Kareem ’20 and Logan ’20


Alzheimer’s and Society

As the sixth leading cause of death in the United States, Alzheimer’s disease (AD) affects millions of people. Ten percent of people over the age of 65 suffer from AD, and it is estimated that as many as 45% of adults over the age of 85 suffer from AD. It is estimated that nearly 50 million people worldwide suffer from Alzheimer’s or other types of dementia. Disrupting both cognition and memory, AD causes progressive decline from minor memory loss, to confusion, behavioral issues and dementia. This disease not only impacts the lives of those who have it, but also the family, friends, and healthcare workers who provide care to them. Alzheimer’s disease also impacts the economy due to the need for both short and long term care, as well as the missed financial opportunities of unpaid caregivers.

Alzheimer’s and the Brain

Alzheimer’s disease impacts areas of the brain responsible for cognition and memory, such as the temporal and parietal lobes, and parts of the frontal cortex and dentate gyrus. A neurodegenerative disease such as Alzheimer’s causes irreversible damage to neurons and the synaptic connections between them. The loss of neurons and neuronal connections can be visualized using MRI scans, seen as a physical decrease in brain matter. Besides the loss of neuronal density, patients with AD typically have a build-up of beta-amyloid plaques and tau fibrillary tangles within their brain. It is important to note that the changes seen in the brains of patients with AD are not due to normal aging.

Genetic Factors Contributing to AD

There are some genetic factors that researchers have identified in possibly playing a role in the development of AD. The apolipoprotein (APOE) gene, which plays a role in cholesterol transport has been shown to be linked with AD. There are 3 forms or alleles of this gene, e2, e3, and e4, and one allele is inherited from each parent resulting in six possible outcomes. For example, inheriting an e4 allele of this gene may increase one’s risk of developing AD, while the e2 form may lower one’s risk. Several studies have been conducted to determine the frequency of these alleles in patients with results ranging from 54-65% of people with AD in the US had at least one copy of the APOE-4 gene. However, it is important to note that having this gene does not mean that individuals will develop AD, other genes and epigenetic factors contribute to the development of AD as well.

So, What about Epigenetics?

Each cell within our bodies must contain DNA. If the DNA from a single cell was laid out flat, it would be nearly 3 meters long. In order for our DNA to fit inside the nucleus of each cell, it must be wound up and packaged very tightly. Due to the highly compacted nature of DNA, not only does its sequence matter, but also the accessibility of this sequence to the machinery necessary for making it into RNA and proteins. Epigenetic modifications alter the ability of DNA to be made into proteins by altering its conformation and accessibility. This is done by adding or removing chemical modifiers to DNA, which then function as a signal, either as “ON” promoting gene activity, or “OFF” reducing gene activity. These epigenetic modifications include DNA methylation, histone methylation and acetylation. DNA methylation occurs at specific CpG sites and promotes tighter coiling of the DNA, making it less accessible to transcription machinery and effectively turning the gene off. Current research has shown that these marks have the ability to be altered over time meaning that gene expression can be altered too. It has been shown that things such as diet, exposure to trauma, maternal and paternal care, physical activity, and exposure to chemicals and drugs of abuse cause lasting changes in the epigenetic profile of our DNA. Essentially, epigenetics is a way to explain nature vs. nurture as a way to encode our experiences into our DNA and alter our gene expression.
If an error occurs in the highly regulated process of DNA methylation issues can arise in regards to genes that are active or inactive, as well as the cells and levels in which they are transcribed. Researchers have shown how different patterns of methylation in genes that are involved in neural development and stability can contribute to the risk of AD. These genes include the HOX and APP genes; dysregulation of their methylation patterns has also been linked to Down syndrome. In analysis of post-mortem brain tissue from patients with AD, alterations in genes affecting learning, memory, the circadian rhythm, and mood have all been found. By using studies to assess genetic and lifestyle factors for aging and risk of AD, researchers were able to identify environmental factors that alter epigenetic profiles. Many factors were significantly associated with AD including smoking behavior, socioeconomic status, cholesterol levels and high blood pressure. This highlights the importance of and the need for future research into other lifestyle factors and how one could try to reduce the risk of developing AD.

Dysregulation of Building Blocks

The dysregulation that occurs in AD may best be understood through an analogy. Trying to repair a house with. Let’s imagine you own a home that you have had for many years. You need to do some repairs on this home and this will require new materials. You placed an order for some new bricks, but for some reason, no bricks are delivered. No matter how many times you place an order for the bricks, they do not come. Over time, the structure and support of the house will begin to deteriorate. This is the same with AD. It is possible that the neuron puts in a request for a specific protein, but the gene that encodes this protein is blocked off, thus the “brick” or protein supply is cut off. Dysregulation of this process can result in the downregulation of genes that are essential for neurons to survive and thrive, such as BDNF, and an upregulation of genes that may be harmful to the brain, such as inflammatory factors.

