Alzheimer’s disease is a progressive condition where the neurons degenerate in the brain, while the brain substance shrinks in volume. Alzheimer’s is also the number one cause of dementia. When it was first noticed, Alzheimer’s was thought to be a pre-senile disease, but now it is known to be responsible for seventy-five percent of the dementia cases in people over sixty-five years of age. Alzheimer’s disease usually causes several years of personal and intellectual decline until death. Because there is an increasing number of elderly citizens in the United States, research into the causes and possible cures for the disease is on the rise (1).

Several theories have been made concerning factors that may cause the condition; however, the cause remains unknown. Some suggest that it may be caused by some type of chronic infection or from exposure to a metal that may be toxic, such as aluminum (1). This line of belief originated from high levels of aluminum deposits being found in Alzheimer’s brain lesions (2). It is also known that people with Alzheimer’s have reduced levels of brain chemicals, such as acetylcholine (1). Additionally, people with Down’s Syndrome are more likely to acquire this dementia, with about fifteen percent of Alzheimer’s patients showing a family history of this disease. This leads many scientists to believe that there is a genetic link to the disease. When twins have been studied, a high agreement rate has been found for the disease. Furthermore, there is sometimes a very dominant pattern of inheritance of this disease, where a person has a fifty percent chance of acquiring it if either parent has Alzheimer’s (autosomal dominant transmission) (1,2).

It is rare to acquire Alzheimer’s disease before the age of sixty; however, the risk increases steadily after that age. It is estimated that up to thirty percent of the people over the age of eighty-five years are affected (1). Also, women are thought to be at a slightly higher risk than men (4).

The symptoms of the disease vary somewhat among individuals. However, there are three distinct stages that a person suffering from Alzheimer’s will experience. In the first stage, the patient experiences some problems with memory loss and will often make lists or other aids to compensate for this loss. The individual can begin to feel depressed or anxious because of the memory problems. This stage often G_oes unnoticed as symptoms of Alzheimer’s (1).

The second stage is marked by the change from forgetfulness to severe memory loss. Long-aG_o events are often easier to recall than things that have happened within the last few days. For example, one might remember childhood events but are unable to remember what they saw on television last night or what they ate for breakfast. Disorientation in relation to time and place occurs often, along with increased anxiety and recurring mood swings. The patient also experiences dysphasia (inability in finding the right word to say), increased difficulty with math problems, and loss of direction in familiar places. Personality changes will soon become noticeable when this second stage is reached (1).

Finally, the third stage is marked by severe disorientation and confusion. Usually, the worst signs of memory loss and disorientation occur at night. In this stage of Alzheimer’s disease, patients often suffer from symptoms of psychosis such as hallucinations and paranoid delusions. Also, nervous system deficits becomes apparent. Patients exhibit incontinence of feces and urine; they also have primitive reflexes (reflexes that occur in newborns). Patients lose their perception of social norms. Some become violent and uncontrollable, while others show signs of helplessness and become very docile. Furthermore, patients wander aimlessly and show disregard for personal hygiene. Many times the burden for care becomes too great for the patients’ families. The patients are given full-time hospital care and nursing until death. When the patients’ conditions worsen until they become bedridden, further complications such as pneumonia, bed sores, and feeding problems hasten their death (1).

A definitive diagnosis for Alzheimer’s disease can only be made by a brain biopsy or by a post mortuary examination of the brain (1). Pathological findings in an Alzheimer’s patient’s brain include diffuse atrophy with flattened cortical sulci and enlarged cerebral ventricles (2). Also, microscopic examination reveals senile plaques, neurofibrillary tangles, and granulovacuolar degeneration of the neurons (2).

Neurofibrillary tangles, which are paired helical filaments existing inside the neurons, are not exclusive to Alzheimer’s patients. Other neurological disorders such as progressive supranuclear palsy, dementia pugilistica, Guam-Parkinson-dementia complex, etc. are also associated with the tangles. In contrast, plaques found in the brain are unique to Alzheimer’s disease, Down’s Syndrome, and to a much smaller degree, normal aging. The presence of a small number of plaques due to aging probably indicates that Down’s Syndrome and Alzheimer’s disease may very well be an accelerated level of the normal aging process. The primary component of the plaques is a protein called beta-amyloid protein. The gene encoded with the template for the beta-amyloid protein is located on chromosome 21 in humans. Down’s Syndrome (trisomy 21) patients have three genes, rather than two, for this protein. Therefore, the extra gene for the beta-amyloid protein may lead to an overproduction of the protein in people with Down’s Syndrome leading to the formation of plaques. Most Alzheimer’s patients do not have an extra gene for the beta-amyloid protein; however, the accumulation of the protein suggest some type of protein storage disease. The over accumulation of the protein is either a cause or an effect of the disease process (2).

