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
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.
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. 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.
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.
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.
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.
HOW IS ALZHEIMER'S DISEASE DIAGNOSED?
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 now three known major causes for dementia in the elderly: Alzheimer's disease, vascular dementia (abnormalities in the vessels that carry blood to the brain), and Lewy bodies variant (LBV), also called dementia with Lewy bodies. As yet, it is very difficult to differentiate among these dementias. LBV was defined in 1997 and is now believed to be responsible for about 20% of people who have been diagnosed with Alzheimer's. It is often hard to distinguish these neurologic disorders. One analysis of a number of studies suggested that patients with vascular dementia had better long term verbal memory than Alzheimer's patients but poorer executive function (less ability to integrate and organize). 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 by Alzheimer's or stroke, is rarely reversible. LBV may cause more mental disturbances related to visual processing but less memory impairment than Alzheimer's. For example, in one study, patients with LBV performed worse than Alzheimer's patients on "design" tasks, such as arranging pictures or assembling objects, but they did better with word recall and tests that scored verbal memory.
Parkinson's disease is a common neurologic disease in the elderly and 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. A number of psychologic tests are used or being developed to assess difficulties in attention, perception, memory, and problem-solving, social, and language skills. Two commonly used tests that are very useful are the Mini-Mental State Exam and the Mattis Dementia Rating Scale. One small study reported that a so-called ten-point clock test might help identify Alzheimer's patients. The patient is given a piece of paper with a circle on it and first asked to write the numbers in the face of a clock and then to show "10 minutes after 11." The score is based on spacing between the numbers and the positions of the hands. In the study, scoring 8 or less identified 71% of Alzheimer's patients and correctly ruled out 82% of subjects without the disease.
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 by identifying changing blood flow patterns 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 or that are under investigation to treat Alzheimer's 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
Drugs have been designed to increase the amount of acetylcholine in the brain. Tacrine (THA or Cognex) was the first of these drugs; donepezil (Aricept) is a more recently approved one. Both drugs have modest benefits; patients taking either drug usually show improvement in functioning and behavior. Tacrine appears to have no effect on patients who carry the ApoE4 gene; the presence of the gene does not affect donepezil. 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. In fact, tacrine's effect on the liver coupled with its few benefits makes it unlikely to continue to be used very much.
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 that only needs to be taken once a day; in trials it has improved mental functioning and behavior. None of these newer drugs have the harmful effects on the liver that tacrine has. One study on physostigmine also reported some improvement or slowing of progression in mental decline but drop-rates were high because of severe stomach and intestinal side effects. Many experts have reservations about developing more 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 d is being studied as a treatment for the disorder, but A 2000 study reported that it had no effect on progress or symptoms of the disease in 120 women with mild to moderate Alzheimer's disease. [ See How Can Alzheimer's Be Prevented? above.] Results to date are mixed on its effectiveness.
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 abnormalities or who are taking blood-thinning drugs.
Selegiline. Selegiline, also called deprenyl (Eldepryl), is a selective monoamine oxidase B (MAO-B) inhibitor, a class of drugs that can cause a number of side effects including a sudden drop in blood pressure upon standing, drowsiness, dizziness, sexual dysfunction, and insomnia. The most serious side effect is severe hypertension, which can be brought on by eating certain foods having a high tyramine content. Such foods include aged cheeses, most red wines, sauerkraut, vermouth, chicken livers, dried meats and fish, canned figs, fava beans, and concentrated yeast products. MAOIs can have serious interactions with a number of drugs, including some common antidepressants and over-the-counter cough medication and decongestants.
Ginkgo Biloba. Ginkgo biloba is a common herb that has antioxidant properties and appears to increase blood flow to the brain. New studies have suggested that ginkgo biloba may slightly improve the memory of Alzheimer's patients, although it is not clear if the improvement is significant. Small studies have indicated that the effects in the brain of a dried-leaf ginkgo extract manufactured in Germany (where standards have been established) were comparable to those of tacrine and donepezil and that gingko has only minimal side effects. The herb is available over the counter, but there are no standards in the US to regulate its quality or effectiveness. No one should take this herb for Alzheimer's disease without consulting a physician; there is a small risk for bleeding, which may increase in combination with other medications, such as warfarin or high-doses of vitamin E.
Investigative Agents and Procedures
Nerve-Growth Factors. Nerve growth factors are agents under investigation. One, AIT-082, is showing promise in early trials.
Nicotine. Nicotine acts on receptors in the cholinergic system in the brain that are depleted by the Alzheimer's disease process. Some studies have suggested that nicotine may protect nerve cells and help prevent the formation of beta amyloid. Nicotine itself, unlike smoking, does not appear to cause cancer. In a 1999 study, patients with mild to moderate Alzheimer's experienced improved attention after four weeks on the nicotine patch, although it did not seem to have any effect on other aspects of the disease, including memory and behavior. Researchers are investigating a number of nicotine-like drugs that may protect nerve cells. The effects of smoking itself on Alzheimer's have been unclear. In any case, smoking is never recommended for either prevention or treatment.
