Alzheimer's Disease | Research & Encyclopedia Articles

Alzheimer's Disease

Alzheimer's disease is a progressive brain disease that produces devastating mental deterioration. Its symptoms, which include increasingly poor memory, personality changes, and loss of concentration and judgment, are caused by the death of brain cells and decreased connections between the cells that survive. The disease affects approximately four million persons in the United States. Although most victims are over age 65, Alzheimer's disease is not a normal result of aging. Medication can relieve some symptoms but there is no effective treatment or cure. Its cause is unknown.

People have long assumed that physical and mental decline were normal and unavoidable features of old age. Such deterioration was called senility. As recently as the early 1970s, much of the public and many physicians and nurses were not familiar with Alzheimer's disease. It was not until the 1980s that scientists and physicians realized that Alzheimer's disease was the most common cause of senility in middle-aged and older people. Since then, the public has become more aware of the disease, especially since Alzheimer's disease has stricken popular celebrities like artist Norman Rockwell, actress Rita Hayworth, and former President Ronald Reagan.

The term Alzheimer's disease is less than a century old. A German neurologist, Dr. Alois Alzheimer (1864-1915), was the first person to describe the disease. In 1906, he studied a 51-year-old woman whose personality and mental abilities were obviously deteriorating: she forgot things, became paranoid, and acted strangely. She died approximately four and one-half years after Alzheimer first treated her. Following an autopsy, Alzheimer examined sections of her brain under a microscope. He noted deposits of an unusual substance in her cerebral cortex-the outer, wrinkled layer of the brain, where many of the higher brain functions such as memory, speech, and thought originate. The substance Alzheimer saw under the microscope is now known to be a protein called amyloid beta-protein.

Many scientists today believe this protein plays an important role in causing Alzheimer's disease. Others believe it is not the primary cause of the disease, but rather a response to it. Eighty years or so after Alzheimer described the first case of the disease, researchers have found that a small percentage of Alzheimer's disease cases are apparently caused by genetic mutations. Most cases, however, are the result of unknown causes.

The first symptom of Alzheimer's disease is usually memory loss of recent events. A slight decline in recent, as opposed to long term, memory is typical in healthy elderly adults. The memory loss seen in Alzheimer's disease, however, is much more severe. As years pass, memory loss becomes greater, and personality and behavioral changes occur. Although victims may remain physically healthy for years, their mental faculties progressively decline. Later symptoms include disorientation, confusion, speech impairment, restlessness, irritability, and inability to care for oneself. Finally, the brain loses the ability to control basic physical functions such as swallowing.

Alzheimer's disease slowly destroys its victim's brains and robs them of the thoughts and memories that make them unique human beings. It creates tremendous problems and stress for those who care for patients. Persons with Alzheimer's disease typically live between five and 10 years after diagnosis, although improvements in health care in recent years have enabled some victims to survive for 15 or even more years. Life-prolonging therapy and treatment, however, does nothing to stop the progression of the disease--they only delay the inevitable. In the absence of other diseases such as heart disease or cancer, Alzheimer's patients usually die from pneumonia or from complications resulting from other infections.

It is not a simple procedure to diagnose Alzheimer's disease. Physicians must use a process of elimination, because there is no simple, standard diagnostic procedure, such as a blood test, for determining who has the disease. Also, Alzheimer's disease symptoms can be mimicked by other medical conditions, such as brain tumors, dietary deficiencies, and side-effects of medication. About one-third of persons with early symptoms who visit physicians on their own or are taken by family members do not have Alzheimer's disease. The only possible physical procedure for definitively diagnosing Alzheimer's disease is to open the skull and to remove a sample of brain tissue, a biopsy, for microscopic examination. This is rarely done, because brain surgery is too drastic a procedure to use simply to obtain a sample of tissue. Ninety years after Alois Alzheimer first saw the amyloid beta-protein under his microscope, direct microscopic examination of the brain is still the only certain method of diagnosis. Nevertheless, by combining the results of medical histories, physical examinations, laboratory tests, and neurological exams to rule out other causes of dementia, physicians can accurately diagnose 90% or more of cases.

