What Is Alzheimer's Disease?
    About half of the people in nursing homes and almost half of all people over 85 have Alzheimer's disease. It is now the fourth leading cause of death in adults and, unless effective methods for prevention and treatment are developed, Alzheimer's will reach epidemic proportions by the middle of the next century. Alzheimer's disease is a degenerative disease of the brain from which there is no recovery. Slowly and inexorably, the disease attacks nerve cells in all parts of the cortex of the brain, as well as some surrounding structures, thereby impairing a person's abilities to govern emotions, recognize errors and patterns, coordinate movement, and remember. At the last, an afflicted person loses all memory and mental functioning. Two significant abnormalities have been observed in brains of people who have died of Alzheimer's. Twisted nerve cell fibers, known as neurofibrillary tangles, are found inside the nerve cells, or  neurons. These tangled fibers are the damaged remains of microtubules, the support structure that allow the flow of nutrients through the neurons. A mutated form of the protein known as tau is found in these tangles, and some experts believe that this defective version attracts and holds normal  tau proteins that ordinarily help in the assembly of a healthy microtubule structure. Glycosaminoglycans, which include the anti-blood clotting factor heparin, may be important companions of tau in the development of these tangled nerve fibers. The second significant finding is a high concentration of patches called neuritic plaques located outside the nerve cells; surrounding these plaques are the debris of dying neurons. The plaques are composed of a long form of a sticky protein known as beta amyloid. Beta amyloid itself is a chip from a larger protein called amyloid precursor protein (PA).  Some researchers think that beta amyloid may break into fragments that release oxygen-free radicals * normal chemicals in the body that cause many damaging processes when they are overproduced. In the brain, excess amounts of free radicals leads to the breakdown of the membrane in the nerve cells. Some work indicates that beta amyloid may cause narrowing of blood vessels in the brain, thereby cutting off the blood supply and killing nerve cells. Beta amyloid is also associated with reduced levels of acetylcholine, a neurotransmitter. (Neurotransmitters are chemicals that stimulate nerve cells to fire electric signals that pass messages to and from the brain.) Acetylcholine is part of the cholinergic system, essential to memory and learning, which is progressively destroyed in Alzheimer's patients.
    Tangled fibers, plaques, or both are found in nearly everyone over 90, in some otherwise normal middle-aged and older people, and in the brain tissue of people suffering from other conditions. In Alzheimer's patients, however, plaques are in very concentrated forms and their presence seems to be related to a depletion of the neurotransmitter acetylcholine.
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What Causes Alzheimer's Disease?
Genetic Factors and Beta Amyloid
    The major target for research on genetic factors has been the apolipoprotein ApoE4, a subtype of ApoE, which plays a role in the movement and distribution of cholesterol for repairing nerve cells during development and after injury. The gene for ApoE comes in three possible types: ApoE2, ApoE3, and ApoE4; people inherit a copy of one type from each parent. ApoE4 has been studied for years as a risk factor for coronary artery disease, and, in fact, a recent study found a link between atherosclerosis, dementia and Alzheimer's disease, and ApoE4. It has been thought to play a major role in late-onset Alzheimer's, but recent studies indicate it is only a risk factor for Alzheimer's that develops before age 70 in people who carry two copies of the gene. ApoE2 appears to have protective qualities, helping to maintain the structure of tiny tubes that carry nutrients to and waste away from brain cells. In the presence of ApoE4, however, the tubes may weaken and become less efficient carriers of waste and nutrients to the brain cells, causing them to break down. Deposits of beta amyloid are highest in people with ApoE4, next highest in E3, and lowest in those with E2. Imaging techniques using positron-emission tomography (PET) scans have found reduced activity in specific areas in the brains of people with the double-ApoE4 gene. This test does not predict who will develop Alzheimer's, however, since abnormalities can be present without symptoms. People can even have dense deposits of beta amyloid and still not exhibit signs of Alzheimer's.
