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Alzheimer's disease (AD) is a degenerative disease of the brain from which there is no recovery. The disease slowly attacks nerve cells in all parts of the cortex of the brain and some surrounding structures, thereby impairing a person's abilities to govern emotions, recognize errors and patterns, coordinate movement, and remember. Ultimately, a person with AD loses all memory and mental functioning.
The major areas of the brain have one or more specific functions.
Researchers are finding specific biologic factors involved with Alzheimer's disease. Various environmental and genetic players appear to contribute to or trigger the process by which these factors destroy nerve cells leading to this disease.
Biologic Factors in the Brain
Imaging techniques in patients with Alzheimer's disease have found significant loss of cells and volume in the regions of the brain devoted to memory and higher mental functioning. Important abnormalities have specifically been observed during biopsies:
Twisted nerve cell fibers, known as
A sticky protein called
other factor also plays a major role
The Effects of Neurofibrillary Tangles and Beta Amyloid in Alzheimer's Disease.
These biologic factors appear to be involved in the development Alzheimer's disease in the following ways:
are the damaged remains of
, 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 the
which in its healthy version helps in the assembly of the microtubule structure. The defective tau, however, appears to block the actions of the normal version.
(also called A beta) is the second significant finding. This insoluble protein accumulates and forms sticky patches called neuritic plaque, which are found surrounded by the debris of dying nerve cells in the brains of Alzheimer's victims.
Amyloid precursor protein
(APP) is a large nerve-protecting protein that is the source of beta amyloid. In Alzheimer's certain enzymes, particularly those called
snip APP into beta amyloid pieces. This process is controlled by factors called
proteins. (Genetic abnormalities that affect either APP or presenilin proteins occur in some inherited cases of early-onset Alzheimer's.)
High levels of beta amyloid are associated with reduced levels of the neurotransmitter
. (Neurotransmitters are chemical messengers in the brain.) Acetylcholine is part of the
, which is essential for memory and learning and is progressively destroyed in Alzheimer's disease.
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.
Researchers have now identified other important proteins in the areas of the brain affected by Alzheimer's disease.
ERAB (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 beta amyloid.
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.
Oxidation and the Inflammatory Response
Researchers are also attempting to discover why beta amyloid is so toxic to nerve cells. Some researchers are focusing on two processes in the body that may be involved with Alzheimer's disease:
. There is some evidence that such events can begin decades before Alzheimer's disease actually develops. One scenario for their role in Alzheimer's is as follows:
The Role of Oxidation.
As beta amyloid breaks down it releases unstable chemicals called oxygen-free radicals. Once released, oxygen-free radicals bind to other molecules through a process called
Oxidation is the result of many common chemical processes in the body, but when oxidants are overproduced, they can cause severe damage in cells and tissue, including even affecting genetic material in cells (its DNA). 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.
The Inflammatory Response.
One result of oxidation is the marshaling of immune factors to repair the cellular injuries it produces. Overproduction of some of these factors, however, produces the so-called
in which the immune process itself can actually damage the body's own cells themselves.
Principle immune cells in the brain are called macrophage/microglia (M phi). In the healthy brain, they play an important protective role against invading organisms. However, when they are activated by beta amyloid oxidation, they release toxic molecules called cytokines, which are known to cause harm. For example, significantly high levels of interleukin-6, a specific cytokine, have been detected in people with Alzheimer's.
Other inflammatory factors of specific interest in Alzheimer's research are the enzyme cyclooxygenase (COX) and its products called prostaglandins. Excess amounts of these factors may increase levels of
. Glutamate is an amino acid that excites nerves and, when overproduced, is a powerful nerve-cell killer.
The inflammatory process has also been associated with the release of soluble toxins called amyloid beta derived diffusible ligands, which some investigators believe may prove to key players in the destructive process.