Other Drugs. Propentofylline has nerve-protective properties and may enhance metabolism in the brain. The drug is showing promise in improving symptoms and slowing disease progression. Alzheimer's disease is associated with insulin resistance, a condition in which insulin, a hormone essential in the metabolism of sugar, becomes ineffective. Some research has suggested that increasing insulin levels may help improve memory. Researchers are investigating vaccines made from beta amyloid that may some day help prevent or slow progression of Alzheimer's. Researchers hope that the vaccine will produce antibodies, proteins in the blood that attack foreign matter, which would attach to beta amyloid molecules. The antibodies would alert the immune system to attack and destroy the beta amyloid molecules considered to be the building blocks of the brain deposits. This study is in its infancy and requires more investigation, but researchers believe that this vaccine will show similar benefits in Alzheimer's patients. Studies on mice are promising, but even if effective, use of such vaccines in humans is years away. In Japan, researchers are working on an extract of the guarana tree that appears to protect cells from the harmful effects of beta amyloid. There have been claims that the Chinese herbal medicine HupA helps prevent brain cell death, but no studies have confirmed this.
Transcutaneous electrical nerve stimulation (TENS) is a well-known treatment that uses low-level electrical pulses to suppress chronic pain; patients are barely aware of the sensation. Some interesting studies observed that TENS produced improvement in memory and functioning in Alzheimer's patients. An experimental surgical technique being tested on animals employs small plastic implants in the brain that release a powerful nerve growth factor that may prevent nerve-cell death.
Treating Symptoms of Alzheimer's
Depression. Major depression with dementia that occurs in elderly people may be an early sign of Alzheimer's; in such cases, it precedes Alzheimer's by two years or less. Some experts believe that disease progression may even be delayed by treating such people with both an antidepressant and a drug, such as donepezil, currently used for Alzheimer's. The antidepressants known as selective serotonin reuptake inhibitors (SSRIs) may be particularly effective in relieving depression, irritability, and restlessness associated with Alzheimer's.
Apathy. Depression is often confused with apathy, which according to one study is more common than depression in Alzheimer's patients and responds to stimulants, such as methylphenidate (Ritalin), rather than antidepressants. An apathetic patient lacks emotions, motivation, interest, and enthusiasm while a depressed patient is generally very sad, tearful, and hopeless.
Wandering, Irritability, and Aggression. Verbally or physically aggressive behavior and wandering have been traditionally treated with standard antipsychotic drugs, such as haloperidol (Haldol). Studies indicate that, although effective, haloperidol has very severe side effects that impair motor control and coordination. Newer, so-called atypical antipsychotics, including risperidone (Risperdal) and olanzapine (Zyprexa), appear to significantly decrease symptoms of psychosis and aggression while posing a very low risk for severe side effects. Carbamazepine, an anti-seizure drug, may also be effective for agitation and dementia.
Disturbed Sleep. Alzheimer's patients commonly experience disturbances in their sleep/wake cycles. Studies suggest that exposure to brighter-than-normal artificial light during the day can reset these cycles and prevent nighttime wandering and sleeplessness. This treatment is not effective for visually impaired patients. Trials on melatonin, a natural hormone that helps trigger sleep at night, are in progress.
WHAT ARE THE PHASES OF ALZHEIMER'S DISEASE AND ITS MANAGEMENT?
The remaining life span of an Alzheimer's victim is generally reduced, although a patient may live anywhere from three to twenty years after diagnosis. The final phase of the disease may last from a few months to several years, during which time the patient becomes increasingly immobile and dysfunctional. Caregivers should understand the phases of this illness in order to help determine their own capacities for dealing with this painfully sad disease.
Home Treatment in Early Stages
Telling the Patient. Often physicians will not tell patients that they have Alzheimer's. Studies indicate that progression may be slowed down with intellectual effort and most investigative drug trials are performed in early stages. If an Alzheimer's patient expresses a need to know the truth, it should be disclosed. Both the caregiver and the patient can then begin to address issues of this disabling disease that can be controlled, such as access to support groups and drug research.
