Running Head: BIOLOGICAL CAUSES

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Biological Causes

Biological Causes

Running head: BIOLOGICAL CAUSES

Biological Causes of Alzheimer’s Disease

Mandy Stevens

Professor Oler

PSYC 1B Biological Psychology, M, W 9:45-11:00 a.m.

GavilanCollege

May 7, 2008

Why I Chose to Write on My Topic

The number one reason I decided to research the biological causes of Alzheimer’s was that this particular disease was the disease that tore my family apart. Starting in 2002, my great-grandfather started showing signs of increased memory loss. This continued memory loss was eventually diagnosed as Alzheimer’s. Up until the year he died in 2004, I noticed the strain this disease put on my family. I could see the pain it caused us to see a man who had once been so strong and independent, being treated like a child. It was like caring for a really big baby. Seeing a man that you have known your whole life not be able to recognize you hurts, and I could see that on my families faces. After my great-grandfather passed away, I realized that I didn’t know much about the disease that slowly killed him. I also recently looked at a picture of the human brain that had been diagnosed with Alzheimer’s. I found this picture fascinating because there was almost nothing left of what would normally look like a human brain. I wanted to find out how and why it got that way.

Last, but not least, Alzheimer’s is an interesting disease that not many people know too much about. I don’t want to be one of those people who know nothing about this disease because it is being diagnosed more often, and I want to understand how a person gets this terrible disease.

What the Research Says About My Topic

Dementia is a brain disorder that tremendously affects a person’s ability to carry out daily functions and activities. The most common form of dementia among older people is Alzheimer’s disease. This disease usually affects parts of the brain associated with thought, memory, and language (NIA, 2007). Alzheimer’s disease, also known as AD, is named after the

German doctor, Alois Alzheimer (NIA, 2007). Back in 1906, Dr. Alzheimer noticed changes in the brain tissue of a woman who had recently died of an unusual mental illness. He found

abnormal clumps, called amyloid plaques, and tangled bundles of fibers, called neurofibrillary tangles (NIA, 2007).

Neurofibrillary tangles are argyrophilic inclusions, which means that they are used to selectively reduce silver salts to metallic silver, and are composed of a filament like tau protein aggregates. Amyloid plaques are extracellular amyloid deposits, which are waxy translucent substances consisting primarily of protein, invested by swollen, degenerating neurites. Fibrillary polymers of the Aβ peptide comprise the structural core of amyloid plaques (Nelson, Jicha, Schmitt, Liu, Davis, Mendinond, Abner, & Markesbery, 2007). Alzheimer’s disease is characterized clinically, by progressive decline in cognitive abilities accompanied by abnormalities in behavior (Li, Yamamori, Tatebayashi, Shafit-Zagardo, & Tanimukai, 2008). The pathological history of Alzheimer’s is senile (amyloid) plaques containing the amyloid-β peptide and neurofibrillary tangles of paired circular or straight filaments of abnormally hyperphosphorylated tau protein (Li et al., 2008). High densities of plaques and neurofibrillary tangles are found predominantly in the hippocampus which is the primary center in the brain used for memory storage and the entorhinal cortex.

Scientists do not yet fully understand what causes Alzheimer’s disease, but they believe that there is probably not one single cause, but several factors that affect each person differently. The first biological cause that is the most important know risk factor is age. Scientists believe that as many as 4.5 million Americans suffer from Alzheimer’s. The disease usually begins after age 60, and after age 60 the risk continues to go up with age. Younger people may also get Alzheimer’s, but it is rare and much less common. Approximately 5% of men and women ages 65 to 74 have Alzheimer’s, and just about half of those people ages 85 and older may have the

disease (NIA, 2007). The number of people with the disease doubles every 5 years beyond age 65.

Another biological cause of Alzheimer’s could be the history of the family. Scientists believe that genetics may play a role in some Alzheimer diagnosis (NIA, 2007). For example, early-onset Alzheimer’s is rare and usually occurs between the ages of 30 and 60, and is inherited. The most common form of Alzheimer’s is known as late-onset. It occurs later in life, and no obvious inheritance pattern is seen in most families (NIA, 2007). A biological marker of a disease can be defined as a change in the physical genetic makeup of a host that indicates the presence of that disease. The successful development of a specific marker for Alzheimer’s disease that could distinguish it from normal aging and other forms of dementia would represent a major advance in the medical field. There has been a great deal of progress, there is no ideal marker currently available (Feldman,Jacova, Robillard, & Garcia, 2008). The leading biochemical markers that have advanced most in research include cerebrospinal fluid levels of ß-amyloid1, total tau, and phospho-tau (p-tau) proteins. Decreased levels of ß-amyloid1 and increased levels of p-tau are currently the most accurate and reproducible chemical markers for early-onset Alzheimer disease. Although currently, these cerebrospinal fluid markers may have a purpose for specialists who seek to distinguish between certain types of dementia (Feldman et al., 2008). There are, however, rare genetic factors that invariably may be the cause of early-onset Alzheimer disease. Several risk factor genes may interact with each other and with non-genetic factors to cause the disease. The only risk factor gene identified so far for late-onset Alzheimer’s is a gene that makes one form of a protein called apolipoprotein E (ApoE) (NIA,

2007). It is likely that other genes also may increase the risk of Alzheimer’s or protect against it, but they remain to be discovered.