Major research targets in Alzheimer's disease are the factors responsible for beta amyloid build-up and concentration in certain people and not in others. Genetic factors are believed to play a role in many cases. In 2003, the National Institute on Aging (NIA) launched the ambitious AD Genetics Initiative, a 3-year national project to bank genetic material from families who have at least two members with late-onset Alzheimer's.
The ApoE Gene and Late-Onset Alzheimer's.
The major target in genetic research on late-onset Alzheimer's disease (called LOAD) 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:
Studies have reported the greatest deposits of beta amyloid in people with ApoE4, which is now believed to be a major risk factor for late-onset Alzheimer's. Some evidence suggests that the ApoE protein removes beta amyloid but the ApoE4 variant does so less efficiently than other ApoE types. (ApoE4 has also been studied for years as a risk factor for heart disease.)
ApoE3 and ApoE2.
Fewer beta amyloid deposits have been observed in people with the ApoE3, and the fewest deposits have been observed in people with ApoE2, which may actually be protective.
People inherit a copy of one type from each parent, but 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:
People without ApoE4 have an estimated risk of between 9 - 20% for developing Alzheimer's by age 85.
In people with one copy of the gene, the risk is between 25 - 60%.
In people with two copies, the risk ranges from 50 - 90%. (Only 2% of the population carries two copies of the ApoE4 gene.)
Some researchers suspect that some specific variation of the ApoE4 gene or combinations with other genes are critical for the disease, since many people who carry the ApoE4 exhibit no signs of Alzheimer's. For example, evidence suggests that genetic factors play a role in a common subtype of late-onset Alzheimer's disease that also includes psychosis. An important 2002 genetic study has identified certain genetic linkages associated with ApoE4 that appear to play a strong role in this subtype.
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.
Mutations in genes known as presenilin-1 (PS1) and presenilin-2 (PS2) account for most cases of early-onset inherited Alzheimer's disease. The defective genes appear to accelerate beta amyloid plaque formation and
, a natural process by which cells self-destruct.
Genetic mutations in the genes that control amyloid precursor protein (APP) are also being targeted as causes of early-onset Alzheimer's. The genetic disease Down syndrome, for example, overproduces beta-amyloid precursor protein (APP), the source of beta amyloid, and almost always leads to early Alzheimer's. Other APP mutations are being identified.
Researchers are also investigating environmental factors (infections, metals, industrial and other toxins) that may trigger oxidation, inflammation, and the disease process, particularly in people with a genetic susceptibility to Alzheimer's.
Slow, infectious viruses cause a number of other degenerative neurologic diseases, such as kuru and Creutzfeldt-Jakob disease.
Alzheimer's disease is the seventh leading cause of death in Americans adults. It affects an estimated 4.5 million Americans and 8 million more people worldwide. Age is the greatest risk factor for Alzheimer's disease. The number of cases of Alzheimer's disease doubles every 5 years in people over 65. By age 85, almost half of all people are afflicted. People with the disease survive, on average, half as long as similarly aged adults without the disease.
With the increasing numbers of aging adults, unless effective methods for prevention and treatment are developed, Alzheimer's disease will reach epidemic proportions, afflicting an estimated 14 million Americans within 50 years. Evidence points to older age, high blood pressure, cholesterol levels, and a family history of the disease as the most important risk factors for Alzheimer's disease.
Gender and Estrogen Loss
Several studies have reported that women have a much higher risk for Alzheimer's disease than men. If there is a gender difference, it is likely to be due estrogen, the primary female hormone, which appears to have properties that protect against the memory loss and lower mental functioning associated with normal aging. Such actions include blocking production of beta amyloid, offering antioxidant protection, and regulating blood sugar (glucose) levels in the brain. The drop in estrogen levels after menopause may explain a higher risk for Alzheimer's disease in older women than in men. (Testosterone, the male hormone, converts to estrogen, which may help protect men.) Studies have been mixed, however, on the association between the decline in natural estrogen levels and mental functioning in older women.
