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Biology 202
2000 First Web Report
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Alzheimer's Disease: The Disease of the New Century

Shigeyuki Ito

The Brain - is wider than the Sky - For - put them side by side - The one the other will contain With ease - and You - beside-

The Brain is deeper than the sea - For - hold them - Blue to Bue - The one the other will absorb - As sponges - Buckets - do

The Brain is just the weight of God - For - Heft them - Pound for Pound - And they will differ - if they do - As syllable from Sound -

Emily Dickinson (1830-1886)

Recently I hear a lot on Alzheimer‚s Disease. Partially due to the media coverage resulting from former-President Reagan, and but more as a result from the increase in people with Alzheimer‚s as people live longer. Exactly what happens to people with Alzheimer‚s? Why do they forget? How does it pertain to the „brain is behaviorš, „brain is everythingš discussions we had in class?

Imagine what it would feel like to start forgetting things, like directions to a familiar place or recent events. A sort of haze starts to surround what used to be the clear picture of reality and self. Then you start to lose the ability to make decisions, or make simple plans, and eventually lose the ability to do everyday activities by yourself, such as eating, or going to the toilet. Perhaps it is like falling down a deep, dark well, as time passes the real world becomes distant, and of course you have no control. Until finally you don‚t even recognize family members, and ultimately yourself. By this point you do not even realize if you are falling , the darkness prohibits you from recognizing what is happening.

Although the thought of it happening to yourself is scary, it is sad and even tragic if it happens to a loved one. Just imagine if one day your grandparents, or your parents not even remembering who you are. The person who loved you since the very day you were born does not even recognize you. Physically they are there, but in reality they are not. If brain is behavior, and the brain is not what it used to be, their behavior is no longer the same.

History and Biological Explanation.

Alzheimer‚s Disease (AD) was found in 1906 by Alois Alzheimer (1864-1915) of Germany. His discovery was made by after performing a neurological autopsy on a 56 year old women who had died due to mental deterioration, with symptoms such as memory loss. From the autopsy Alzheimer observed irregularities in her cerebral cortex (area responsible for memory and reasoning). Alzheimer observed clumps (senile plaques) and knots (neurofibrillary tangles). At this point while he speculated that senile plaques and the neurofibrillary tangles were related to the women‚s condition, he was not sure why they formed, whether they were the direct cause or a mere result of the another source (1).

While nearly a hundred years has passed since Alzheimer‚s discovery, Alzheimer‚s Disease has only become a important issue in recent years. Because increasing age is such a big factor in getting Alzheimer‚s it was only a rare disease in the early-mid 20th century when people only lived until they were fifty. However with the increase in life expectancy in recent decades where many people live well into their seventies and eighties, Alzheimer has become a disease that effects quite a large proportion of the population. Most sources put the figure as 3% of the population between 65-74, 19% of the population between 75-84 and half of the population over 85 (1).. Although it has been observed that there has been several cases of people under 60 being diagnosed with Alzheimer‚s but these are considered rare cases.

Perhaps one of the main reasons why a cure to Alzheimer‚s is yet to be found has to do with doctors not even knowing the cause of it until quite recently. Research on senile plaques has been progressing steadily since the 1980‚s when scientists connected amyloid precursor protein (APP) with the formation of the plaques(1). Our bodies produce three enzymes alpha, beta, and gamma secretase that cut the APP into shorter forms. The alpha secretase splits up the APP into a harmless protein, but the beta and gamma enzymes create a stickier protein called beta amyloid-42 (A-beta) (2). While we all produce A-beta, what happens to Alzheimer‚s patients is that the A-beta builds up in the fluid surrounding the neurons to form plaques.

People with Alzheimer‚s produce as much A-beta as would a normal person, but for some reason they have difficulty disposing it. What happens in a healthy person is that after A-beta drifts away from the cell it just dissolves. However as we age, these A-beta folds into an insoluble form called fibrils. The nervous system sees these fibrils as foreign substance and initiates an inflammatory response. What ultimately happens is that neurons die from the free radicals, the toxin used to fight infections (2).

Presently, it is seen that neurofibrillary tangles are connected to a protein called tau which exists in the cerebrospinal fluid(1). In a healthy person, the appendages of neurons are built around microtubles that gives the neuron its shape while also transporting chemical messangers and nutrients. Tau serves to bind and reinforce the microtubules with the neurons (2). What happens in people with Alzheimer‚s is that these tau molecules detach themselves and form knot like shapes. As this happens, both the microtubles and neurons die off, thus people start to lose memory, and eventually control over their body.

The next step in trying to solve the mystery behind the cause of Alzheimer‚s is why the normal tau molecules suddenly stop doing what they have been doing for 60-70 years. Just a few months ago a team of Harvard researchers connected the enzyme cdk5 as the source of tau tangling.

Some researchers say that amyoid (A-beta) plaques pressing against the neurons causes chemical reactions to take place, and that the detaching and tangling of tau molecules are one of the results of the chemical reaction (2).

There has been other researchers who have been looking towards other causes. A possible source is calcium. Researchers claim that Alzheimer‚s disease causes a change in the calcium regulation system and thus result in an accumulation of calcium in the brain that eventually kills the brain. Another possibility is aluminum; this comes from the fact that some Alzheimer‚s victims have high levels of aluminum in their brain tissues. Researchers now say that any connection with aluminum probably has more to do with Alzheimer‚s making the brain tissues more susceptible to aluminum, rather than aluminum being the main reason (3).

