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 2 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 over 8 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). As an extreme example, nearly all patients who inherit Down's syndrome develop Alzheimer's if they live into their 40s. 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, and more research is needed to determine whether women are more susceptible to Alzheimer's. The disease is rare in West Africa, but African-Americans have four times the risk as white Americans; Hispanics have over twice the risk as whites. 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 reduced short-term memory and attention, Alzheimer's disease, and dementia. The higher the blood pressure the greater the risk for mental impairment. Studies indicate, however, that 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 mutated form of a protein known as tau is found in these tangles. 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 plaques (sticky patches) of a protein known as beta amyloid, which forms patches called neuritic plaques. These plaques are found outside the nerve cells surrounded by the debris of dying neurons. Beta amyloid (also called A beta) is actually a chip from a larger protein called amyloid precursor protein (App), which is under heavy investigation. 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; they include ERAB (endoplasmic-reticulum associated binding protein) and AMY (AMY117) plaques. ERAB appears to combine with beta amyloid, which in turn attracts new beta amyloid from outside the cells. High amounts of ERAB also may also enhance the nerve-destructive power of this protein partner. AMY plaques resemble beta amyloid so closely that only with the use of highly sophisticated techniques were researchers able to detect them. Researchers have also found elevated levels of a protein called prostate apoptosis response-4 (par-4) protein in the brains of patients with Alzheimer's disease. 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.
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 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. Alzheimer's disease is not inevitable, however, 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%; and 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, and some studies have found a higher risk for atherosclerosis 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. 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 such 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. 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, which may contribute to 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 antidiarrheal medications. Abnormal zinc metabolism has also been found in Alzheimer's patients.
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.
How Can Alzheimer's Disease Be prevented
Increasingly, studies are reporting that estrogen may protect against Alzheimer's disease. A number of studies have reported that women taking hormone replacement therapy (in various combinations) score better on memory and learning than women not on HRT and have slower decline in mental functioning. Two studies found that women who took HRT had a reduced risk for Alzheimer's disease -- in one the risk was lower by 60%. Estrogen therapy may even help women with existing Alzheimer's disease; one study found that women with mild to moderate Alzheimer's showed improved mental functioning after taking estrogen, and another reported less evidence of Alzheimer's in brains of women taking estrogen than those not taking it. These reports are backed up by studies indicating that estrogen stimulates blood flow in the brain, increases production of a beneficial form of beta amyloid, and triggers the temporary growth of nerve pathways in the memory portion of the brain.
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 have dangerous effects on the gastrointestinal tract and should not be taken without the recommendation of a physician. Acetaminophen (Tylenol) is not an anti-inflammatory drug and has no effect on this disease.
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 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. Vitamin E 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 a new study, eating plenty of fruits and vegetables may slow brain aging; they are recommended in any case for good health. Such foods also tend to be lower in calories -- which may be another protective feature. In another 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. An ongoing study of nuns 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.
What Are the Symptoms of Alzheimer's Disease
The early symptoms of Alzheimer's disease may be overlooked because they resemble signs of natural aging. These symptoms include forgetfulness, loss of concentration, unexplained weight loss, and motor problems, including mild difficulties in walking. In healthy individuals, similar symptoms can result from fatigue, grief or depression, illness, vision or hearing loss, the use of alcohol or certain medications, or simply the burden of too many details to remember at once. But when memory loss worsens, family and friends perceive that more serious problems exist (see Table, Differences between Normal Signs of Aging and Dementia, below). One clue to differentiating Alzheimer's from normal aging may be the patient's inability to understand the meaning of words. Accompanying sensory problems, such as hearing loss and a decline in reading ability, as well as general physical debility in newly diagnosed Alzheimer's patients indicate shorter survival time. A number of other disorders may be causing these extreme symptoms and must be ruled out before a diagnosis of Alzheimer's disease can be certain (see How Is Alzheimer's Disease Diagnosed, below). About 20% of suspected Alzheimer's cases turn out to be some other disorder, half of which are potentially treatable or controllable. Strictly speaking, a definitive diagnosis of Alzheimer's can only be made at autopsy after death.
Early Signs of Alzheimer's
|Memory And Concentration||Memory And Concentration|
|periodic minor memory lapses or forgetfulness of part of an experience.
Occasional lapses in attention or lapses in attention or concentration.
|Misplacement of important items.
Confusion about how to perform simple tasks.
Trouble with simple arithmetic problems.
Difficulty making routine decisions.
Confusion about month or season.
|Mood And Behavior||Mood And Behavior|
|Temporary sadness or anxiety based on appropriate and specific cause.
Increasingly cautious behavior.
|Unpredictable mood changes.
Increasing loss of outside interests.
Depression, anger, or confusion in response to change.
Denial of symptoms.
Later Signs of Alzheimer's Disease
|Language And Speech||Language And Speech|
|Unimpaired language skills.||Difficulty completing sentences or finding the right words.
Reduced and/or irrelevant conversation.
|Movement/ Coordination||Movement/ Coordination|
|Increasing caution in movement.
Slower reaction times.
|Visibly impaired movement or coordination, including slowing of movements, halting gait, and reduced sense of balance.|
Source: Alzheimer's Disease: Early Warning Signs and Diagnostic Resources. The Junior League of NYC, Inc., 1988.