Family History and Populations Differences
People with a family history of the disease are at higher than average risk for Alzheimer's disease. Researchers are identifying important genetic factors, notably the ApoE4 gene, that may be responsible for late- and early-onset cases.
Dietary and other cultural factors that increase the risk for hypertension and unhealthy cholesterol levels may also play a role. For example, a study of Japanese men showed that their risk increased if they emigrated to America. And the disease is much less common in West Africa than in African Americans, who share the same or higher risk with Caucasians Americans.
Risk Factors for Cardiovascular Disease
High blood pressure and unhealthy cholesterol levels -- the same important risk factors for heart disease and stroke -- may also be risk factors for Alzheimer's disease. In fact, they appear to be more important than ApoE4, the genetic factor most commonly associated with Alzheimer's disease.
Blood pressure is the force applied against the walls of the arteries as the heart pumps blood through the body. The pressure is determined by the force and amount of blood pumped and the size and flexibility of the arteries.
High Blood Pressure.
Studies have reported an association between Alzheimer's disease and systolic hypertension (the higher and first number in blood pressure measurement). High blood pressure can cause problems with the vascular system, which is responsible for delivering blood to the brain. Recent research suggests that some types of blood pressure medication may lower Alzheimer's risk.
High Cholesterol Levels.
Research indicates an association between high cholesterol levels and Alzheimer's disease in some people. One theory is that cholesterol regulates the processing and accumulation of amyloid beta-protein.
Click the icon to see an image of cholesterol.
Patients with diabetes often have high blood pressure, lipid imbalances, and circulatory disorders that affect the heart and vascular system. Research suggests that diabetes can also affect cognitive function and increase the risk of developing Alzheimer's disease.
High Homocysteine Levels.
Homocysteine is an amino acid that has been identified as a modest risk factor in heart disease. It has also been associated with a higher risk for Alzheimer's disease. High levels are general due to deficiencies of the B vitamins B6, B12, and folate. Such vitamins are also related to nerve protection. Researchers theorize that homocysteine impairs the ability of DNA to repair nerve cells. The weakened cells are then more vulnerable to the harmful effects of oxidized beta amyloid.
Nearly all patients who inherit Down 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 syndrome are also at much higher risk for Alzheimer's.
Although there is no strong evidence that any lifestyle change can prevent Alzheimer's disease, studies suggest that certain behaviors may help protect against mental decline. In particular, medications and lifestyle choices that protect the heart may be of specific importance. Various preventive drugs are under investigation, including antioxidant and anti-inflammatory therapies.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) as Prevention
In 2004, the National Institutes of Health (NIH) halted a large clinical trial that was investigating the use of anti-inflammatory drugs in preventing Alzheimer's disease. While prior data had confirmed that NSAIDs were not effective in treating AD, research continued to explore these drugs' potential preventive benefits
The Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) investigated whether long-term use of naproxen (Aleve) or celecoxib (Celebrex) could decrease the risk of developing AD. The NIH suspended this trial due to evidence that the NSAID naproxen was associated with increased incidence of cardiovascular and cerebrovascular events among participants. (The evidence is not uniform; other research has not implicated naproxen as a cardiovascular risk.) No adverse effects appeared during this trial for the COX-2 inhibitor celecoxib. However, safety concerns about this drug had been raised in other trials. Investigators did not believe that celecoxib's potential benefits outweighed its risks.
Heart-Protective Medications and Behaviors
The same lifestyle and medical choices that reduce risk factors for heart disease and diabetes may be important for reducing the risk for Alzheimer's disease. The following are some heart-protective medications that may also protect the brain.
Blood Pressure Drugs.
Because high blood pressure is associated with increased risk of Alzheimer’s, researchers have been studying whether blood pressure medication can reduce this risk. In a 2006 study of patients who took high blood pressure drugs, researchers found that potassium-sparing diuretics reduced the risk of developing Alzheimer’s by 70%. Beta-blockers and certain calcium channel blockers also helped to a lesser extent. ACE inhibitors appeared to offer no protection.