The beta-amyloid protein has been studied extensively and has been sequenced. It’s structure indicates it functions as a transmembrane protein and serves as a receptor, but its actual function is unknown (2). The beta-amyloid protein is between 39 and 42 amino-acids in length (5). Also, the beta-amyloid forming the central-core of the senile plaques is the same as that deposited around small blood vessels(6).

Since Alzheimer’s disease cannot be diagnosed without examination of brain tissue, most patients believed to have Alzheimer’s disease are diagnosed as having primary degenerative dementia of the Alzheimer’s type (DAT). Specific diagnostic criteria have been laid out by the Diagnostic and Statistical Manual of Mental Disorders—volume 3 revised (DSM-111-R) as follows (7):

a. Dementia—significant loss of intellectual abilities such as memory capacity, severe enough to interfere with social or occupational functioning:

b. Insidious onset of symptoms—subtly progressive and irreversible course with documented deterioration over time;

c. Exclusion of all other specific causes of dementia by history, physical examination, laboratory tests, psychometric, and other studies.

There is no known prevention or cure for Alzheimer’s disease. Patients are given proper nutrition and exercise, and their symptoms, such as anxiety, depression, and agitation, are managed with drug treatment (2).

In recent years, evidence has accumulated that functional abnormalities in the amyloid precursor protein (APP) biochemical pathway may be causal in the disease process of Alzheimer’s. Beta-amyloid peptide in the cerebral vessels or the plaque are both derived from APP (9).

The data has been accumulating, indicating amyloid has a causal role in Alzheimer’s disease. This evidence can be grouped into four cateG_ories. First, there have been APP gene mutations found in families with autosomal dominant Alzheimer’s disease (AD). Second, a consensus among most researchers is that amyloid is toxic to neurons. The third finding is animals have been produced using an APP transgene and then develop plaque-like structures in the brain. The last fact is that aged Down’s syndrome patients who develop a dementia late in life develop amyloid-containing plaques (9).

In reviewing recent studies which indicate beta-amyloid having a central role in molecular events causing Alzheimer’s, one finding is believed to stand out as the most intriguing. Altered APP processing is believed to use the endosomal-lysosomal pathway and produce increased amounts of a precursor for the beta-amyloid peptide. This area is assured to bring about now studies. Also, altered structural forms of the beta-amyloid protein that contain the amino acid L-isoaspartate at the 1 and 7 positions have been found in plaques of AD brains. This finding indicates that abnormal deposition of beta-amyloid may be due to defects in the normal catabolic mechanisms for the protein’s breakdown. A most recant finding suggests that synthetic beta-amyloid protein forms cation channels in a lipid bilayer. These channels can be used to transport calcium effectively, and the calcium-mediated excitatory degeneration may explain the beta-amyloid toxicity even before the plaques are formed. Finally, recent results indicate that APP is a receptor coupled with G_o (a major GTP-binding protein) in the brain. They also suggest that APP-G_o receptor abnormalities have a role in GTP expression in the brain of Alzheimer’s patients (9).

These new findings indicate research has been directed in finding amyloid’s role in molecular events in the brain. The rapid achievements in this area so far give hope of the beginning of the ultimate elucidation of the end to Alzheimer’s Disease research.

Notes and References:

1. Clayman, C. B. Alzheimer’s Disease. The American Medical Association: Encyclopedia of Medicine, 1989, 91.

2. Kaplan, H. I. and Sadock, B. J. Primary Degenerative Dementia of the Alzheimer’s Type. Synopsis of Psychiatry, 6th ed., 1991, 810: 249-252.

3. Nee, L. E., R. Eldridge, T. Sunderland, and C. B. Thomas, Dementia of the Alzheimer’s type: Clinical and family study of 22 twin pairs. Neurology, 1987, 37, 359-3B3.

4. Thomas, C. L. Alzheimer’s Disease. Taber’s Cyclopedic Medical Dictionary, 15th ea., 1985, 61.

5. Murray, R. K., Cranner, D. K., Hayes, P. A. and Rodwell, V. W. Deposition of Amyloid Beta Protein is Involved in the Causation of Alzheimer’s Disease. Harper’s Biochemistry, 23rd ed., 1993, 750-752.

6. Miyakskawa, T., Katsuragi, S., Watanabe, K., Shimoji, A. and Ikouchi, Y. Ultrastructure Studies of Amyloid Fibrils and Senile Plaques in the Human Brain,1986,70: 202-208.

7. Frazier, S. H. American Psychiatry Glossary, 5th. ed., 1988, 11; 50: 153.

8. Cohen, C. D. Useful Information on Alzheimer’s Disease. Department of Health and Human Services, 1990, 5-7.

9. Rosenberg, R. N. A Causal Role for Amyloid in Alzheimer’s Disease: The end of the beginning. Neurology, 1993, 43:851-854.