Diagnosing Alzheimer's Disease
Ruling Out Other Causes Memory Loss or Dementia. A definitive test to diagnose Alzheimer's disease even in patients showing signs of dementia has not yet been devised, so the first step is to rule out other conditions that might be causing memory loss or dementia. Some elderly people have a condition called mild cognitive impairment, which involves more severe memory loss than normal but no other symptoms of Alzheimer's. There are two major causes for dementia in the elderly: Alzheimer's disease and vascular dementia (abnormalities in the vessels that carry blood to the brain). Experts currently believe that 60% of cases of dementia are due to Alzheimer's, 15% to vascular injuries, and the rest are a mixture of the two. Vascular dementia is primarily caused by multiple small strokes (called multi-infarct dementia) or Binswanger's disease, which affects tiny arteries in the midbrain. In general, dementia, whether caused of Alzheimer's or stroke, is rarely reversible. parkinson's disease may also cause dementia. Other disorders that cause reversible delirium, which might account for symptoms of dementia, include severe depression, drug abuse, or certain medications. Less common conditions that cause dementia or delirium are thyroid disease, severe vitamin B12 deficiency, blood clots, hydrocephalus (excessive accumulation of spinal fluid in the brain), syphilis, Huntington's disease, Creutzfeldt-Jakob disease, and brain tumors. It is important that the physician recognize any treatable conditions that might be causing symptoms or worsening existing dementia caused by Alzheimer's or vascular abnormalities.
psychological Testing. The physician will administer a number of standard psychological tests to assess difficulties in attention, perception, memory, and problem-solving, social, and language skills.
Electroencephalography. Electroencephalography (EEG) traces brain-wave activity; in some Alzheimer's patients this test reveals "slow waves". Although other diseases may evidence similar abnormalities, EEG data helps distinguish a potential Alzheimer's patient from a severely depressed person, whose brain waves are normal.
Imaging Tests. Computerized tomography (CT) or magnetic resonance imaging (MRI) scans can detect the presence of multi-infarct dementia, stroke, blood clots, tumors, or hydrocephalus. Vascular dementia is more likely if the onset of dementia was abrupt and if the physician finds signs that abnormalities exist in specific locations in the brain. MRI and pET (positron emission tomography) scans and other advanced imaging techniques may eventually be able to diagnosis Alzheimer's be identifying changes in the brain or predict severity of existing disease.
Blood Test for ApoE4. A blood test for the ApoE4 gene may be useful for confirming a diagnosis in patients who have symptoms and other indications of Alzheimer's, although finding evidence of ApoE4 is still not definitive. Other blood tests may also rule out metabolic abnormalities.
Determining Severity of Existing Alzheimer's Disease
Once a diagnosis has been made, some experts observe that certain factors at the time of diagnosis indicate a higher risk for a more rapid decline: older age; being male; high blood pressure; signs of loss of motor control and coordination; tremor; social withdrawal; loss of appetite; and problems walking.
What Are the Latest Drug Treatments for Alzheimer's Disease
Most drugs currently being used to treat Alzheimer's or are under investigation are aimed at slowing progression; there is no cure. In fact, the improvements from some of these drugs that are considered significant in studies may not even be noticed by the patients or their families, but they may delay the need for admission to nursing homes. Since nearly all the studies are conducted on Alzheimer's patients in mild to moderate stages of the disease, it is important to seek out clinical drug trials as soon as Alzheimer's disease is diagnosed. Caregivers need to be available to help patients comply with any experimental therapies.
Drugs That protect the Cholinergic System
Tacrine (THA or Cognex) and donepezil (Aricept) are designed to increase the amount of acetylcholine in the brain. Both drugs have modest benefits; patients taking either drug usually show improvement in functioning and behavior. One study found that tacrine had no effect on women who carried the ApoE4 gene (although it did help those who carried the ApoE2 or ApoE3 type). In the same study, the addition of estrogen therapy enhanced tacrine's benefits. Typical side effects of both drugs include nausea and diarrhea. Donepezil appears to be better tolerated than tacrine, however, and may be more effective in improving mental functioning and for more people than tacrine. It also does not seem to be as harmful to the liver as tacrine, which has been found to have severe effects in high doses. Discontinuing the drug reverses liver problems. Tacrine needs to be taken four times a day, but donepezil only needs to be taken once a day. The benefits of these and other drugs that protect the cholinergic system are far from dramatic, however; about half of patients with mild to moderate disease show slight improvement, and when they go off the drugs the deterioration continues.
Other cholinergic protective drugs showing promise in trials include rivastigmine (Exelon), metrifonate, and physostigmine (Synapton). In one 1998 study, rivastigmine improved performance on a standard scoring system for Alzheimer's patients by nearly five points -- which were the best results at that time of any similar drug. Improvement was seen even in patients with advanced disease Metrifonate is a long-acting drug and in trials has improved mental functioning and behavior. None of these newer drugs have the harmful effects on the liver that tacrine has. Many experts have reservations about drugs that affect the cholinergic system, because such drugs, at best, only slow progression but will never cure the disease.
Because the inflammatory process may play a role in Alzheimer's, a number of anti-inflammatory drugs are being studied. Nonsteroidal anti-inflammatory drugs (NSAIDs), which include aspirin and ibuprofen, are under intense scrutiny. Corticosteroids are the most often-prescribed anti-inflammatory drugs, but long-term use may actually cause memory loss and they do not appear to effect prostaglandins, substances that appear to be factors in the development of Alzheimer's and which are targets of NSAIDs. Other anti-inflammatory agents being considered include corticotropin releasing factor (CRF), thalidomide, and tenidap.
Estrogen and Other Hormones
Estrogen replacement therapy appears to slow progression and even prevent Alzheimer's disease, causing interest in possible other hormone therapies (see How Can Alzheimer's Be prevented, above).
One study found that two daily doses of vitamin E (1000 IU each dose) or of selegiline (5 mg each) delayed the progression of the disease or its symptoms. These two agents appeared to provide equal benefits, but combining them did not add any advantage.
vitamin E. High doses of vitamin E can cause nausea and cramping, and may increase the risk for bleeding in patients with coagulation abnormali
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