Statins are common drugs used to lower cholesterol levels. In past years, a number of studies reported a significantly lower risk for Alzheimer's disease in patients who took statins. However, newer studies have failed to prove that statins can help prevent Alzheimer's disease. In these recent studies, large numbers of elderly people had their dementia evaluated at baseline and then monitored over several years. The results indicated that statin use did not predict onset of AD. In the meantime, the NIH is conducting a clinical trial to investigate whether simvastatin can slow the progression of AD.
Male and Female Hormone Replacement Therapies
Hormone Replacement Therapy.
Hormone replacement therapy (HRT) has been studied for years for health effects after menopause, including its effect on mental decline. A number of studies, including a major 2003 analysis, have found no differences in mental performance and no protection from Alzheimer's disease in women taking HRT compared to non-users. The 2003 trial, called the Women's Health Initiative Memory Study (WHIMS), enrolled 4,500 women over 65 years of age. The WHIMS study showed that older postmenopausal women who took combination HRT (estrogen plus progestin) had twice the risk of developing dementia than similarly aged women who received placebo pills. In addition to increasing the risk for dementia, (including Alzheimer's disease), combination HRT failed to prevent the development of mild cognitive impairment. Based on these results, the researchers from the National Institute on Aging (NIA) recommended against prescribing combination hormone therapy to older women for maintaining or improving cognitive function. The NIA continued to research whether estrogen-only therapy could prevent or delay the onset of Alzheimer's disease. Results released in 2004 indicated that women ages 65 years and older who took estrogen-only HRT had a slightly increased risk of developing dementia.
Some testosterone converts to estrogen, which may be why older men appear to have a lower risk for Alzheimer's disease than older women. Animal studies have suggested that testosterone may help reduce levels of beta amyloid. There is also some evidence that low testosterone levels may be a particular risk factor in men with the APOE4 gene. Some experts believe that giving testosterone to elderly men and combinations of testosterone and estrogen to older women may prove to be protective. Side effects of testosterone in women include increased body hair, acne, fluid retention, anxiety, and depression. Long term benefits or serious adverse effects are unknown.
Dehydroepiandrosterone (DHEA) is a male-like hormone in the body that declines with age. Some evidence suggests that it may help reduce mental decline in older women, but not in older men. Studies are under way. The hormone may, however, reduce HDL (the so-called good cholesterol) when taken in higher doses and its effect on cancer-cell growth is unknown. Some evidence indicates that high levels may increase cancer risk. In any case, DHEA is not regulated and brands vary widely in their content.
Because of differences in Alzheimer's disease rates among different populations, investigators are researching how diet can help in prevention. 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. However, that in patients with existing Alzheimer's, weight loss is a strong indicator of mental decline.
Fats and Oils.
The following are some studies that suggest an association between fat and Alzheimer's disease:
In China and Nigeria, where fat intake is low, the risk of developing Alzheimer's is 1% at age of 65 compared to 5% in the U.S.
A study in the Netherlands reported an association between dementia and diets high in total fat, saturated fat, and cholesterol.
A number of studies suggest that a high-fat high-calorie diet in people who carry the ApoE4 gene may confer a particularly high risk. For example, in one study, adults who carried the ApoE4 gene and whose diet consisted of 40% fat calories had 29 times the risk for Alzheimer's compared to non-ApoE4 carriers on the same high-fat diet.
Fish oil contains omega-3 fatty acids. These fatty acids are found in fish such as salmon, halibut, swordfish, and mackerel. In one study, eating oily fish at least once a week was associated with a lower risk for Alzheimer's disease. Studies indicate that a particular type of omega-3 fatty acid, called docosahexaenoic acid (DHA), may especially help protect the aging brain.
The early symptoms of Alzheimer's disease (AD) may be overlooked because they resemble signs of natural aging. Older adults who begin to notice a persistent mild memory loss of recent events may have a condition called mild cognitive impairment (MCI). MCI is now believed to be a significant sign of early-stage Alzheimer's in older people. Studies now suggest that older individuals who experience such mild memory abnormalities can later develop Alzheimer's disease.
