4. Alzheimer’s Disease: Beyond Genes

4. Alzheimer’s Disease: Beyond Genes


What day is it today? What state or town are you in? Can you identify the following pictures?

spoon                                     pencil

While this may have seemed easy for you, people suffering from Alzheimer’s disease struggle with these seemingly basic tasks. Dementia, which describes a number of conditions, is most often characterized by profound impairment of memory and affects 47 million people worldwide, far more than both HIV/AIDS and cancer, which affect 35 million people (WHO) and 33 million people worldwide (CDC, 2015), respectively. The Alzheimer’s Association estimates that one in three elderly people will die with some form of dementia. It is a very expensive disorder, costing $818 billion a year, making it the 18th largest economy in the world if “Dementia Care” were a country. This number is expected to rise to $1.1 trillion in the next 30 years.

If you are in a room with nine people, at least one will be diagnosed with a specific form of dementia known as Alzheimer’s disease (AD). There is a new diagnosis every 67 seconds (Alzheimer’s Association, 2016). AD is a fatal disease with approximately five years between diagnosis and advance disease or death (Alzheimer’s Association, 2016). In the United States, it is the sixth leading cause of death, and the only in the top ten list that cannot be cured (Alzheimer’s Association, 2016). Despite intensive study, there is limited understanding of the causes of AD, and there is no cure. For these reasons, studying changes in gene expression could hold the key to understanding the course of the disease as well as providing new avenues for reversing or even preventing AD.

Alzheimer’s: What We Know

Dementia includes a range of symptoms affecting memory, thinking, and social skills that can interfere with daily life. While memory loss is part of normal aging, dementia is a much more significant loss. Dementia is a term used to describe a wide range of disorders that affects mental processes as a result of a number of factors, including disease and brain damage. AD is the most common type of dementia, and it eventually destroys the ability to carry out the simplest tasks, even speaking and eating. There are 2 types of AD, referred to as early onset, which appears before age 65, and late onset which appears after 65. Patients in early stages of the disease have slight confusion, which can be initially interpreted as normal forgetfulness. As the disease progresses, so does the patients’ confusion. In later stages of the disease, patients lose the ability to remember dates, places, and close family members, accompanied by changes in mood, appetite, sleeping habits, and more. This devastating disorder has profound effects on both patients and their caregivers, who are often family members. Actress Judy Parfitt described it well when she said, “… Alzheimer’s is such a terrible disease: the body of the person you love is there, but they’ve gone – your husband is gone – and they become your child…”

It is important to understand the changes seen in AD patients’ behavior are a result of physical changes in the brain, which cannot be controlled or prevented with current knowledge. A hallmark of AD is irreversible brain damage related to the formation of β-amyloid protein plaques and tau protein tangles. Proteins are essential building blocks of the body. β-amyloid plaques are clumps of a specific protein that accumulate between cells in the brain. Cells need to send and receive messages to get information about what other cells are doing, just as a group working on a project needs to communicate to be successful. Without this communication, the cells will die, just as the project would fail. These β-amyloid plaques damage and destroy brain cells by blocking messages between cells, preventing successful communication. Tangles are clusters of twisted tau protein that accumulate within brain cells. Normally, this protein provides structural support as well as transport of nutrients. Tangles are similar to a garden hose getting kinked and blocking the flow of water out. When the tau proteins are abnormally shaped, cells are not able to receive the nutrients they need and die. Both forms of abnormal proteins lead to massive cell death in the brain, shown in the picture below. This cell death is what results in the changes seen in AD patients.

Alzheimer’s Mysteries: Development

While much is known about the symptoms of AD, relatively little is known about its development. Approximately half of diagnosed cases can be attributed to the physical characteristics passed from parents to children, which are called heritable genes. There are many heritable genes, including skin color, eye color, height, and even several genes that have been shown to increase the risk of developing AD. It is important to remember that the presence of these genes does not guarantee development of AD. There are likely other factors that affect development of AD, especially when considering that half of cases are attributable to non-genetic factors. These non-genetic, possibly environmental factors could be explained by changes in the brain related to what happens earlier in life, also known as experience-dependent changes. These experience dependent changes, known in the scientific community as epigenetics, are a promising area of study. There are a great deal of researchers trying to understand how experience changes the brain, as well as how these changes can influence AD development.

Unraveling the Mystery: Current Research

How It Might Work: One of the most studied experience-dependent changes is the methylation of DNA. DNA is the foundation of genes, the recipe for the body to make everything that defines you. This DNA recipe is used to make proteins, which form bones, skin, muscles, and everything in between. DNA methylation is the addition of a small tag to DNA that can change gene expression, as well as the number of proteins produced from DNA. It functions as a stoplight, a red light for protein production. A recent study looks at all the tags attached to DNA throughout a region of the brain involved in speech and hearing, called the superior temporal gyrus. This study showed a lot of turning off genes in this area of the brain. While the superior temporal gyrus is not directly related to Alzheimer’s, patients often show deficits in speech, making these results particularly good guides for future research. In the future, scientists can use this information to study of the development of AD, as well as what genes to focus on.

Don’t Stress About This Article: Other studies look at how other environmental changes could impact development of AD, such as your stress levels. One study found a link between Major Depressive Disorder (MDD) in middle life and later development of AD. This study showed that the epigenetic changes that occur as a result of MDD, such a stress receptor changes, can also contribute to the changes associated with AD. The brain receives chemical signals that are understood by stress receptors during stressful situations, similar to sending messages through email. These signals can trigger a chain of events that affect many parts of the body, including the heart, stomach, muscles, and brain. Depression triggers the stress response over an extended period of time, and can lead to long lasting changes on the brain that increase the likelihood of developing AD (Herbert and Lucassen, 2016).