The "amyloid cascade hypothesis" is the most widely discussed and researched hypothesis about the cause of Alzheimer's disease. The strongest data supporting the amyloid cascade hypothesis comes from the study of early-onset genetic Alzheimer's disease. Mutations associated with Alzheimer's disease have been found in about half of the patients with early-onset disease. In all of these patients, the mutation leads to excess production in the brain of a specific form of a small protein fragment called ABeta (Aβ). Many scientists believe that in the majority of sporadic (non-inherited) cases of Alzheimer's disease, there is too little removal of this Aβ protein rather than too much production (Crystal, Shiel, Marks, Bronstein, & Pulst, 2007).

Common forms of certain genes increase the risk of developing Alzheimer's disease, but do not invariably cause Alzheimer's disease. The best-studied "risk" gene is the one that encodes apolipoprotein E (apoE). The apoE gene has three different alleles: apoE2, apoE3, and apoE4. The apoE4 form of the gene has been associated with increased risk of Alzheimer's disease in most populations studied. People with one copy of the E4 gene usually have about a two to three fold increase of developing Alzheimer's disease. People with two copies of the E4 gene about a nine-fold increase in risk (Crystal et al., 2007).

Everyone has ApoE, which helps carry cholesterol in the blood. Only about 15% of people have the form that increases the risk of Alzheimer’s disease (NIA, 2007). The 4th allele of the apolipoprotein E gene found on chromosome 19 has been identified as a genetic risk factor for sporadic Alzheimer’s disease. The presence of the 4th allele has been shown to be in

correlation with earlier age of symptom as well as with atrophy in olfactory regions of the brain such as the hippocampus even in healthy older adults who do not show symptoms of dementia (Sundermann, Gilbert, & Murphy, 2007).

“Characteristic neuropathological changes associated with Alzheimer disease, such as senile plaques and neurofibrillary tangles have been documented in areas of the brain that process olfactory information such as entorhinal cortex, transentorhinal cortex, hippocampus, periamygdala, anterior olfactory nucleus, and orbital frontal cortex” (Sundermann, et al., 2007, p. 5). These changes have been shown to affect the primary regions of the brain involved in olfaction but have little effect on other primary sensory areas. One of the primary behavioral characteristics associated with Alzheimer’s is progressive memory decline. Because Alzheimer’s affects regions of the brain important to olfaction (smell), studies have looked at odor memory in patients with Alzheimer’s and have reported a decline in short-term recognition memory for odors. The combination of damage to both the entorhinal cortex and the hippocampus may leave patients with Alzheimer’s particularly vulnerable to memory decline for olfactory stimuli due to the role of these structures in mnemonic processing as well as olfactory processing (Sundermann et al., 2007).

Prior research has also suggested that recognition memory and identification of odors may be more affected than memory for visual stimuli even very early in the progression of Alzheimer’s and may therefore contribute to an early diagnosis. To show this, a study was done to demonstrate that individuals at risk for Alzheimer’s were impaired relative to a comparison group in odor detection and odor memory. Some studies have also shown that the presence of

the 4th allele may be associated with impaired olfactory memory in elderly individuals without dementia that are at risk for Alzheimer’s (Sundermann et al., 2007).

Another important biological risk factor that has been studied over and over again is the affects of stress related to Alzheimer’s. Oxidative stress is included among the most important mechanisms implied in neurodegenerative pathogenesis. Oxidative stress in Alzheimer’s has been recently highlighted because of the sensitivity of the central nervous system due to its high oxygen uptake and relatively low level of antioxidant defenses (Spalletta, Bellincampi, Federici, & Trequattrini, 2007). It’s been known that glutathione S-transferases (GSTs) may play an important role as risk factors for Alzheimer’s because GSTs detoxify commonly encountered products generated by oxidative damage, and a reduced GSTs activity has been reported in multiple brain regions and in cerebrospinal fluid in postmortem Alzheimer patients. It has been demonstrated that, in some cases, polymorphisms in GST genes result in the encoding of enzymes with reduced catalytic activity. Therefore, they may represent important factors that can influence diseases (Spalletta et al., 2007).

Studies have also suggested that emotional stress can increase the risk of a person developing Alzheimer’s. A study done at the Salk Institute for Biological Studies looked at the gene called type 1 corticotropin-releasing factor receptor (CRFR1), which is involved in the brain’s reaction to stress (Barry, 2007). An experiment was performed on mice to see if accumulated stress would lead to the development of neurofibrillary tangles in their neurons. These mice were subjected to extreme stress by being forced to swim in cold water, starvation, or heat did in fact develop these neurofibrillary tangles like those of a person with Alzheimer’s. They also performed milder stress tests to see if mild stressors would cause the neurofibrillary

tangles as well. To do this, mice were physically restrained in tubes for 30 min. each day. After doing this for two weeks, the mice had developed the tangles in their brains just like the mice that were exposed to extreme stress (Barry, 2007). These studies have shown that humans, like mice, could develop these neurofibrillary tangles in their neurons which could lead to a diagnosis of Alzheimer’s.