Early symptoms of Alzheimer's disease may include:
Forgetfulness (particularly of recent events or information)
Loss of concentration (having trouble planning or completing familiar tasks, difficulty with abstract thinking such as simple arithmetic problems)
Language problems (forgetting the names of objects, mixing up words, difficulty completing sentences)
Confusion about time and place (difficulty recognizing familiar neighborhoods or remembering how arrived at a location, confusion about months or seasons )
Impaired judgement (dressing inappropriately or making poor financial decisions)
Impaired movement and coordination (slowing of movements, halting gait, reduced sense of balance)
Mood and behavior changes (rapid mood swings, emotional outbursts, personality changes, increased fear or suspicion)
Apathy and depression (loss of interest in activities, increased sleeping, sitting in front of the television for long periods of time)
A definitive test to diagnose Alzheimer's disease, even in patients showing signs of dementia, has not yet been developed. A number of expert groups have developed criteria to help diagnose Alzheimer's disease and rule out other disorders. A diagnosis often involves answering questions about the patient:
Do psychologic tests indicate dementia?
Does the patient have deficits in two or more areas of mental functioning (such as language, motor skills, and perceptions)?
Has memory and mental functions gotten progressively worse?
Is consciousness disturbed? (It is not in Alzheimer's disease.)
Is the patient over age 40?
Are other medical or physical conditions present that could account for the same symptoms?
Are daily activity impaired or has the behavior changed?
Is there a family history of Alzheimer's disease?
Are there other symptoms, such as depression, insomnia, incontinence, delusions, hallucinations, dramatic verbal, emotional or physical outbursts, sexual disorders, and weight loss?
Other steps involved in making a decision include laboratory tests (EEG and possibly tests to rule out other diseases) and psychological testing to determine the presence of dementia.
Ruling out Conditions of Normal Aging that Can Cause Alzheimer's-like Symptoms
Although some memory impairment occurs in many people as they age, only some of these people develop Alzheimer's disease. Many similar symptoms can occur in healthy older individuals from other conditions associated with aging:
Grief or depression
Vision or hearing loss
The use of alcohol or certain medications
Simply the burden of too many details to remember at once
Ruling Out Other Causes Memory Loss or Dementia
The first step in diagnosing Alzheimer's disease is to rule out other conditions that might cause memory loss or dementia. There are a number of causes for dementia in the elderly besides Alzheimer's disease:
Vascular dementia (abnormalities in the vessels that carry blood to the brain)
Lewy bodies variant (LBV), also called dementia with Lewy bodies
Experts 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 or caused by other factors.
Vascular dementia is primarily caused by either multi-infarct dementia (multiple small strokes) or Binswanger's disease (which affects tiny arteries in the midbrain). One major analysis suggested that patients with vascular dementia have better long term verbal memory than patients with Alzheimer's disease, but poorer executive function (less ability to integrate and organize).
Lewy Bodies Variant.
Lewy bodies are abnormalities found in the brains of patients with both Parkinson's disease and Alzheimer's. They can also be present in the absence of either disease; in such cases, the condition is called Lewy bodies variant (LBV). In all cases, the presence of Lewy bodies is highly associated with dementia. LBV was defined in 1997 and some experts believe it may be responsible for about 20% of people who have been diagnosed with Alzheimer's. They can be difficult to distinguish. Compared to Alzheimer's disease patients, those with LBV may be more likely to have hallucinations and delusions early on, to walk with a stoop (similar to Parkinson's disease), to have more fluctuating attention problems, and to perform better than Alzheimer's disease patients on verbal recall but less well with organizing objects.
Dementia is about six times more common in the elderly Parkinson patient than in the average older adult. It is most likely to occur in older patients who have had major depression. Unlike in Alzheimer's, language is not usually affected in Parkinson's related dementia. Visual hallucinations occur in about a third of people on long-term medications.