Epigenetic changes due to Alzheimer’s

Using the analogy above, we can take a look at some of the epigenetic changes occuring because of Alzheimer’s Disease. One example of this, BDNF. BDNF plays an important role in the growth of neurons and the maintenance of neurons. In people with AD, BDNF is hypermethylated. This means that the gene for BDNF is blocked off from the transcription machinery. When the gene is blocked from the transcription machinery, no proteins of it can be made, thus leading to a decrease in the overall amount of BDNF in the neuron. No BDNF causes the cell to have no maintenance. This decrease in the maintenance could lead to complications in the neurons, cause them to not work properly, and eventually death. BDNF is the “brick” described in the situation above. The “house” or neuron needs the BDNF to upkeep its maintenance. However, every time you try and get more BDNF, nothing gets through because the DNA for BDNF is blocked off.
The opposite can also occur in AD. It is possible that the gene is hypomethylated. This means the gene is too open to the transcription machinery. The authors of Epigenetic modifications in frontal cortex from Alzheimer’s disease and bipolar disorder patients analyzed samples of the post-mortem brains of AD patients. From their analysis the authors discovered that AD brains showed a hypomethylated COX-2 promoter region. COX-2 plays an important role in cell proliferation and apoptosis. Because COX-2 is hypomethylated, more of it is produced. It would be like the cell placed an order for maybe 10 COX-2 proteins, but instead 1,000 are shipped over. This would cause dilemmas because COX-2 wants to do its job whether it needs to or not.
The authors also saw a significant increase in DNA methylation at the promoter region of synaptophysin. This may be another reason for the synaptic degradation that occurs during AD. Synaptophysin is an integral membrane protein for synaptic vesicles. Over-methylation of its promoter region can cause a decrease in its transcription, thus leading to an overall decrease in synaptophysin and degradation of the synaptic vesicles in neurons. Just like BDNF, when the cell tried to put in more orders for synaptophysin none came through.
Finally, the authors also highlighted that there was a significant decrease in methylation of NF-kB promoter region. The NF-kB pathway can cause the expression of many different inflammatory genes. Some of these may be neuroinflammatory genes. Therefore, an increase in the amount of NF-kB could lead to inflammation in the neurons. Again, this is like COX-2. Too much of the NF-kB would lead to complications of neurons and if persistent could eventually lead to degradation.
All in all, there are various different types of epigenetic changes due to AD. Many of these examples focused on DNA methylation specifically. It is important to note that both hyper and hypo methylation of DNA was involved. Hypermethylation of genes that help maintain neurons and hypomethylation of genes that could lead to complications in the neurons.

As simple as changing my diet?

Although it is not the only factor which is involved, recent studies have highlighted the importance of diet and nutrition in epigenetic changes leading to AD. In a paper titled, Environment, epigenetics and neurodegeneration: Focus on nutrition in Alzheimer’s disease, authors demonstrate the impact B-12 levels, alcohol consumption, and heavy metal exposure can have on DNA methylation. Heavy metals were shown to impact DNA methyltransferases (DNMTs) which are the enzymes responsible for the methylation of DNA. Alcohol was shown to impact DNA in another way, by degrading DNMTs and preventing methyl groups from being available at all. When DNMTs are degraded there are no longer as many enzymes to transfer methyl groups to DNA, resulting in reduced methylation. Deficiencies in B-vitamins have also been shown to impact the availability of methyl groups, meaning that no signals can be added to the DNA, thus altering gene expression. This paper indicates the role that diet may play in the development of AD, as well as the need for future research into this topic. By identifying the role of other dietary factors on DNA methylation, it may be possible to reduce intake of foods associated with the development of AD as a potential preventative measure.

Moving Forward

All in all, understanding the epigenetic changes that come with Alzheimer’s disease will aid us in finding and developing treatments for the disease. Additionally, understanding the relationship between our environment and how it affects our epigenetics, like diet, can help us find clever ways to maintain a healthy epigenome. It is important to note as well, that many of the epigenetic changes that we talked about here were specifically about DNA methylation. There are still many more different types of epigenetic changes that could be caused by Alzheimer’s that we do not know about. That is why there still needs to be more research dedicated to understanding what is changing during Alzheimer’s Disease.

References:

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