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Alzheimer's Disease - โรคอัลไซเมอร์
WHAT IS ALZHEIMER'S DISEASE?
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.
WHO GETS 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. Almost 4 million Americans have Alzheimer's disease, and unless effective methods for prevention and treatment are developed, it will reach epidemic proportions by the middle of the next century, afflicting between 8 and 14 million people. In addition to the elderly, people at higher than average risk are those who have a family history of the disease. [ See Genetic Factors under What Causes Alzheimer's Disease.] Nearly all patients who inherit Down's syndrome develop changes in the brain that resemble Alzheimer's if they live into their 40s, although onset varies and can occur as late as age 70. Women under the age of 35, but not older mothers, who give birth to children with Down's syndrome are also at much higher risk for Alzheimer's. A number of studies suggest that women are more likely to develop Alzheimer's, while one reported that men are more likely to suffer age-related brain damage. Studies are not consistent, however. Few well-conducted studies have been conducted on differences among population groups. The disease is rare in West Africa, but African-Americans have the same risk as white Americans, possibly even a higher one. Hispanics may also have a higher risk than Caucasian Americans. Genetic factors are at work in all groups but the same genes may have different effects depending on the ethnic population. Alzheimer's disease occurs less in the Native American Crees and Cherokees and in Asians than in the general American population. A study of Japanese men, however, showed that their risk increased if they emigrated to America. Chronic high blood pressure is associated with mental deterioration in older people, including increased risks for short-term memory and attention, Alzheimer's disease, and dementia. The higher the blood pressure the greater the risk for mental impairment. (Controlling blood pressure may help ward off memory loss to begin with and treating blood pressure in older patients can reduce the risk of dementia in elderly patients with elevated systolic pressure.)
WHAT CAUSES ALZHEIMER'S DISEASE?
Biologic Factors in the Brain
Two significant abnormalities occur in brains of people affected by Alzheimer's: twisted nerve cell fibers, known as neurofibrillary tangles, and a sticky protein called beta amyloid . Other factors also play a role.
Neurofibrillary Tangles. The tangled fibers are the damaged remains of microtubules, the support structure that allows the flow of nutrients through the neurons (nerve cells). A key component in these tangled fibers is an abnormal form of a protein known as tau. Some experts believe that this defective version blocks the activity of normal tau proteins, which help in the assembly of a healthy microtubule
structure.
Beta Amyloid. The second significant finding is a high concentration of an insoluble protein known as beta amyloid (also called A beta), which is a fragment of a larger protein called amyloid precursor protein (APP). (APP itself appears to be important for nerve protection.) Peseniline proteins appear to regulate enzymes (or actually are the enzymes) involved in snipping amyloid precursor protein (APP) into fragments so that beta amyloid is formed. (Genetic abnormalities that affect these proteins occur in some inherited cases of Alzheimer's.) Beta amyloid forms sticky patches called neuritic plaques. These plaques are found outside the nerve cells surrounded by the debris of dying neurons. High levels of beta amyloid are associated with reduced levels of the neurotransmitter acetylcholine. Neurotransmitters are chemical messengers in the brain. Acetylcholine is part of the cholinergic system, which is essential for memory and learning, and which is progressively destroyed in Alzheimer's patients. Beta amyloid may also disrupt channels that carry sodium, potassium, and calcium; these elements serve the brain as ions, producing electric charges that must fire regularly in order for signals to pass from one nerve cell to another. If the channels that carry ions are damaged, an imbalance can interfere with nerve function and signal transmission.
Other Proteins. Researchers have now identified other important proteins in the areas of the brain affected by Alzheimer's disease. . E RAB (endoplasmic-reticulum associated binding protein) appears to combine with beta amyloid, which in turn attracts new beta amyloid from outside the cells. High amounts of ERAB may also enhance the nerve-destructive power of this protein partner. AMY plaques resemble beta amyloid so closely that researchers were able to detect them only with the use of highly sophisticated techniques. Elevated levels of a protein called prostate apoptosis response-4 (Par-4) may cause nerve cells to self-destruct.
Other Neurotransmitters. Although studies have emphasized acetylcholine, other neurotransmitters, including serotonin and norepinephrine levels, are also affected in Alzheimer's disease.