Parkinson's disease is a slowly progressive disorder that affects movement, muscle control, and balance. Part of the disease process develops as cells are destroyed in certain parts of the brain stem, particularly the crescent-shaped cell mass known as the substantia nigra. Nerve cells in the substantia nigra send out fibers to tissue located in both sides of the brain. There the cells release essential neurotransmitters that help control movement and coordination.
Most drugs currently being used or that are under investigation to treat Alzheimer's are aimed at slowing progression. To date, none are cures. In fact, the improvements from some of these drugs may be so modest that even the patients and their families are not aware of them. Even in these cases, however, the drugs may delay the need for admission to nursing homes. There are currently two drug classes that have been approved by the U.S. Food and Drug Administration (FDA) to treat the cognitive symptoms of Alzheimer's disease:
Cholinesterase inhibitors (generally used to treat mild-to-moderate Alzheimer's)
N-methyl-D-aspartate (NMDA) receptor antagonists (used to treat moderate-to-severe Alzheimer's)
Cholinesterase inhibitors are designed to protect the cholinergic system, which is essential for memory and learning and is progressively destroyed in Alzheimer's. These drugs work by preventing the breakdown of the brain chemical acetylcholine and are recommended for the treatment of mild-to-moderate Alzheimer's. The first cholinesterase inhibitor, tacrine, was approved in 1993 but is rarely prescribed today due to safety concerns. The three most commonly prescribed cholinesterase inhibitors are donepezil (approved in 1996), rivastigmine (approved in 2000), and galantamine (approved in 2001).
Cholinesterase inhibitors may increase the risk for gastrointestinal bleeding or ulcers, and patients should be cautious about concurrent use of NSAIDs (which can also cause gastric irritation). Common side effects of cholinesterase inhibitors, especially when taken at higher doses, may include nausea, vomiting, diarrhea, and upset stomach.
Donepezil (Aricept) is taken once a day and has only modest benefits but it does help slow loss of function and reduce caregiver burden. It works equally in patients with or without the ApoE4 gene. In a 2004 study, donepezil appeared to help improve memory and daily living ability in patients with moderate-to-severe Alzheimer's when taken in combination with memantine. Several trials, including an important 2005
New England Journal of Medicine
) study, have found that donepezil may have short-term benefits for patients with mild cognitive impairment by delaying progression to AD. In the
study, donepezil slowed progression during the first year of therapy, but demonstrated no benefits by the conclusion of the 3-year trial.
Rivastigmine (Exelon) targets two enzymes (the major one, acetylcholinesterase, and butyrylcholinesterase). It is taken twice a day. This drug may be particularly beneficial for patients with rapidly progressing disease. It has slowed or slightly improved disease status even in patients with advanced disease. Rivastigmine may cause significantly more side effects than donepezil, including nausea, vomiting, and headache.
Galantamine not only protects the cholinergic system but also acts on nicotine receptors, which are also depleted during Alzheimer's. Studies report that it improves daily living, behavior, and mental functioning, including in patients with mild to advanced-moderate Alzheimer's disease and those with a mix of Alzheimer's disease and vascular dementia. Some studies have suggested that the effects of galantamine may persist for a year or longer and even strengthen over time. In 2005, the name of galantamine was changed from Reminyl to Razadyne.
Tacrine (Cognex) was the first cholinergic protective drug. It needs to be taken four times a day, has only modest benefits, and has no benefits for patients who carry the ApoE4 gene. In high doses, it can also injure the liver. In general, newer cholinergic protective drugs that do not pose as great a risk for the liver are now used for Alzheimer's.
About half of patients with mild to moderate disease show slight improvement with these drugs. Comparative studies have reported little differences in effectiveness among them. All drugs have gastrointestinal side effects, including nausea. Of note, some of the drugs used often used in elderly Alzheimer's disease patients are known as anticholinergics and may offset the effects of the Alzheimer's disease
-cholinergic drugs. Such drugs include antihistamines, antipsychotic drugs, and some anti-incontinence drugs.
