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Biology 202, Spring 2005 Third Web Papers On Serendip

Deconstructing Alzheimer's Disease

Patrick Wetherille

As human beings, we have learned ways to take better and better care of ourselves such that we have been able to live longer and longer. However, despite the progress we have made, we have discovered a barrier to the long life of some: Alzheimer's disease (AD), an ailment that affects people in old age. Is AD simply an extreme form of the normal aging of the brain, or is it different? As we continue to understand more about it, what are we doing to combat it? What can be done to help those with the disease cope with it? How the disease works, what approaches have been taken to prevent and cure it, and the implications those measures might have on society as a whole, are all issues we shall take up in this discussion.

AD was first discovered in 1907 by German neurologist Alois Alzheimer (1). AD afflicts its patients with a dementia that increases in malignance over time: the older an AD patient is, the worse the dementia is. Dementia is a result of the loss of neurons in the brain that assist in engagement of intellectual activities. The loss of neurons specifically affects the hippocampus, which is a central region for memory operation, and the cerebral cortex. The cerebral cortex is also involved in memory functions, but also works to accomplish reasoning and language functions (1).

In asking what causes AD, we must really ask two questions: first, what factors determine a person's increased likelihood of getting AD and second, what are the specific chemical and neurobiological operations that cause these neurons to deteriorate? In answering the first question, we find that there is no one factor that causes a person to have AD. Age seems to be the across the board prerequisite for developing AD, but it is not the only factor. Family genetics seems to be an important factor in some cases (2). While the studies vary, it seems that somewhere between 50% and 75% of an individual's propensity to develop the disease arises from family genetics (3). In fact, there appears to be a split in the kinds of AD one can get. Sporadic AD happens among people who have no pattern of it in their family while Familial AD is caused by a set of inherited chromosomes. Unlike many inherited diseases such as Huntington's disease, AD is caused by gene mutations on multiple chromosomes, rather than a single one: numbers 1, 14, and 21, to be exact. If any of these mutated genes are inherited from either the mother or the father, the child has a 50% chance of developing Familial AD (4). This high probability of receiving the AD genes are due to the autosomal dominant inheritance pattern of the gene.

Unlike Familial AD, there is no agreed upon factor that causes Sporadic AD among the general population. Exercise (5), eating a good diet, and keeping one's mind stimulated (6) are all factors that have been said to reduce the risk of developing AD. However, age is the overriding factor that seems to enhance the likelihood of developing either Familial or Sporadic AD. Unfortunately, researches still do not know what it is specifically that causes sporadic AD, but for now, they believe it to be a combination of the environmental and genetic factors listed above. Now let us turn to the chemical and neurobiological side of AD.

While no one is certain what causes AD, there is one working theory that seems to get it less wrong than the others. A big difference between a normal brain and a brain afflicted with AD is the presence of protein clusters inside and between neurons. The clusters inside are known as neurofibrillary tangles, which consist of a protein named tau (1). Another type of protein known as beta-amyloid are the proteins that exist between neurons. While the presence of tau seems to be proportionate to the degree of dementia experienced by the patient, indicating a possible connection to the cause of AD, it is not unique to AD the way beta-amyloid plaques are in their unique concentrations. These beta-amyloid proteins that cluster between neurons and are accompanied by the immune system's microglia, reactive inflammatory cells that are thought to remove already damaged neurons and/or the amyloid plaques themselves (1). They originate from the beta-amyloid precursor protein (bAPP) when a bAPP fragment that is 99 amino acids is cut by gamma-secretase, creating a beta-amyloid peptide (1). Some of these resulting strings (about 10%) have two more amino acids than the rest. It is this longer form of the beta-amyloid string that has a harmful effect on neurons, ranging from calcium deregulation to damage of mitochondria, to the inflammation of the cell, which could, in conjunction with other damage, create an ongoing cycle of damage that can result in deterioration of neurons (1). While the amyloid plaques themselves are present in most old people, the high concentration of them in the hippocampus and cerebral cortex in AD patients suggests a role in the neuronal degenerative process. While researchers still do not know whether the beta-amyloid plaques are responsible for, or a simply the result of AD's degenerative process, their presence is a fundamental component to understanding how AD works (7).

Is AD just a part of getting old? For a long time, many held the belief that AD was simply the aging process at the very far end of the spectrum. That is, that aging inherently involves the loss of neurons and brain capacity and that AD is simply a more extreme end of a range of brain loss. However, that view has been refuted in recent years. Scientists have no reason to believe that the brain will deteriorate simply from aging. While mild cognitive impairment (MCI) has been identified as a "borderline" state between AD and normal brain functioning (3), it is more an early stage of AD than of a middle range in a spectrum of aging-related dementia. In fact, a study that looked at the loss of neurons in the aging of both AD and control subjects, found no link between aging and loss of neurons (8). Using statistically unbiased methods, researchers approximated neuron counts in the entorhinal cortex and the superior temporal sulcus, two regions known to be affects by AD. They found that, while severe cases of AD resulted in 66% and 52% losses to those regions, respectively, there were no significant losses in those regions with the non-AD control group.