Another study conducted concluded that people who “most often experience negative emotions such as depression and anxiety were twice as likely to develop Alzheimer’s disease as those who were least prone to experience negative emotions” (FDA Consumer, 2004, p. 8). In this study, 797 people with an average age of 75 were evaluated when they started the study and then evaluated on a yearly basis. Participants were evaluated on their level of proneness to stress with a proven rating scale. Participants rate their level of agreement with statements such as "I am not a worrier," "I often feel tense and jittery," and "I often get angry at the way people treat me." During an average of 4.9 years of follow-up, 140 people in the study developed Alzheimer's disease. “Those high in proneness to stress, in the 90th percentile were twice as likely to develop Alzheimer's disease as those in the 10th percentile” (FDA Consumer, 2004, p. 8).
"People differ in their tendency to experience psychological distress, and this is a stable personality trait throughout adulthood, and since chronic stress has been associated with changes in the hippocampus area of the brain and problems with learning and memory, we wanted to test the theory that psychological distress may affect the risk of developing Alzheimer's disease" (FDA Consumer, 2004).

To prove whether proneness to stress was an early sign of Alzheimer'sdisease, the researchers studied the brains of 141 study participants who died during the course of the study. Of those, 57 met the criteria for probable Alzheimer's disease. The researchers found that proneness to stress was not related to measures of Alzheimer's disease pathology, such as plaques and tangles in the brain. The results suggested that stress proneness is a co-factor leading to dementia in Alzheimer's disease (FDA Consumer, 2004).

Many studies have also found that women have a higher risk for Alzheimer's disease than men. The apparent increased frequency of Alzheimer's disease in women has led to a large amount of research about the role of estrogen in Alzheimer's disease. Recent studies suggest that estrogen should not be prescribed to post-menopausal women for the purpose of decreasing the risk of Alzheimer's disease. However, the role of estrogen in Alzheimer's disease remains an area of research focus (Crystal et al., 2007).

Scientists still need to learn a lot more about what causes Alzheimer’s, but a lot of new research has been done. In addition to genetics, ApoE, and the relationship with stress, scientists are also studying education, diet, and environment to learn what role they might play in the development of this disease. They are finding increasing evidence that some of the risk factors for heart disease and stroke, such as high blood pressure, high cholesterol, and low levels of the vitamin folate, may also increase the risk of Alzheimer’s (NIA, 2007). Evidence for physical, mental, and social activities as protective factors against Alzheimer’s is also increasing (NIA, 2007). Scientists have also found other brain changes in people with AD. Nerve cells die in areas of the brain that are vital to memory and other mental abilities, and connections between nerve cells are disrupted. There also are lower levels of some of the chemicals in the brain that

carry messages back and forth between nerve cells. Alzheimer’s disease may impair thinking and memory by disrupting these messages (NIA, 2007).

Scientists have come a long way in their understanding of Alzheimer’s. Findings from years of research have begun to clarify differences between normal age-related memory changes and Alzheimer’s. Scientists also have made great progress in defining the changes that take place in the Alzheimer’s brain, which allows them to pinpoint possible targets for treatment.

What I Learned Personally, Interpersonally and Professionally

After completing my research on this topic, and personally experiencing a family member with this disease, I have learned that this disease not only affects the person who actually has it, it affects the entire family. I say this because I have witnessed the emotions that came out of my grandmother when her father was diagnosed with this disease. She would talk to her father and he would have no idea who she was. It hurts the entire family because someone you care about and love is no longer able to remember everything that you have done together or even remember who you are.

I learned interpersonally that people with Alzheimer’s disease get frustrated easily and may wind up in a depression state because they can’t remember things when everyone wants them too and they feel bad because they can’t. I have also learned that it is really stressful on family members and caretakers because a person with Alzheimer’s is like a giant toddler. They are not able to care for themselves and must be watched at all times.

Professionally, I learned that many of the elderly people that come into my store may forget things easily, but it may or may not be caused by Alzheimer’s. Getting older doesn’t

mean that a person will have Alzheimer’s disease; it only means that the risk for them getting it goes up. When people forget things, it could just be that they had a long day and forgot what they came in for.

How I Plan to Apply What I Learned Personally, Interpersonally and Professionally

I plan to apply what I learned personally by being more forgiving of a family that is going through this experience. It is difficult and hard for everyone to have to experience the slow decline of a person that you care for. I can now better understand what they are going through, because I have gone through it also. I will let them enjoy their time with the person because I know how good the person who has Alzheimer’s will feel with people around them.