In any case, the benefits of these drugs are far from dramatic. In fact, many experts have reservations about developing any additional drugs that affect the cholinergic system since, at best, they only slow progression and do not appear to affect the basic destructive disease process. When patients go off the drugs the deterioration continues. In 2005, the United Kingdom’s National Institute for Clinical Excellence (NICE) recommended against the use of donepezil, rivastigmine, galantamine, and memantine for Alzheimer’s disease treatment. The agency contended that the costs of these drugs outweigh their modest benefits.
N-methyl-D-aspartate (NDMA) Receptor Antagonist
Memantine (Namenda) is currently the only drug approved for treatment of moderate-to-severe Alzheimer’s disease. (Cholinesterase inhibitors are generally used to treat mild-to-moderate stages of the disease.) By blocking NDMA receptors, memantine protects against the overstimulation of glutamate, an amino acid that excites nerves and, in excess, is a powerful nerve-cell killer.
Memantine is prescribed either alone or in combination with donepezil. Studies indicate that memantine may help improve cognitive function and delay the progression of Alzheimer’s disease for up to one year. Side effects are generally mild but may include dizziness, drowsiness, or fainting.
In one study of effects on moderate-to-severe Alzheimer's, patients who received memantine showed a small but statistically significant benefit in cognitive function and performance of daily abilities compared with those patients who were given placebo. In a 2004 study, memantine was added to the drug regimen of patients with moderate-to-severe Alzheimer's who had taken donepezil for at least 6 months. In comparison to patients who took only donepezil, patients who received the combination donepezil-memantine therapy showed a greater improvement in measures of cognitive function, activities of daily living, and behavior parameters.
Although cholinesterase inhibitors and memantine are the best available medications for Alzheimer's, their benefits are, unfortunately, quite modest. More effective methods of prevention and treatment are urgently needed.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) as Treatment
There has been considerable controversy over whether NSAIDs may help in the treatment of Alzheimer's disease. As inflammation is involved in the destruction of brain cells, it has been suggested that anti-inflammatory drugs might be able to halt this process and thus slow the progression of the disease. In a rigorous 2003 study, patients with mild-to-moderate Alzheimer's were randomized to receive either naproxen (Aleve) or rofecoxib (Vioxx) or placebo. After 12 months of treatment, patients in the anti-inflammatory groups did not show any difference in cognitive improvement compared to those patients who received placebo.
Results from another large study, published in 2004, also failed to demonstrate improvement in cognitive function for patients with mild-to-moderate Alzheimer's who were treated with rofecoxib. Since the completion of these studies, rofecoxib was withdrawn from the market and the NIH suspended a clinical study assessing naproxen’s preventive benefits (see Nonsteroidal Anti-Inflammatory Drugs as Prevention). As mentioned earlier, patients should be cautious about taking NSAIDs in combination with cholinesterase inhibitors as they may increase the risk of gastrointestinal bleeding.
Nicotine enhances the actions of the cholinergic system (which is depleted in Alzheimer's disease) and is known to improve concentration and memory in the short term. Some studies have suggested that nicotine may protect nerve cells and help prevent the formation of beta amyloid. One study indicated that nicotine might help protect against Alzheimer's disease in carriers, but not noncarriers, of the ApoE4 gene. Another reported improvement in verbal recall and word retrieval in healthy relatives of Alzheimer's disease patients who wore a low-dose nicotine patch. Research to date, however, has found no strong evidence of improvement in Alzheimer's disease patients with nicotine replacement methods. No one should smoke to prevent or treat Alzheimer's disease.