Factors: How do we know who will get Alzheimer‚s?

Genes:

Perhaps the root of the mystery surrounding Alzheimer‚s is that it is hard to point to one real factor of who gets Alzheimer‚s. It is not like HIV/AIDS a disease caused by a virus nor is it like sickle cell anemia and many cancers a genetic one. Presently it is believed that there are more than one factor for people to get Alzheimer‚s and different people get it for different reasons (4).

Perhaps the most obvious and likely factor is genes. A research conducted in 1996 of 13,000 people found that people who had/has two parents with Alzheimer‚s have a 54% risk, which is 1.5 times the percentage for people with only one parent, and 5 times the risk for people who‚s parents did not have Alzheimer‚s (1). Yet it is wrong to point to genetics as the cause because there are cases of identical twins with one having Alzheimer‚s and the other being perfectly healthy (2).Surveys have found that people who have an identical twin with Alzheimer‚s have a 40-50% risk which is much higher than the average person but not high considering the identical twins originally share the same genes (1).

In recent years a few genetic mutations have been found which are known to be connected to Alzheimer‚s. Chromosome 21 which is more known for its connection to Down syndrome also happens to be the gene which controls APP. People with Down syndrome produce extra APP, and thus have more A-beta. Thus it has been seen that people with Downsyndrome almost always develop Alzheimer‚s if they live onto their 40‚s and 50‚s (1).

Environment:

The example of the identical twins shows that although they probably play a major role, is not the only factor and that the environment plays a significant role. A study conducted on African Americans older than 65 showed that people of rural backgrounds with less than seven years of education were 6.5 times more likely to have Alzheimer‚s than an educated person of urban background. Another research found that people with more than five siblings are more likely to have Alzheimer‚s. These two findings show that people with „more nurturedš brains are more resistant to forming Alzheimer‚s (2).

Another research supporting the environmental factor over the genetic one involves Japanese-American males and Japanese males. A test conducted over a thirty year period showed that while the percentage of Japanese-Americans with Alzheimer‚s was 5.4% while the Japanese in Japan had a mere 1.5%. This shows that while Japanese-Americans are genetically no different from Japanese in Japan, the percentage of people with Alzheimer‚s is much closer to European and American males.

Virus:

Some scientists believe that viruses trigger Alzheimer‚s disease. These viruses possibly are the source of changes in the brain tissue which initiates the declining process inside the brain.

Some interesting facts:

At all ages, women are more likely to get Alzheimer‚s. By the time they reach 93 they are 13% more likely then men to get Alzheimer‚s (1).

Research has found that Cherokee Indians are resistant to Alzheimer‚s. Research conducted amongst people of Cherokee Indian ancestry has found that the stronger one‚s ancestry is to Cherokee Indians the less likely the changes became of having Alzheimer‚s.

It is hard to isolate one source, and what is most likely the case is that like cancer, environmental factors instigate the gene to start to behave differently, thus causing the disease.

Treatment, improvements, and a cure:

Presently there are two drugs available for Alzheimer‚s, Tacrine (Cognex) and Donepezil (Aricept). These two drugs are cholinesterase inhibitors, thus act to slow down the process rather than cure patients. Unfortunately even these two limited drugs do not work for some people. Even for those people who respond to it, the results are limited and several side effects come with it.

Recent research has shown that vitamin E, non-steroidal anti-inflammatories (NSAID), and estrogen delay the onset of Alzheimer‚s (5).

Though there still is no cure, or even an effective treatment for Alzheimer‚s researchers are very optimistic. Dr. Bruce Yankner of Harvard Medical School says "We've learned more about Alzheimer's in the past 15 years than in the previous 85," (1). Importantly, there has been several new discoveries involving the nature of the disease, cures, symptoms, and treatments just within this past year. Although many mysteries still surround Alzheimer‚s many doctors and researchers are quite optimistic about the chances of finding a cure.

Conclusion:

It is estimated that 12 million people worldwide have Alzheimer‚s (6); another source has the US as having approximately 4 million (1). (if this is the case the world figures would be more than 12 million). As living standards improve in the world and the number of elderly people increase it is going to be more important then ever to find a cure to Alzheimer‚s in the near future.

If Emily Dickinson is right, and the brain is wider than the sky, for people with Alzheimer‚s it‚s like the sky is falling down, if the Brain is deeper than the sea, for people with Alzheimer‚s it become a puddle, and if the Brain is just the weight of God, than people with Alzheimer‚s is no more than a mere man.

WWW Sources

1)http://www.alzheimers.com, This site has probably the most information ranging from causes, symptoms, to cures

2)http://newsweek.com/nw-srv/printed/us/so/a54596-2000jan23.htm, An article from Newsweek that came out 2 weeks ago that wrote about recent developments

3)http://www.pslgroup.com/ALZHEIMER.HTM

4)http://www.alzheimers.org/index.html ,Alzheimer's Association

5)http://www.alz.org/, Alzheimer's Disease Education and Referral (ADEAR) Center's website

6)http://www.alz.co.uk/alz/index.html, Website of Alzheimer's Disease International

Additional Websites on Alzheimer's Disease

A)http://www.alzweb.org

B)http://www.pslgroup.com/ALZHEIMER.HTM,

C)http://www.alzheimers.org.uk/ , Alzheimer's Disease Society

D)http://newsweek.com/nw-srv/printed/us/so/a54600-2000jan23.htm , From Newsweek showing drawings of what happens in the neurons




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