Over the last few decades, Alzheimer's disease has come to be recognized as the most common form of dementia among the world's older population, affecting an estimated 4 million people in the United States alone (1, 2). It is characterized by progressive loss of memory, language and reasoning skills, and other cognitive functions, as well as changes in personality, such as increased aggressiveness (1, 2). No definite cause has been discovered, and it is as yet without a cure; however, much progress has been and continues to be made, and many scientists believe that a cure will eventually be developed.
Although the causes are unknown, research has shown that the disease begins in the entorhinal cortex and spreads first to the hippocampus and then proceeds to other parts of the brain, particularly the cerebral cortex. Since these two regions are primarily involved with memory and language and reasoning skills, respectively, short-term memory loss followed by language dysfunctions are among the first recognizable symptoms. The disease functions by causing neurons to degenerate and lose their synapses with other nerves, thus cutting down severely on the intercellular communication which lies at the heart of all behavior. (1).
Degeneration is characterized by clumps of beta amyloid (a protein fragment derived from amyloid precursor protein, or APP) called neuritic plaques which form outside and around neurons, as well as by the twisting and 'tangling' of a neuron's microtubules, a phenomenon referred to as neurofibrillary tangles (1, 2). These tangles specifically involve a protein known as tau, which usually forms the crosspieces or rungs of the parallel-running tracks of microtubules. In Alzheimer's patients, however, these crosspieces twist into helical shapes, thus breaking down the neuron's inner transportation system. The precise functions of beta amyloid and tau are not yet known; however, various studies suggest that beta amyloid may be involved in altering the concentrations of various chemicals both inside and outside of neurons, either by creating extra channels in the neuronal membrane or by changing already existing channels (see 1 for more details). (1)
Research targeting the cause, or possibly, causes of Alzheimer's disease has a number of areas of focus, including several neurotransmitters, various postsynaptic events, genetic factors, cell metabolism, and possible environmental contributors (1, 2). A description of all of these would require more than the length stipulated by this assignment; therefore, I shall focus on pre-and postsynaptic events, since these correspond to the material that has been covered in class so far, and then go on to explain the differences between early and late onset subtypes of the disease.
Scientists have discovered that the levels of certain neurotransmitters in patients with Alzheimer's disease, including somatostatin, serotonin, noradrenaline, and particularly acetylcholine, were unusually low. Deficits of these chemicals lead to such symptoms as unregulated release of growth hormones (somatostatin), aggression (serotonin), and memory impairment (acetylcholine) (1, 2). Most research, however, focuses on acetylcholine, as it is known to play a crucial role in memory formation and reasoning and is the neurotransmitter used by neurons in both the hippocampus and cerebral cortex (1). Such biochemical deficiencies may prove to be causal factors in the development of Alzheimer's. It is, however, unclear what causes these drops in neurotransmitter production. One study suggests that reduced acetylcholine levels may be linked to beta amyloid, which, in this particular study, was seen to reduce concentrations of choline, which is necessary to form acetylcholine, in neurons (1).
Research on postsynaptic suspects has focused mainly on the receptors embedded in the neuronal membrane. Receptors may be involved through their interaction with the cell membrane or independently of it. Regarding the former, certain studies have shown abnormalities in the phospholipid bilayer comprising the greater part of the membrane, which might have adverse effects on the receptor proteins with which the fat molecules are chemically bound. Such abnormalities might change the structure and behavior of the proteins, causing the message to be altered or lost. Independent of the phospholipids, there are many different kinds of receptors for acetylcholine, whose own behavior and shapes might contribute to the development of the disease. Beyond the cell membrane, there is also the possibility that other proteins involved in the subsequent cascade of biochemical events within the neuron could be dysfunctional, as could a number of other intracellular processes (e.g., metabolism), interfering with the messages being passed. Two such proteins, beta amyloid and tau, have already been mentioned above. (1).
Even with this partial overview of possible contributors to the development and spread of Alzheimer's disease, it is clear that the complexity of the brain makes searching for a cure, let alone a cause, a difficult task. To add to this confusion, researchers have found that there are two distinct subtypes of Alzheimer's, early and late onset, each having its own distinctive features. Not only must scientists search for (at least) two different causes, but different treatments, as well. (2).
