Alzheimer's disease

Alzheimer's disease (AD), named after the German physician Alois Alzheimer, is the most common form of dementia (the loss of mental function) among peopleage 65 and older. Alzheimer's disease is an irreversible, progressive braindisorder that occurs gradually and results in memory loss, erratic behavior,mood and personality changes, and a decline in thinking and reasoning abilities. These changes are related to the death of brain cells and the breakdown of the connections between them. The course of AD varies from person to person, as does the rate of decline. On average, people with AD live for eight to ten years after they are diagnosed; however, they can live with the disease for up to 20 years.

Alzheimer's disease is the fourth leading cause of death in adults after heart disease, cancer, and stroke. Between two and four million Americans have AD; that number is expected to grow to as many as 14 million by the middle of the 21st century as the general population ages. While a small number of people in their 40s and 50s develop the disease (called early-onset AD), AD predominantly affects the elderly. Alzheimer's disease strikes about 3% of all people between ages 65 and 74, about 19% of those between 75 and 84, and about 47% of those over 85. Slightly more women than men are affected with AD, but this may be because women tend to live longer, so there are more women in the most affected age groups.

Slightly more than half of people suffering from AD are cared for at home, while the others are placed in various types of health care institutions. During their years of caregiving, families experience a wide range of emotional, physical, and financial stresses. They watch their loved ones grow increasingly forgetful, frustrated, and confused. Also, they often must juggle child care and jobs with caring for relatives with AD who cannot function independently.

Alzheimer's disease also puts a heavy economic burden on society. The cost ofcaring at home or in a nursing home for one AD patient with severe cognitiveimpairments has been estimated at $47,000 a year. For a disease that can last up to 20 years, the overall cost of AD to families and society is staggering. The annual economic toll of AD in the United States in terms of health care expenses and lost wages of both patients and their caregivers is estimatedat $80 to $100 billion.

The Disease Process

Alzheimer's disease affects brain cells, preferentially those in brain regions responsible for learning, reasoning, and memory. Autopsy of a person with AD shows that these regions of the brain become clogged with two abnormal structures, called neurofibrillary tangles and senile plaques. Neurofibrillary tangles are twisted masses of protein fibers inside nerve cells, or neurons. Senile plaques are composed of parts of neurons surrounding a group of brain proteins called beta-amyloid deposits. While it is not clear exactly how thesestructures cause problems, some researchers now believe that their formationis in fact responsible for the mental changes of AD, presumably by interfering with the normal communication between neurons in the brain. Two drugs approved by the Food and Drug Administration (FDA) as of January 1998 both act toincrease the level of chemical signaling molecules in the brain, known as neurotransmitters, to make up for this decreased communication ability.

What triggers the formation of plaques and tangles is unknown, although thereare several possible candidates. Inflammation of the brain may play a role in their development, and use of nonsteroidal anti-inflammatory drugs (NSAIDs)may reduce the risk of developing AD. Restriction of blood flow may also bepart of the problem. In addition, highly reactive molecular fragments calledfree radicals damage cells of all kinds, especially brain cells, which have smaller supplies of protective antioxidants thought to protect against free radical damage.

Several genes have been implicated in AD, including the gene for amyloid precursor protein, or APP, responsible for producing amyloid. Mutations (changes)in this gene are linked to some cases of the relatively uncommon early-onsetforms of AD. Other cases of early-onset AD are caused by mutations in the gene for another protein, called presenilin. Alzheimer's disease eventually affects nearly everyone with Down syndrome, caused by an extra copy of chromosome 21. Mutations on other chromosomes have also been linked to other early-onset cases.

Potentially the most important genetic link was discovered in the early 1990son chromosome 19. A gene on this chromosome, called apoE, codes for a protein involved in transporting lipids into neurons. ApoE occurs in at least threeforms, called apoE2, apoE3, and apoE4. Each person inherits one apoE from each parent, and therefore can either have one copy of two different forms, ortwo copies of one. Compared to those without ApoE4, people with one copy areabout three times as likely to develop late-onset AD, and those with two copies are almost four times as likely to do so. Despite this important link, noteveryone with apoE4 develops AD, and people without it can still have the disease. Why apoE4 increases the chances of developing AD is not known.

Causes and Risk Factors

Researchers have discovered that AD is caused by a complex series of events that takes place inside the brain. As a result, they believe that there is nosingle cause of AD, but that the disease can be triggered by a number of small changes in the brain. Although these changes affect each person differently, in most cases, scientists believe that genetic risk factors alone are not enough to trigger AD. Other risk factors may combine with an individual's genetic makeup to increase his or her chances of developing the disease.

The most significant risk factor is, of course, age; older people develop ADat much higher rates than younger ones. Another risk factor is having a family history of AD, Down syndrome, or Parkinson's disease. People who have had head trauma or hypothyroidism may manifest the symptoms of AD more quickly. Noother medical conditions have been linked to an increased risk for AD.