Mood and Emotional Behavior. Alzheimer's patients display abrupt mood swings and can become aggressive and angry. Some of this erratic behavior is caused by chemical changes in the brain. But certainly, it can also be attributed to the terrible and real experience of losing the knowledge and understanding of one's surroundings, causing fear and frustration that they can no longer express verbally. It is important for the caregiver to control the environment by keeping distractions and noise at a minimum and to speak clearly. Most experts recommend speaking slowly to an Alzheimer's patient, but some caregivers suggest that Alzheimer's patients respond better to clear, quickly spoken sentences they can more easily remember. Being offered too many choices (such as clothing selection) or activities that are normal, but may feel threatening (people talking outside the room) can trigger agitation and aggression. Offering a distraction, such as a snack or car ride, in response to shouting or other disruptive behavior may be helpful. One study suggests that simply touching and talking may also help to relieve anxiety and aggression. Caregivers should maintain as natural an attitude as possible; many Alzheimer's patients are highly sensitive to the caregiver's underlying emotions and react negatively to signals of patronization, anger, and frustration. Although much attention is given to the negative emotions of Alzheimer's patients, some become extremely gentle, retaining an ability to laugh at themselves or appreciate simple visual jokes even after their verbal abilities have disappeared. Some appear not unhappy, but to be in a drug-like or "mystical" state focusing on the present experience as their past and future slip away. Encouraging this state may bring some comfort to a caregiver. One study found that anxiety and frustration may be relieved by watching movies or videos of family members and events from the patient's past. Alzheimer's patients may be delusional at times and must be reassured and redirected to other activities. There is no single Alzheimer's personality, just as there is no single human personality. Each patient must be treated as the individual he or she continues to be even after the social self has vanished.
Appearance and Cleanliness. For the caregiver, grooming the Alzheimer's patient may be an alienating experience. For one thing, many patients resist bathing or taking a shower. Some spouses find that showering with their afflicted mate can solve the problem for a while. Often the Alzheimer's patient loses the sense of color and design and will put on odd or mismatched clothing. This may be very frustrating to a loved one, particularly since (certainly in the beginning) embarrassment is a common and painful emotion experienced by the caregiver. It is important to maintain a sense of humor and perspective and to learn which battles are worth fighting and which ones are best abandoned.
Driving and Wandering. As soon as Alzheimer's is diagnosed, the patient should be prevented from driving. A Swedish study found that over half of elderly people involved in fatal accidents had some degree of neurologic damage. Another potentially dangerous trait is the Alzheimer's patient's tendency to wander. At the point the patient develops this tendency, many caregivers feel it is time to seek out nursing homes or other protective institutions for their loved ones. For those who remain at home, locks should be installed outside the door, which the caregiver can open, but the patient cannot. Alarms might be installed at exits. A daily exercise program should be implemented, which may help tire the patient out; one study showed that walking 30 minutes, three times a day also improved communication. A program offered by the Alzheimer's Association provides a patient with an identification bracelet with the Safe Return 800 number, clothing labels, and an ID number. Personal and medical information about the patient and critical phone numbers are stored in a central database. If a patient is discovered missing, the police should be called first. Next, the caregiver calls Safe Return and gives them the patient's ID number and any appropriate information. An alert is then sent to law enforcement agencies nationwide.
Sexuality. In many cases, the Alzheimer's patient becomes uninhibited sexually; at the same time, the patient's physical deterioration and receding capacity to recognize the spouse as a known and loved individual can make sexual activity despairing and repellent for the caregiving spouse. Other patients may lose interest in sex. If sexual issues are a problem, they should be discussed openly with the physician, and ways should be found to maintain non-sexual physical affection that can bring comfort to both the patient and the spouse.
Home Treatment During Later Stages
The Alzheimer's patient needs 24-hour a day attention. Even if the caregiver has the resources to keep the Alzheimer's patient at home during later stages of the disease, outside help is still essential.
Incontinence. An Alzheimer's patient's incontinence is generally devastating to the caregiver and a primary reason why many caregivers decide to seek nursing home placement when the patient reaches this stage. When the patient first shows signs of incontinence, the doctor should ascertain that it is not caused by an infection. Urinary incontinence may be controlled for some time by trying to monitor times of liquid intake, feeding, and urinating. Once a schedule has been established, the caregiver may be able to anticipate incontinent episodes and get the patient to the toilet before they occur.
Immobility and Pain. As the disease progresses, Alzheimer's victims become immobile, literally forgetting how to move. Eventually, they become almost entirely wheelchair-bound or bedridden. Bedsores can be a major problem. Sheets must be kept clean, dry, and free of food. The patient's skin should be washed frequently, gently blotted thoroughly dry and moisturizers applied. The patient should be moved every two hours and the feet kept raised with pillows or pads. Exercises should be administered to the legs and arms to keep them flexible. One expert reported that 62% of patients with mild to moderate dementia report pain, usually in joints, yet very few patients in late-stage dementia receive pain medication, even though there is no evidence that they are not experiencing the same pain.