What is being done to combat AD? While several drugs have been developed to slow the process, there is no cure to AD. Researchers have been using the beta-amyloid plaque theory we discussed earlier in their search for a cure. Inhibiting the gamma-secrease enzyme that causes the bAPP protein to be cut is an approach drug companies have tried, however the side effects have been undesirable in animal trials, as gamma-secrease does more for the body than just snip bAPP proteins (3). Anti-inflammatory drugs seem more promising, as they have been successfully conducted on animals. The idea is to reduce the inflammation caused by the beta-amyloid proteins in neurons to prevent the brain's immune system from attacking and eliminating neurons with those proteins in it (3). However, the effects of this treatment do not amount to a cure, though it does have the ability to slow the process. Another approach that could be taken is the introduction of stem cells to the affected regions of the brain. Transplanting healthy cells into a region that is plagued with dying cells could potentially reverse some of the effects of AD. The idea is that harnessing one's own stem cells could have a better effect on the patient than the introduction of someone else's cells (3). The effects of this procedure are not yet known as the use of stem cells in research is very limited due to its intersection with the broader ethical debate on reproductive issues.

While the curative approach is certainly crucial to combating the effects of AD, one avenue we might consider looking down is a focus on supplemental measures. The development of new technologies that could help AD patients cope with loss of mental function might be appropriate, given the nature of the ailment. Developments in information technology could be offer assistance to AD patients in way that could supplement the loss of biological function with mechanical functions. For example, a computer could be used to keep records of family members to help remind the patient about his or her past. While a desktop PC seems somewhat impractical for this, a computer small enough to fit into someone's eyeglasses, coupled with voice and image recognition technology, could provide AD patients with the kinds of information they need to continue to function. This, along with drugs to at least slow the process, could provide a treatment that could restore a quality of life to the patient in a way that is currently unavailable.

This kind of merger between IT and AD has already begun. In 2003, Intel entered into a consortium with the Alzheimer's Association, granting $1 million in IT research to be directed towards AD patients (9). Technology such as sensor networks is being used to study the habits of AD patient behavior in hopes of finding ways to learn more about AD and to make it more livable. This is just one example of how IT can work for AD patients.

An example of the merger of IT and AD in the extreme can be found in some more radical proposals. Scientist Hans Moravec has suggested that someday, entire human brains and the consciousnesses they hold will be able to be downloaded into a computer (10). This would certainly obviate the problem of neuronal deterioration, but it's possible that by the time we have the technology to move minds into machines, we'll know enough about AD to make it a livable or curable illness.

While scientists have learned a lot about AD, there is still a long way to go. I began studying AD thinking that it was merely an advanced form of the inevitable loss of neurons and intellectual capacities that comes with the aging process. In seeing the mechanics of the proteins that are believed to play a role in AD, I could begin to see how AD is different from aging and how aging itself does not cause the kind of loss of neurons associated with dementia. In thinking about ways of dealing with AD, the development of drugs to lessen the effects of the disease and to cure it seem like an important avenue to pursue. However, I could not help but think about the ways AD affects a person's consciousness. If the I-function draws upon input resources to make sense of the world, why cannot those inputs be supplemented through technology? It seems to me that the pursuit of advanced technologies that link the brain and the computer may yield ways of dealing with AD that might help people inflicted with the disease. This might be worth pursuing if technology advances faster than a treatment or cure.

References

1) St. Georges-Hyslop, Peter H. "Piecing Together Alzheimer's." Scientific American, December 2000, Vol. 283 Issue 6, p76-83.

2) National Institute on Aging: Causes of Alzheimers, Information on what can cause AD.

3) Schmiedeskamp, Mia. "Preventing Good Brains from Going Bad." Vol. 14 Issue 3, p84-91.

4) National Institute on Aging: AD Genetics Factsheet, a page about the genetic factors in AD.

5) CNN story, 4/28/98, how exercise influences the chances of getting AD.

6) Alzheimer's Association: Risk Factors, more information on what can increase risk of getting AD.

7) National Institute on Aging: Unraveling the Mystery, a source on the current working theory of the neurobiology of AD.

8) Petersen, Ronald C. Mild Cognitive Impairment. New York: Oxford University Press, 2003.

9) Intel Press Release, July 24, 2003, how IT is working to fight AD.

10) Chip, Walter. Scientific American, January 2005, Vol. 292 Issue 1, p36-38.

11) Alzheimer's Information website, a good source for current AD issues.

12) PBS info page on AD, a general source for the effects of AD.


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