Many environmental factors have been suspected of contributing to AD, but population studies have not borne out these links. Among these have been pollutants in drinking water, aluminum from commercial products, and amalgam dentalfillings, which contain mercury. To date, none of these factors has been shown to cause AD or increase its likelihood. Further research may yet turn up links to other environmental culprits, although no firm candidates have been identified.

Symptoms

The symptoms of Alzheimer's disease appear gradually, usually with memory lapses. Occasional memory lapses are, of course, common to everyone, and do notby themselves signify any change in cognitive function. The person with AD may begin with only the routine sort of memory lapse forgetting where they putthe car keys but progress to more profound or disturbing losses, such as forgetting how to drive a car. Becoming lost or disoriented on a walk around theneighborhood becomes more likely as the disease progresses. A person with ADmay forget the names of family members, or forget what was said at the beginning of a sentence by the time he hears the end.

As AD progresses, other symptoms appear, including inability to perform routine tasks, loss of judgment, and personality or behavior changes. Some patients have trouble sleeping and may suffer from confusion or agitation in the evening ("sunsetting"). In some cases, people with AD repeat the same ideas, movements, words, or thoughts, a behavior known as perseveration. In the final stages of the disease, people may have severe problems with eating, communicating, and controlling their bladder and bowel functions.

The Alzheimer's Association has developed a list of ten warning signs of AD.An individual with several of these symptoms is advised to see a physician for a thorough evaluation if he or she experiences any of the following signs:

  • memory loss that affects job skills
  • difficulty performing familiar tasks
  • problems with language
  • disorientation of time andplace
  • poor or decreased judgment
  • problems with abstract thinking
  • misplacing things
  • changes in mood or behavior
  • changes in personality
  • loss of initiative

Other types of dementing illnesses, including some that are reversible, can cause similar symptoms. It is important for the person with these symptoms tobe evaluated by a professional who can weigh the possibility that his or hersymptoms may have another cause. Approximately 20% of those originally suspected of having AD turn out to have some other disorder; about half of these cases are treatable.

Diagnosis

Diagnosing Alzheimer's disease is a complex process, and may require office visits to several different specialists over several months before a diagnosiscan be made. Although a confident provisional diagnosis may be made in mostcases after thorough testing (in specialized research facilities physicians can diagnose AD with 90% accuracy), AD cannot be diagnosed conclusively untilan autopsy examination of the brain for senile plaques and neurofibrillary tangles has been performed.

The diagnosis of AD begins with a thorough physical examination and completemedical history. Except in the disease's earliest stages, accurate history from family members or caregivers is essential. Since there are both prescription and over-the-counter (OTC) drugs that can cause the same mental changes asAD, a careful review of the patient's drug, medicine, and alcohol use is important. Alzheimer's disease-like symptoms can also be provoked by other medical conditions, including tumors, infection, and dementia caused by mild strokes (multi-infarct dementia). These possibilities must be ruled out as well through appropriate blood and urine tests, brain magnetic resonance imaging (MRI) or computed tomography scans (CT), tests of the brain's electrical activity (electroencephalographs or EEGs), or other tests. Several types of oral andwritten tests are used to aid in the AD diagnosis and to follow its progression, including tests of mental status, functional abilities, memory, and concentration. Still, the neurologic exam is normal in most patients in the earlystages of the disease.

One of the most important parts of the diagnostic process is to evaluate thepatient for depression and delirium, since each of these can be present withAD, or may be mistaken for it. (Delirium involves a decreased consciousness or awareness of one's environment.) Depression and memory loss are both commonin the elderly, and the combination of the two can often be mistaken for AD.Depression can be treated with drugs, although some antidepressants can worsen dementia if it is present, further complicating both diagnosis and treatment.

A genetic test for the ApoE4 gene is available, but is not used for diagnosis, since possessing even two copies does not ensure that a person will developAD.

Treatment

Although AD is currently incurable, the immediate goals in treating and managing the dementia symptoms of AD are to slow, reduce, or reverse its mental and behavioral symptoms. Scientists are investigating medications that work onmany patients, remain effective for a long period of time, alleviate a broadrange of symptoms, improve patients' daily lives and cognitive function, andhave no serious side effects.

As of 1999 only two drugs tacrine (Cognex) and donepezil hydrochloride (Aricept) have been approved by the FDA to help treat mild to moderate symptoms insome AD patients and delay progression for from 6 to 12 months. Alzheimer's disease is marked by the loss of neurons that produce acetylcholine, a key brain chemical in cognitive function. Both Aricept and Cognex act by inhibitingacetylcholinesterase, and enzyme that normally breaks down acetylcholine. However, neither drug stops or reverses the progression of the disease. Occasional side effects of Aricept include diarrhea and nausea. The drug can also cause an irregular heartbeat, especially in patients with heart problems. Fainting spells have also been reported in some patients. Most researchers agree that neither Aricept nor Cognex works for all, or even most, AD patients. Thusthe drugs' effects and duration of usefulness are limited.