Ginkgo biloba is a common herb that has antioxidant properties and appears to increase blood flow to the brain. A 2002 study of healthy people who took over-the-counter ginkgo for six weeks reported no improvements in memory or mental function. Studies are reporting that a ginkgo biloba extract, called Egb 761, may slightly improve the memory of patients with mild to moderate Alzheimer's disease. The herb poses a small increased risk for bleeding, which may be hazardous in combination with other blood-thinning medications, such as warfarin or high-doses of vitamin E.
Studies suggest that circumin, a compound found in the spice turmeric, has properties that may protect against Alzheimer's disease process.
Melatonin, a natural hormone involved in sleep regulation, is of interest to researchers. It is an antioxidant, it may break down beta amyloid, and it is able to pass through blood-brain barrier. Deficiencies have been observed in patients with Alzheimer's disease. A number of studies (but not all) report that melatonin may improve sleep habits in these patients. Some studies reported slower progression of mental impairment.
A number of drugs are being investigated for treatment and prevention of Alzheimer's disease. Intense areas of research are focusing on drugs that prevent beta amyloid build-up, its toxic effects on nerve cells, or other mechanisms of the disease process.
. Alzhemed (NC-758) is an experimental drug designed to prevent beta-amyloid accumulation in the brain.
Flurizan may help reduce amyloid plaque development. It is currently being studied in Phase III trials for adults with mild Alzheimer’s disease
. Vitamin E and selenium are being investigated for their preventive effects. Antioxidant treatment trials include curcumin, (the yellow pigment found in turmeric spice), and a combination trial with fish oil and alpha-lipoic acid. A 2005 study found no benefit for Vitamin E treatment.
. This Chinese herbal cholinesterase inhibitor is being studied for improvement of cognitive function.
. The antipsychotic drug quetiapine (Seroquel) is being investigated for treatment of AD-associated agitation and psychosis. Valproate (Depakote), an anticonvulsant drug, is in trials for delaying emergence or slowing the progression of agitation and psychosis.
. Simvastatin, and other cholesterol-lowering drugs, are being investigated for slowing the progression of Alzheimer’s disease.
Treating Symptoms Associated with Alzheimer's
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 2 years or less. (It is, in fact, sometimes difficult to differentiate major depression from early stage Alzheimer's disease.) Antidepressants known as selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (Prozac) and sertraline (Zoloft), may be effective in relieving depression, irritability, and restlessness associated with Alzheimer's in some patients.
Depression is often confused with apathy. According to one study, apathy is more common than depression in patients with Alzheimer's disease. It 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.
Antipsychotic drugs can treat verbally or physically aggressive behavior and hallucinations. Because older antipsychotic drugs such as haloperidol (Haldol) have severe side effects, most doctors now prescribe newer atypical antipsychotics such as risperidone (Risperdal) or olanzapine (Zyprexa). Although these new antipsychotic drugs appear to have fewer side effects than older drugs, a 2005 study suggested that they may pose a slightly increased risk for death in patients with Alzheimer’s disease or dementia. A 2006 study published in the
New England Journal of Medicine
found that there are no differences in treatment between placebo and Zyprexa, Risperdal, and the investigational drug Seroqul when used to calm agitation and aggression in people with Alzheimer's. More research is needed.
Some experts recommend that doctors delay prescribing antipsychotic medication unless absolutely necessary. They recommend first trying behavioral treatments and antidepressant drugs. Anti-seizure drugs such as carbamazepine (Tegretol) or valproate (Depakote) can also sometimes treat agitation and other psychotic symptoms.
Patients with Alzheimer's disease commonly experience disturbances in their sleep/wake cycles. Moderately short-acting sleeping drugs such as temazepam (Restoril), zolpidem (Ambien), or zaleplon (Sonata) or sedating antidepressants such as trazodone (Desyrel, Molipaxin) may be useful in managing insomnia. Some research suggests that exposure to brighter-than-normal artificial light during the day for patients with normal vision may help reset wake/sleep cycles and prevent nighttime wandering and sleeplessness. Trials on melatonin, a natural hormone that helps trigger sleep at night, are in progress.
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