Inflammatory Response
Some researchers think that beta amyloid may break into fragments that release oxygen-free radicals. These are unstable chemicals in the body that, through a process called oxidation, bind to other molecules and cause damage by affecting DNA and triggering other harmful processes. Oxidation is known to play a role in many serious diseases, including coronary artery disease and cancers, and experts believe it may also contribute to Alzheimer's. One of its effects is the so-called inflammatory response, in which the immune system overproduces factors normally intended to fight harmful agents, but in excess, they can actually injure the body's own cells. Of specific interest is cyclooxygenase (COX), which produces prostaglandins, substances important in the inflammatory response and which, in Alzheimer's, may increase levels of glutamate, an amino acid that is a powerful nerve-cell killer.
Genetic Factors
Genetic Factors for Late-Onset Alzheimer's. The major target in genetic research on late-onset Alzheimer's disease has been apolipoprotein E (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 major types: ApoE2, ApoE3, and ApoE4. People inherit a copy of one type from each parent. Studies have reported greatest deposits of beta amyloid in people with ApoE4, fewer in ApoE3, and lowest in those with ApoE2. Some research indicates that ApoE3 and ApoE4 may induce changes in beta amyloid that trigger an inflammatory response in the brain. ApoE2 appears, on the other hand, to have protective qualities. It should be noted that although the ApoE4 gene increases susceptibility to Alzheimer's, it does not appear to regulate the disease process itself.
Alzheimer's disease is not inevitable even in people with two copies of the ApoE4 gene. Reports vary widely in estimating the extent of risk. In people without ApoE4, estimates for the risk of developing Alzheimer's by age 85 range from 9% to 20%; in those with one copy of the gene, the risk is between 25% and 60%; in people with two copies, the risk ranges from 50% to 90%. Only 2% of the population carry two copies of the ApoE4 gene. Some research indicates that a specific variation of the ApoE4 gene may be the primary culprit in the development of Alzheimer's, which would explain why many people with ApoE4 exhibit no signs of Alzheimer's. A number of studies also indicate that ApoE4 gene occurs in about 20% of cases of vascular dementia, which is dementia caused by blockage in blood vessels to the brain. ApoE4 has been studied for years as a risk factor for coronary artery disease, but the relationship between the genetic type, heart disease, and Alzheimer's is inconclusive. Some studies have found a higher risk for heart disease in people with Alzheimer's disease who also carry two copies of the ApoE4 genotype.
Most people with Alzheimer's disease, however, do not carry the ApoE4 gene. Increasingly, researchers believe that many cases of late-onset Alzheimer's disease are a result of a collaboration of genetic factors that participate in the process of producing or degrading beta amyloid. Another apolipoprotein called Apo(a) may be involved in amplifying the effects of ApoE4. Other research has identified genetic abnormalities in the mitochondria (the source of energy within cells) in about 20% of people with late-onset Alzheimer's; such defects are passed only from mother, not father, to child. Researchers have detected mutations in proteins called beta amyloid precursor protein (BAPP) and ubiquitin-B (Ubi-B), which may account for some cases of late- and early-onset Alzheimer's. Such mutations are not inherited, but appear to be genetic mistakes that occur during transcription, the coding process in which DNA establishes the pattern for the production of proteins and other molecules.
Genetic Factors for Early-Onset Alzheimer's. Scientists are coming closer to identifying defective genes responsible for early-onset Alzheimer's, an uncommon, but extremely aggressive form of the disease. Research has found that mutations in genes known as presenilin-1 (PS1) and presenelin-2 (PS2) account for most cases of early onset inherited Alzheimer's disease. The defective genes appear to cause Alzheimer's by accelerating beta amyloid plaque formation and apoptosis, a natural process by which cells self-destruct. People with Down's syndrome, who almost always develop Alzheimer's, overproduce beta-amyloid precursor protein (APP), which, in turn, manufactures beta amyloid.
Environmental and Other Factors
Genetics factors play a major role but do not offer a complete answer to the development of Alzheimer's. Other factors, then, are involved with nerve destruction in many of these patients.