Differences between the two forms of Alzheimer's disease involve not only the age of onset, but also the symptoms, mechanisms, and areas of the brain involved. Patients with the early onset form have greater language dysfunction than those suffering from later onset of the disease; these latter individuals, however, tend to have more problems with visuoconstructual functions (i.e., spatial relations). The two groups also seemed to have opposite areas of relative strengths and weaknesses. Based on their scores on a test known as the Modified Mini-Mental State Examination (MMMS), early onset patients performed worse on attention-related tasks, whereas those with late onset had a harder time with recall and naming tasks (2). These symptoms imply that in each case, a different part of the brain is being targeted by the disease: in the case of early onset, the left hemisphere (involved in language), the right hemisphere in late onset. (2)
Although the early onset form of Alzheimer's tends to cause more rapid neural degeneration, this does not necessarily mean that it is a more severe form of the disease; rather, it is a reflection of the neurobiological characteristics and resulting rates of progression which differentiate early from late onset forms. It has been shown that in patients with early onset Alzheimer's, a greater proportion of the brain is affected by acetylcholine deficiency; in those with late onset, such cholinergic deficiencies are restricted to the hippocampus and the temporal lobe. Furthermore, early onset patients also tend to have more deficiencies of other neurotransmitters, which helps to explain why the disease is observed to be so much more widespread than in late onset cases. As might be expected given these circumstances, neural degeneration occurs at a faster pace in early onset cases, and the amount of grey matter lost is greater, as well. Nevertheless, the degree of impairment in early and late onset forms seems to be virtually the same (see 2 for more detail), implying that the rate of progression alone does not reflect the severity of the disease, but the areas of the brain which are affected, as well. (2)
I have outlined just a few of the many puzzle pieces currently available to scientists today; to present them all would require not only more time and space, but also greater knowledge than I can presently offer. Nevertheless, even with the limited knowledge provided in these few pages, one can approach the question, "Brain=Self?" with a (hopefully) somewhat more informed basis for one's arguments, whatever they may be. In reading through my sources, I was particularly struck by the following statement:
In its final stages, Alzheimer's disease wipes out the ability to recognize even close family members or to communicate in any way. All sense of self seems to vanish, and the individual becomes completely dependent on others for care. (1, emphasis added). Given these observations, the statement "Brain=Self" gains validity as a hypothesis, in my eyes, at least. And yet, one might argue, how do we know that the individual has no sense of Self? Is the Alzheimer's patient not perhaps a case comparable to the paraplegic's spinal cord, impossible to test, and therefore unfalsifiable? What if it becomes possible someday to reverse the disease, could we ask them and know the answer then? Or would we have to dismiss any answer, if there should be any, because the original neurons and their connections are forever lost?
Both camps will always find arguments to uphold their beliefs, no matter what the 'scientific' evidence might be, and maybe it is best that way. All else aside, this very ability to constantly readjust and form new ideas (the very essence of Science) seems to speak against the notion of a Selfless, mechanical life. It seems that the majority of us have accepted that, for what else but the belief in the value of individual lives could drive us to exert the efforts we do to help those who (in our eyes) are losing theirs? Perhaps we are capable of altruistic behavior after all.....
Alzheimer's Disease: Unraveling the Mystery is an online information booklet published by the National Institute on Aging (NIA) and the National Institutes of Health (NIH), intended for anyone who wishes to learn more about Alzheimer's disease, professional or not. It covers the basic features and statistics of the disease and goes on to provide a comprehensive summary of current research regarding the causes, diagnosis, and treatment of Alzheimer's, including care. In addition to this wealth of information, the site has excellent graphical representations accessible by links throughout the text, as well as a glossary of technical terms at the end.2. http://hcs.harvard.edu:80/~husn/BRAIN/vol3/b96txt.html#EarlyandLate:
Early and Late Onset as Subdivisions of Alzheimer's Disease, an article by Elizabeth Kensinger published in the online journal, The Harvard BRAIN. Explores and explains research to date regarding these two different forms of Alzheimer's disease, covering the "symptomatic, biological, genetic, neurophysiological and neurological characteristics" of both early and late onset subtypes. Then proceeds to draw conclusions from this data, regarding future approaches to diagnosis and treatment.
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This paper reflects the research and thoughts of a student at the time the paper was written for a course at Bryn Mawr College. Like other materials on Serendip, it is not intended to be "authoritative" but rather to help others further develop their own explorations. Web links were active as of the time the paper was posted but are not updated.