Eating Problems. Weight loss and the gradual inability to swallow are two major related problems in late-stage Alzheimer's and are associated with an increased risk of death. Weight gain, however, is linked to a lower risk of dying. The patient can be fed through a feeding syringe, or the caregiver can encourage chewing action by pushing gently on the bottom of the patient's chin and on the lips. The caregiver should offer the patient foods of different consistency and flavor in case the patient can handle one form better than another. Because choking is a danger, the caregiver should learn to administer the Heimlich maneuver, which may be taught by the local Red Cross. Dehydration can also become a problem; it is essential to encourage fluid intake equal to eight glasses of water daily. It should be noted that coffee and tea are diuretics and will deplete fluid.
Care for the Caregiver
It is important for the caregivers to receive counseling and support for themselves as well. The most common difficulty reported by caregiving spouses from 15 different European countries was the loss of communication with the partner. According to one study, when caregivers took part in counseling and support programs, institutionalization of the patient was delayed by a year. Alzheimer's is a particularly devastating disease; the patient's family endures two separate losses and grieves twice; first, for the disappearance of the personality they recognize, and finally, for the actual death of the person. No one should endure such agony alone. Few diseases disrupt a patient and his or her family so completely or for so long a period of time as Alzheimer's. The disease may even have negative effects on the immune systems of the patients' partners. Dealing with the Alzheimer's patient throughout the course of the disease is like Alice's fall down the rabbit hole into Wonderland. No sooner has the caregiver grappled with one set of problems, then the patient's further deterioration creates new and more intractable ones. Often, caregivers themselves begin to show signs of mental disorder or ill health. Depression, empathy, exhaustion, guilt, and anger can play havoc with a normally healthy individual faced with the care of a loved one suffering from Alzheimer's. Often, adult children find they have to care for the healthy parent as well as the parent affected by Alzheimer's, particularly if the marriage was one in which the healthy spouse was overly dependent on the other. Many books and pamphlets seem to presume the possession of almost superhuman mental health and physical strength on the part of caregivers. This is rarely the case. The care-giving spouse is usually elderly, often frail. Children are likely to be grown-up and may live far away. Forms of abuse, including neglect, physical or emotional attacks, and financial exploitation, are common with Alzheimer's patients. Although 96% of caregivers interviewed in a survey stress the need for help, only 2% of Alzheimer's families receive outside support services.
Nursing Homes and Other Outside Services
A point comes when the most devoted caregiver will probably need to institutionalize the Alzheimer's patient. That point is determined not only by the caregiver's emotional endurance, but also by his or her physical strength and stamina, as an Alzheimer's adult typically takes on the random, undisciplined behavior of a very young child. Financial considerations in finding a nursing home are often paramount, but the kind of care is equally important. Although fully half of all nursing home patients are victims of Alzheimer's, not all nursing homes have programs specifically designed for them. Some institutions may claim that they do, but often they simply group patients together without offering any special programs. If a caregiver manages to find a facility that offers good services, it may be located far from home, making visits difficult. The caregiver must then decide whether superior care at a distant institution is worth seeing the patient less frequently, still one more painful issue. A hospice program, if it is available, offers a more humane and compassionate option than the nursing home or hospital during the final months of a terminal illness. Medicare coverage now includes hospice care for Alzheimer's patients.
Well-Connected reports are written and updated by experienced medical writers and reviewed and edited by the in-house editors and a board of physicians at Harvard Medical School and Massachusetts General Hospital. The reports are distinguished from other information sources available to patients and health care consumers by their quality, detail of information, and currency. These reports are not intended as a substitute for medical professional help or advice but are to be used only as an aid in understanding current medical knowledge. A physician should always be consulted for any health problem or medical condition. The reports may not be copied without the express permission of the publisher.
Board of Editors
Harvey Simon, MD, Editor-in-Chief, Massachusetts Institute of Technology; Physician, Massachusetts
Stephen A. Cannistra, MD, Oncology, Associate Professor of Medicine, Harvard Medical School;
irector, Gynecologic Medical Oncology, Beth Israel Deaconess Medical Center
Masha J. Etkin, MD, PhD, Gynecology, Harvard Medical School; Physician, Massachusetts
John E. Godine, MD, PhD, Metabolism, Harvard Medical School; Associate Physician, Massachusetts
Daniel Heller, MD, Pediatrics, Harvard Medical School; Associate Pediatrician, Massachusetts
General Hospital; Active Staff, Children's Hospital
Paul C. Shellito, MD, Surgery, Harvard Medical School; Associate Visiting Surgeon, Massachusetts
Theodore A. Stern, MD, Psychiatry, Harvard Medical School; Psychiatrist and Chief, Psychiatric
Consultation Service, Massachusetts General Hospital
Carol Peckham, Editorial Director
Cynthia Chevins, Publisher
Lea Kling, Update Editor