    The disease is not inevitable even in people with two copies of the ApoE4 gene. Reports vary in estimating the risk for those with E4. In people without E4, the risk for developing Alzheimer's by age 85 ranges from 9% to 20%, in those with one copy of the gene, the risk is between 25% and 60%, and in people with two copies, the risk ranges from 50% to 90% (only 2% of the population carry two copies of the E4 gene). Not everyone who has late-onset Alzheimer's disease has the E4 gene, and many people with E4 exhibit no signs of Alzheimer's. Alzheimer's patients who carry a copy of the E4 gene appear to develop dementia at an earlier age than those with the E3 gene; individuals with the E3 gene seem to develop the disease at a younger age than those with the E2 gene. How fast the disease  progresses, however, does not seem to be related to the presence of the  E4 gene.
    Researchers have identified a number of other defective genes responsible for early-onset Alzheimer's, an uncommon but extremely aggressive form of the disease; they are presinilin-1 (PS1), presinilin-2 (PS2), and amyloid precursor protein (PA). Recent research has suggested that the mutated presinilin gene may enhance apoptosis, a process that governs cell death, in nerve cells. PS1 accounts or 80% of early-onset Alzheimer's and is associated with increased amounts of beta amyloid, and some researchers believe that this mutation may turn out to be common for all genetic forms of Alzheimer's disease. Nearly all patients who inherit Down's syndrome develop Alzheimer's if they live into their 40s. Women under the age of 35 who give birth to children with Down's syndrome are also at much higher risk for Alzheimer's, although mothers older than 35 who deliver children with this syndrome are not.
    Genetics factors play a major role but do not offer a complete answer to the development of Alzheimer's. Environmental factors also appear to have an effect.
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Environmental Factors
    Environmental and other nongenetic causes appear to contribute to Alzheimer's disease. Alzheimer's disease is rare in West Africa, for instance, but American descendants of West Africans have as high a rate of Alzheimer's as other Americans. Alzheimer's disease also occurs less in the Native American Crees and Cherokees and in people from China or Japan.  A study of Japanese men, however, showed that those who emigrated to the U.S. experienced an increased rate of Alzheimer's.)
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Virus
    Because a number of other degenerative neurologic diseases, such as kuru and Creutzfeldt-Jakob disease, are caused by a slow, infectious virus, researchers are exploring the viral route as a possible cause of Alzheimer's disease. No evidence exists that Alzheimer's is transmissible, but a possible scenario is a genetic susceptibility coupled with a breakdown of the immunologic system that leaves a person vulnerable to such a virus. One study has indicated that herpesvirus 1 may provide this link; its results found  that the risk for Alzheimer's is very high in people with ApoE4 who also have evidence of this virus, but risk is normal in those with only one of these factors.
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Metals
    In spite of some early concern that aluminum may have some role in
 Alzheimer's, studies have found no relationship between the development of Alzheimer's and exposure to aluminum in cooking, occupational work, or drinking water. Alzheimer's does create a condition that results in aluminum ions replacing iron ions and accumulating in cells, therefore possibly contributing to already existing dementia. Some researchers believe that excessive amounts of zinc may promote formation of amyloid plaques. In one experiment, this process was accelerated when zinc was combined with aluminum silicate, a substance found in non-dairy creamers and nonprescription antidiarrhea medications. Abnormal zinc metabolism has also been found in Alzheimer's patients.
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Electromagnetic Fields
    Some studies have reported a higher incidence of Alzheimer's in people exposed to intense electromagnetic fields. Some researchers believe that magnetic fields may interfere with the concentration of calcium inside cells, and others believe that they may increased production of beta amyloid.
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Inflammatory Response
    Some researchers are directing their attention to the inflammatory response, a process which normally activates the immune system to attack infections and other microscopic invaders. In some cases, however, the process goes awry and the immune system attacks the body's own tissue * in the case of Alzheimer's, possibly its own brain tissue.
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Gender
    A recent study suggests that Alzheimer's disease risk factors may be different in women and men. The women at greatest risk were those who  had a copy of ApoE4, a history of high blood pressure, a low level of  education, and no estrogen replacement therapy.
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Head Injury
    Injury to the head can accelerate the development of Alzheimer's in people who are already susceptible to it.
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Atherosclerosis
    A recent study found a link between atherosclerosis, or hardening of the arteries, and Alzheimer's, particularly in people who carry the ApoE4 gene.
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