Researchers are studying a new generation of cholinesterase inhibitors that might have greater usefulness and fewer side effects. Preliminary evidence suggests that one such drug, phenserine, may be more effective in enhancing performance and learning than currently prescribed drugs. Also several experimental drugs (arecoline and physostigmine) seem to hold promise for improving cognitive function. None of these drugs, however, are able to prevent the inevitable process of nerve cell death. Therefore, researchers are investigating drugs to help nerve cells survive longer and to slow or prevent AD.

Verbal and physical aggression, agitation, wandering, depression, sleep disturbances, and delusions are some of the behavioral problems that influence family members' decisions to move loved ones to care facilities outside the home. Finding effective treatments for these behaviors could delay or even prevent placement in long-term care facilities, maintain patients' dignity, reducecaregiver stress, and lower overall costs to families and society.

However, the mainstay of treatment for a person with AD continues to be goodnursing care (either inside or outside of the home), providing both physicaland emotional support for a person who is gradually able to do less and lessfor himself, and whose behavior is becoming more and more erratic. Modifications of the home to increase safety and security are often necessary. The caregiver also needs support to prevent anger, despair, and burnout from becomingoverwhelming. Becoming familiar with the issues likely to lie ahead, and considering the appropriate financial and legal issues early on, can help both the patient and family cope with the difficult process of the disease. Regularmedical care by a practitioner with a non-defeatist attitude toward AD is also important so that illnesses such as respiratory or urinary tract infections can be diagnosed and treated properly, rather than being incorrectly attributed to the inevitable decline seen in AD.

Prevention

There is currently no sure way to prevent AD, although some of the drug treatments discussed above may eventually be proven to reduce the risk of developing the disease. The most likely current candidates are estrogen, NSAIDs, vitamin E, and selegiline (Eldepryl), although this list may grow or shrink withfurther research.

In searching for factors associated with earlier or later onset of AD, researchers found that estrogen replacement therapy (ERT) was associated with a reduced incidence of AD in a group of older women. Women who took estrogen for longer than one year after menopause had a reduced risk of developing AD; their risk was reduced by about 80%, as compared to women who did not take estrogen. This benefit is in addition to the lower incidence of heart disease and osteoporosis (bone loss) for women who take ERT after menopause.

Estrogen is a hormone, a body chemical that initiates or regulates bodily functions. Some scientists believe that estrogen's role is in helping brain cells survive, which in turn delays the onset of AD. Other researchers think thatestrogen aids the metabolism of APP, preventing it from forming beta-amyloidfibers. Still others propose that estrogen may work as an antioxidant to protect nerve cells. While this research is encouraging, it does not confirm that taking estrogen can prevent cognitive decline.

An increasing body of evidence suggests a link between inflammation and somechanges that occur in the brain of AD patients. However, scientists do not yet know whether inflammation is a cause or an effect of the disease.

One group of researchers believe they have found a link between NSAIDs and alowered risk of AD. The NSAIDs include ibuprofen (Advil or Motrin), naproxensodium (Aleve), and indomethacin (Indocin), among others. Tylenol has no anti-inflammatory properties. Aspirin had only a slightly decreased risk of AD. Although scientists are unsure about the way in which NSAIDs might reduce therisk of cognitive decline, some think that these medications may help preventthe inflammation found in the brains of people with AD. However, researchersadvise against taking NSAIDs to prevent AD until more research is conducted,since NSAIDs have potentially serious side effects, including stomach irritation and cause more emergency room visits among the elderly than any other problem.

Oxidative changes are also seen in the brains of AD patients. Thus studies ofdrugs that fight oxidation are part of the effort to understand processes that damage cells and find ways to treat and possibly prevent AD. Both selegiline and vitamin E (alpha-tocopherol) are antioxidants. Selegiline, which has been used to treat patients with Parkinson's disease, works by inhibiting an enzyme in the brain that impairs certain systems of neurotransmitters.

Research shows that treatment with selegiline or vitamin E reduced moderatelyimpaired AD patients' risk of death, institutionalization, loss of the ability to perform the tasks of daily life, or severe dementia by an average of about six months. However, investigators warn that selegiline may have potential side effects and adverse interactions with other drugs. Also, the dosage ofvitamin E used in the clinical trials was much higher than that typically found in daily supplements. Such a dosage could increase the risk of bleeding in some people.

There is also a growing interest in the use of ginkgo biloba extract for thetreatment of AD. Ginkgo biloba extract is a traditional Chinese herb made from the leaves of the ginkgo tree. It has antioxidant, anti-inflammatory, and anticoagulant properties. While preliminary research has found a modestly positive effect on AD, there have been some reports linking ginkgo to hemorrhages, especially when combined with daily use of aspirin. Other possible side effects are still unknown. Although Germany has approved ginkgo extract (240 mga day) to treat AD, researchers in the United States believe that there is not enough information to recommend its widespread use.

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