Un-”Wine”-Ding The Epigenetics: Another really interesting area of research suggests that some environmental factors may affect how your brain ages, including diet. These changes could also help delay or prevent developing Alzheimer’s. Several studies have shown that moderate wine consumption can be effective in slowing down age-related mental decline, where a magic ingredient called resveratrol is suspected of being the driving force (Wang et al., 2006; Panza et al., 2012; Corona et al., 2013). Resveratrol is an activator of another building block called sirtuin, which also has been linked to longevity. While we’re on the topic of food and wine, and going back to the analogy of DNA as the recipe for the body to make everything that defines you, we can now think of DNA as the famous chef Julia Child. She was well known for the famous string of pearls she always wore while cooking. We can think of the individual pearls as representing a tag on DNA called acetyl groups, which normally allow DNA to cook (transcribe) its protein recipe. These acetyl groups act as green lights for protein production and make it easier for the DNA recipes to be read. Sirtuin, the protein that red wine activates, acts like a jewel thief, pulling pearls off the necklace, which makes it hard for the DNA to use its recipes to make protein. While this is normally bad, sirtuin may actually support healthy brain function. It acts as a shield and protects against other possible harm in the brain (Sweatt, 2013). Resveratrol (AKA wine) kicks sirtuin into gear to reduce shrinking of the brain and prevent learning impairments (Kim et. al., 2007).

Potential Treatments

Yet another study of mice found a potential treatment for those already suffering from the disease. This research suggests that preventing changes to cells involved in memory could restore normal function. The main goal of this study was to reduce the memory loss that comes from β-amyloid protein plaques, one of the hallmarks of AD. Essentially, these scientists used a chemical to prevent the removal of the pearl acetyl groups, or green lights. Keeping the green lights for protein production on the DNA recipe allows for more protein to be made. This return to normal protein production leads to increased ability to remember information. This study provides hope for those already suffering memory deficits (Krishna et. al., 2016).

What Does This Mean?

While these studies are quite convincing and offer exciting insights, there are an equal number of studies that show each of these mechanisms are not active in AD. Other changes also affect AD risk, including exercise, environmental poisoning (such as lead), DNA structure changes, and others. It is also important to note that while these studies reveal correlations between AD risk and a variety of factors, there is no proof that one causes the other. A great deal of future research is necessary to understand exactly what mechanisms are in play here. Funding for this research is essential to better understand the disease, as well as to continue the search for cures. Indeed, a better understanding of this devastating disease will be essential to providing a better future for the millions of Americans that are and will be affected by it.

Links for Further Reading

Recommended for further reading, “Kitchen Sink Hypothesis”: http://www.nytimes.com/2010/12/14/health/14alzheimers.html?pagewanted=all

Facebook article mentioned in the podcast: http://www.scientificamerican.com/article/new-clues-show-out-of-control-synapse-pruning-may-underlie-alzheimer-s/

Nova Piece on Alzheimer’s mentioned in the podcast: http://www.kued.org/whatson/nova/can-alzheimers-be-stopped

Resources

“Alzheimer’s Association.” Alzheimer’s Association. N.p., n.d. Web. 12 Apr. 2016.

Corona G., Vauzour D., Hercelin J., Williams C. M., Spencer J. P. E. (2013). Phenolic acid intake, delivered via moderate champagne wine consumption, improves spatial working memory via the modulation of hippocampal and cortical protein expression/activation. Antioxid. Redox Signal. 19, 1676–1689 10.1089/ars.2012.5142

“Global Cancer Statistics.” Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 02 Feb. 2015. Web. 5 Apr. 2016.

Herbert, Joe, and Paul J. Lucassen. “Depression as a risk factor for Alzheimer’s disease: Genes, steroids, cytokines and neurogenesis–What do we need to know?.” Frontiers in neuroendocrinology (2015).

“HIV/AIDS.” WHO. WHO, n.d. Web. 5 Apr. 2016.

Kim D., Nguyen M. D., Dobbin M. M., Fischer A., Sananbenesi F., Rodgers J. T., et al. (2007).SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO J. 26, 3169–3179 10.1038/sj.emboj.7601758

Krishna, Shagun, Vikash Kumar, and Mohammad Imran Siddiqi. “Recent Advances in Computer-Assisted Structure-Based Identification and Design of Histone Deacetylases Inhibitors.” Current topics in medicinal chemistry 16.9 (2016): 934-947.

Panza F., Frisardi V., Seripa D., Logroscino G., Santamato A., Imbimbo B. P., et al. (2012). Alcohol consumption in mild cognitive impairment and dementia: harmful or neuroprotective? Int. J. Geriatr. Psychiatry 27, 1218–1238 10.1002/gps.3772

Sweatt, J. David. Epigenetic Regulation in the Nervous System: Basic Mechanisms and Clinical Impact. London: Academic, 2013. Print.

Wang J., Ho L., Zhao Z., Seror I., Humala N., Dickstein D. L., et al. (2006). Moderate consumption of Cabernet Sauvignon attenuates A beta neuropathology in a mouse model of Alzheimer’s disease.FASEB J. 20, 2313–2320 10.1096/fj.06-6281com

Image Sources

http://forum.alzheimers.org.uk/attachment.php?attachmentid=39477&stc=1&d=1395661604

http://uhealthsystem.com/images/health-library/ei_2702.jpg

http://weknowyourdreamz.com/spoon.html

http://www.jetpens.com/Tombow-2558-Pencil-HB/pd/11390

Audio Sources

Veronica by Elvis Costello: https://www.youtube.com/watch?v=zifeVbK8b-g

Still Alice: https://www.youtube.com/watch?v=v06K9RJj9LI&nohtml5=False

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