Prescription drugs are useful for treating symptoms like insomnia, anxiety, and depression, but there is no cure or drug that will stop the progressive degeneration produced by the disease. A drug called Tacrine has provided temporary improvement for only a few patients.

Estimates by the Alzheimer's Association indicate that Alzheimer's disease is the fourth leading cause of death in the United States, after heart disease, cancer, and stroke. It causes the deaths of more than 100,000 adults in the United States each year.

There were an estimated 2.5 million Alzheimer's disease cases in the United States in the mid-1970s. Today the number of cases has increased to four million, according to estimates by the National Institute on Aging. The Alzheimer's Association claims the cost of caring for these patients is $80-90 billion per year.

The apparent increase in the number of Alzheimer's disease cases-from 0.4 per 100,000 in 1979 to 4.2 per 100,000 in 1987-could be the result of more accurate reporting of cases, an increase in the actual number of cases, or a combination of both, according to the Centers for Disease Control. Canada, Australia, and parts of Europe report similar increases. As more and more citizens live into their 80s and 90s, the number of Alzheimer's disease cases could reach 12-14 million or more before the middle of the next century.

Alzheimer's disease is in most cases a disease of old persons. Ten percent of everyone 65 years of age or older and 40-50% of everyone 85 or older has or will get the disease. Except for a small number of cases of inherited Alzheimer's disease, the disease is rarely seen in persons in their 30s or 40s.

The brains of Alzheimer's disease victims appear shrunken compared to nondiseased brains. The atrophy is particularly apparent in large parts of the neocortex, the outer layer of gray matter responsible for higher brain functions such as thought and memory. The hippocampus (a part of the brain near the temple) and the area around it are also heavily affected in Alzheimer's disease patients. This area plays an important role in forming memories. Much of the shrinkage of the brain is due to loss of brain cells and decreased numbers of connections, or synapses, between them.

In the surviving brain cells of an Alzheimer's patient, two hallmark features of the disease can be seen under the microscope: neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles are abnormal collections of bunched and twisted fibrils in neurons. The fibrils are derived from components of a network of tubules and filaments that provide cells with structure and organization. The protein in neurofibrillary tangles is called tau. Such tangles are not specific to Alzheimer's disease but are also found in a dozen or so other brain diseases. The severity of mental impairment, however, correlates best with loss of connections between brain cells (synaptic loss), followed by neurofibrillary tangles; plaques appear to correlate only slightly or not at all.

Amyloid plaques consist of a core of amyloid beta-protein and other proteins surrounded by neurites. Neurites are the long projections of nerve cell bodies called axons and dendrites. Axons send signals to other cells and dendrites receive them. In addition to amyloid beta-protein, plaques contain other proteins, such as those normally found in blood serum.

Scavenger cells called microglia can be found in the center of plaques, and astrocytes, a type of cell that usually helps protect neurons, are found around the outside of the spherical plaques. The microglia may be part of an inflammatory response of the body to the plaques. Some researchers believe this response may actually end up killing brain cells rather than destroying plaques.

Amyloid plaques can be found in the brains of healthy persons in small numbers, but they are greatly increased in the brains of Alzheimer's disease patients. The disease, in fact, is defined by the presence of a large number of plaques in a section of brain tissue. The concentrations of many types of neurotransmitters (chemical messengers used by brain cells to communicate with one another) are also lower in the brains of Alzheimer's disease victims.

Scientists are studying many factors that may contribute to Alzheimer's disease. These include toxins, metabolic abnormalities, and infectious agents alone and in combination with each other. Among the known risk factors for Alzheimer's disease are head trauma, age, Down's syndrome, and in a small percentage of cases-approximately 10%-gene mutations.

Several studies have indicated that head injury suffered late in life and serious enough to produce unconsciousness is a significant risk factor for the disease. Both former President Ronald Reagan and artist Norman Rockwell suffered head injuries prior to developing Alzheimer's disease. It is not known if these injuries contributed to the onset of their dementia, but their cases are consistent with studies linking head trauma and Alzheimer's disease.

