late-onset form. Many studies have been carried out to establish the extent of environmental influences on the development of Alzheimer’s. Due to the fact these factors are largely modifiable, they have attracted a great deal of interest.
^Click to enlarge.
Diet and exercise are thought to have critical importance in the development of Alzheimer’s. To discuss the science that explains this, we can look at the theory of oxidative stress.
Oxygen free-radicals are very reactive forms of oxygen which are produced as a by-product of respiration. The free radicals react with other molecules inside the cell to oxidise them. Antioxidants are substances which stop this oxidation. Oxidative stress occurs when more oxygen free-radicals are produced than are counteracted by protective antioxidants. It is thought to be particularly prevalent in the brain, where a great deal of respiration occurs. The current theory suggests that oxidative stress contributes to cognitive decline in normal ageing, but this effect is increased in Alzheimer’s disease.
In this way diet has a direct impact on the ageing process. Theoretically, a diet high in antioxidants should decrease the prevalence of oxidative stress and thus decrease the risk of Alzheimer’s Disease. An experiment in 2005 investigated this. Aged beagles were fed an antioxidant-enriched diet over a period of three years and their cognitive functions were tested. Beagles were selected as test subjects because of their cognitive functions can be assessed in similar ways to humans. The results showed improvements in memory and learning. In addition, the amyloid plaques became visibly reduced during the three year period, suggesting that the antioxidants actually helped to destroy the deposits.
Regular exercise is also believed to lower the risk of developing Alzheimer’s. In 2012, experiments were carried out into the effects of exercise. Researchers controlled the level of exercise in two groups of mice. The mice were then placed in a water maze* as a test of learning and memory skills. The mice that had experienced a higher level of exercise performed better on these tests. Brain scans also showed that high levels of exercise increased levels of brain derived neurotrophic factor (BDNF). This is a protein which is produced in normal brain function, but its levels are significantly lower in Alzheimer’s patients.
In 2003, the Human Genome Project successfully completed the mapping of the entire human genome. Since then, genetic research has sky-rocketed. One of the most useful applications of genomics is comparative genome mapping, wherein we can look at the susceptibility genes for different conditions. That's incredible in itself, but what scientists are starting to do now is compare pathologies of different diseases and the genes associated with them. In Alzheimer's research, scientists have looked at illnesses such as diabetes and Downs Sydrome to study their genetic links with Alzheimer's.
A gene has been found which suggests a link between diabetes and Alzheimer’s. People with type 2 diabetes have an increased risk of dementia. In diabetes, insulin resistance affects the metabolic processes of the body, including those of the nervous system. Researchers at The City College of New York studied the APL-1 gene in the nematode worms C.Elegans. APL-1 is an APP-related protein that seems to disrupt the insulin pathway. When scientists removed APL-1 from the worms, the worms died. Although the exact function of APP is not clear to scientists, this study suggests that it may be involved in the insulin processes of the nervous system.
Slight side track - C. Elegans worms are seriously cool.
Nobel prize winner Sydney Brenner discovered these worms in his backyard compost, and quickly realised how useful they would be as scientific models. One of their most useful features is their transparency, making them easily observable in microscopy. They're small, easily maintained and have a very simple anatomy of which scientists understand in its entirety. They exist in two sexes - male and hermaphrodite, and scientists can use these hermaphrodite worms to create millions of genetically identical models in a short space of time. Their anatomy, surprisingly, also has similarities to humans. They have an intestine, skin, muscles, reproductive organs and a nervous system. Although this nervous system consists of only 302 neurones, these neurones are very well described. They also use the same neurotransmitters as humans do (such as dopamine and acetylcholine). And even more surprisingly, scientists have actually discovered how to teach learning and memory in these worms so they can be studied for diseases like Alzheimer's. In fact, the presenilin genes (PSEN-1, PSEN-2) that were discussed in the last blog post were discovered through work done with these worms.
Yep, pretty awesome for something that could be digging around your compost right now...
Sufferers of Down’s Syndrome are also known to have an increased risk of developing Alzheimer’s. For sufferers in their 60s, the risk can be as high as 50%. They also tend to develop the disease much earlier (between 40-50 years old). Down’s Syndrome is a chromosomal condition based on the trisomy of chromosome 21; the same chromosome where the APP gene is located. Scientists reason that the presence of the third chromosome 21 causes the overproduction of APP and therefore increases the formation of amyloid beta plaques.
It's clear that genes do play some role in the development of Alzheimer's, as family history of the disease can increase an individual’s risk significantly. However, it’s also clear that environmental factors must also account to some extent for the majority of cases which cannot be attributed to genetics alone. More information on the environmental factors of Alzheimer’s in the next blog post!