Virus and Bacteria. Because a slow, infectious virus causes a number of other degenerative neurologic diseases, such as kuru and Creutzfeldt-Jakob disease, researchers are exploring the viral route as one possible cause of Alzheimer's disease. No evidence exists that Alzheimer's is transmittable, but a possible scenario is a genetic susceptibility coupled with a breakdown of the immunologic system that leaves a person vulnerable to a virus. One study has indicated that herpesvirus 1 may provide this link. The study's results found that the risk for Alzheimer's was very high in people with both ApoE4 and evidence of this virus, but risk was normal in those with only one of these factors. Another study detected Chlamydia pneumoniae , a bacterium that causes respiratory infections in parts of the brain affected by late-onset Alzheimer's, but not in unaffected parts. The presence of the bacterium may have been the result of Alzheimer's disease rather than its cause, but the finding warrants more research.
Metals. Some laboratory studies have associated the formation of amyloid plaques with excessive amounts of metal ions such as zinc, copper, aluminum, and iron. Such ions may also change the chemical architecture of beta amyloid making it more harmful. A mildly acidic environment appears to be important in the process that binds these metals to beta amyloid. Experts observe that such conditions (acidic environment and higher levels of zinc and copper) commonly occur as part of the inflammatory response to local injury.
Electromagnetic Fields. Some, but not all, studies on people exposed to intense electromagnetic fields have reported a higher incidence of Alzheimer's. Some researchers believe that magnetic fields may interfere with the concentration of calcium inside cells, and others believe that they may increase production of beta amyloid.
Head Injury. Injury to the head can accelerate the development of Alzheimer's in people who are already susceptible to it.
Childhood Malnutrition and Vitamin Deficiencies. According to one study, poor nutrition in childhood may render the brain more susceptible to mental impairments later in life, including Alzheimer's disease. Other recent studies suggest an elevated homocysteine level may be a risk factor for Alzheimer's. Homocysteine is a substance in the blood that increases with deficiencies of vitamins B12 and folate. No evidence exists that supplements of these vitamins offer any protection against Alzheimer's disease.
The Alzheimers-Reversing Breakthrough
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HOW CAN ALZHEIMER'S DISEASE BE PREVENTED?
There have been no proven methods for preventing Alzheimer's disease since the cause of it is still unknown. Still, certain factors are showing some evidence of reducing risk.
Male and Female Hormones
Estrogen. Estrogen, the primary female hormone, appears to have properties that protect against the memory loss and lower mental functioning associated with normal aging. A number of studies have reported that women taking hormone replacement therapy (in various combinations and even for brief periods) score better on verbal memory than women not on HRT. However, one study of young women who had hysterectomies found no association between estrogen levels and mental functioning. Another on older women found no association between differing levels of natural estrogen and better or worse mental functioning, and an analysis of major studies reported that the largest and more rigorously-conducted one found no benefits from estrogen supplements on mental functioning in healthy postmenopausal women.
Studies continue to report, however, an association between estrogen replacement therapy and protection against both Alzheimer's and dementia in Parkinson's disease. Five studies suggested a 40% to 60% reduction in the risk of Alzheimer's in women who have taken supplemental hormones. In addition, estrogen may enhance the benefits of such drugs, including Tacrine, which are used to treat Alzheimer's, but these data are preliminary. Recent laboratory studies suggested that estrogen may help ward off Alzheimer's by blocking the production of the beta-amyloid peptides, which are the primary culprit in causing this disease. Estrogen may also trigger the temporary growth of nerve pathways in the memory portion of the brain and stimulate production of the neurotransmitters acetylcholine and serotonin, which are depleted in Alzheimer's patients. And because estrogen may reduce the risk of atherosclerosis (the build-up of plaque in blood vessels), some doctors hypothesize that it may improve blood flow to the brain. While taking estrogen may prove to reduce the risk of Alzheimer's, its use for this purpose is still unproven, and women should not choose hormone replacement therapy solely to prevent Alzheimer's disease.
Testosterone. One small study suggested testosterone might be helpful in reducing levels of beta amyloid. More research is warranted to determine if testosterone supplements may be protective in elderly men.