Down's syndrome is a genetic disorder that causes retardation. It results when a person is born with three copies of chromosome 21 instead of two. Virtually everyone with Down's syndrome develops plaques and tangles typical of Alzheimer's disease if they live long enough. It is intriguing that the gene for amyloid beta-protein is found on chromosome 21.

Familial Alzheimer's disease, an inherited form of the disease, accounts for approximately 10% of cases. Approximately 100 families in the world are known to have rare genetic mutations that are linked with early onset of disease symptoms. Some of these families have an aggressive form of the disease in which symptoms appear before age 40. The early onset genes are on chromosome 21, chromosome 14, and an unidentified chromosome. The mutation on chromosome 14 accounts for more than 80% of familial or inherited Alzheimer's disease cases.

In the majority of Alzheimer's disease cases, symptoms appear after age 65 and are not linked to a specific mutation. Some scientists suspect that the genes that are mutated in persons with familial Alzheimer's may play some role in the disease in victims without the mutations. While genes alone may cause 10% of all cases, the remaining 90% may be caused by various combinations of genetic and as yet undefined environmental factors. It is possible that most cases result from a genetic predisposition combined in varying ways with other factors.

Recently scientists have discovered that the gene for apolipoprotein E (ApoE), a protein that moves cholesterol in the bloodstream and can bind to amyloid beta-protein and other proteins, can affect a person's risk of developing the disease. There are three forms of the ApoE gene: ApoE2, ApoE3, and ApoE4. These three forms of the gene are not mutations but are normally occurring variations found in many populations. Unlike the genes inherited by the families with familial Alzheimer's disease, it is not a mutation in the ApoE gene that increases the risk factor; rather, it is the variety or type of ApoE gene someone inherits that affects his or her chances of developing Alzheimer's disease.

No one knows how this gene contributes to Alzheimer's disease, but it is known that inheritance of ApoE4 increases the risk and lowers the age of onset of the disease. Inheritance of ApoE2 decreases the risk and increases the age of onset. The ApoE gene seems to be a "susceptibility gene."

Researchers are attacking the problem of Alzheimer's disease by studying the basic biology of the disease and by trying to develop drugs they hope will affect those changes. Because no one knows what causes Alzheimer's disease, or how brain lesions like plaques form, or why connections between brain cells are destroyed, it is difficult to know what kind of drugs will help. Until the exact biological causes of Alzheimer's disease are identified, drug trials may be used more for research than therapy.

Many scientists are convinced that the key to understanding the disease and the best hope for an effective treatment lies in understanding beta-amyloid protein. This is the same substance Alois Alzheimer saw in plaques in the brain of his demented patient in 1906. Scientists still want to know how it is made and what its purpose is. These researchers hope one day to decrease the production of beta-amyloid protein or of the larger protein, amyloid precursor protein, from which it is derived.

After years of effort, several research groups have succeeded in producing animal models of Alzheimer's disease. By introducing genes for mutated human beta-amyloid protein into mice, they have created animals which experience brain degeneration and plaques. Tests with these animals may one day help determine the role of beta-amyloid protein in Alzheimer's disease and could help researchers find drugs for treatment.

Other scientists believe beta-amyloid protein is not the key to understanding and treating the disease. They believe accumulation of large amounts of beta-amyloid protein is a response to an as-yet undiscovered cause.

The pharmaceutical industry is developing drugs for a variety of therapeutic approaches to treating Alzheimer's disease. These include drugs that will inhibit the inflammatory response the brain appears to mount against plaques. In this approach, it is assumed that the inflammatory response contributes to cell death. By inhibiting it, the researchers hope to decrease the loss of brain cells in Alzheimer's disease. Other drug companies are continuing to develop drugs they hope will increase the amounts of neurotransmitters like acetylcholine in the brains of Alzheimer's disease patients. Acetylcholine is an important chemical messenger in the brain that is severely lowered in Alzheimer's disease. By preventing the breakdown of remaining acetylcholine, researchers hope to alleviate some of the symptoms of the disease.

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