Nonsteroidal Anti-Inflammatory Drugs
Common nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen (Advil, Motrin), and naprosyn, have properties that block specific factors in the inflammatory response believed to play a major role in nerve-cell degeneration. A long-term study found that people who took ibuprofen for two years or more had a 50% reduction in the incidence of Alzheimer's compared to those who did not take the drug. In the same study, long-term use of aspirin appeared to confer no benefit, perhaps because the dose was often very low. Long-term use of NSAIDs can cause bleeding and ulcers in the gastrointestinal tract. Combinations of NSAIDS and gastro-protective agents, such as diclofenac and misoprostol (Arthrotec), may reduce this risk considerably. Still, NSAIDS are not necessarily appropriate for all patients and should not be taken without the recommendation of a physician. Newer NSAIDs called COX-2 inhibitors (Vioxx, Celebrex) may have nerve-protecting properties without as severe side effects, but long-term studies are needed to determine this. Acetaminophen (Tylenol) is not an anti-inflammatory drug and has no effect on this disease.
Statin Drugs. Of considerable interest was a preliminary 1999 study that reported a significantly lower risk (63% to 73%) for Alzheimer's disease in people who were taking cholesterol lowering drugs known as statins. The statins noted in the study were lovastatin (Mevacor) and pravastatin (Pravachol).More Studies are needed.
Diet
Fats and Oils. A preliminary analysis of dietary habits in eleven countries suggests that a low-fat diet might reduce the risk of Alzheimer's. In countries with low-fat diets, such as China and Nigeria, the risk of developing Alzheimer's is 1% at age 65 compared to 5% in the US. A study in the Netherlands reported an association between dementia and diets high in total fat, saturated fat, and cholesterol. Saturated fats (found in animal products) and trans-fatty acids (found in fast foods and commercial baked goods) should be avoided. Some fats, however, such as omega-3 fatty acids, which are found in fish such as salmon, halibut, swordfish, and tuna are essential for the development of the nervous system. These fatty acids also may help protect against mental decline in old age. Some reports have suggested that certain dietary antioxidants, such as vitamin C, E, and selenium may be protective against mental decline.
Antioxidant-Rich Supplements and Foods. Much research on Alzheimer's disease has indicated that oxygen-free radicals may play an important role in the disease process. These particles are released during normal chemical processes and after injuries and can cause great dramage. Vitamin E is an important antioxidant and is of particular interest. Most foods are not rich in this vitamin, but it can be obtained in vegetable oils (particularly wheat germ oil), sweet potatoes, avocados, nuts, sunflower seeds, and soy beans. According to several studies, eating plenty of darkly-colored fruits and vegetables may slow brain aging; they are recommended in any case for good health. In a 1999 study on animals, extracts taken from blueberries and strawberries actually reversed age-related decline in brain function. Blueberries were the most effective. Such foods are rich in antioxidants. Red wine, which also contains powerful antioxidants, has also been associated with a lower risk for Alzheimer's.
Calorie Restriction. Caloric intake itself may play a role in brain health. In one study on animals, restricting calories below normal (but above starvation levels) helped prevent age-related nerve degeneration. It should be pointed out, however, that in patients with existing Alzheimer's, weight loss is a strong indicator of mental decline.
Continuing Education and Mental Acuity
A number of studies have reported a higher risk for Alzheimer's disease in people with less education and a lower risk for dementia and Alzheimer's in those who remain mentally active. A few experts speculate that learning itself stimulates more neurons to grow and thus may create a larger reserve in the brain so that it takes longer for brain cells to be destroyed. Others believe that socioeconomic forces, such as diet and environmental toxins, may make less educated people more susceptible to Alzheimer's. A 2000 study found no differences in educational levels between patients with Alzheimer's and those without dementia. An ongoing study of nuns also found no association between education and Alzheimer's, but did find a high risk for Alzheimer's among those whose youthful writings showed a paucity of ideas and a low risk in those whose writings were idea-rich. Some experts postulate that this study offers evidence that Alzheimer's is lifelong, beginning at a young age and that continuing education is not protective. This study was very small, however, and when cases outside the study were assessed using the same criteria, the same results did not occur. In any case, staying mentally active and interested in life is always good advice.
The Alzheimers-Reversing Breakthrough
A Groundbreaking Scientifically Proven Method For Curing Alzheimers
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