Alzheimer's Disease

Definition

Alzheimer's disease (AD) is the most common form of dementia, a neurologic disease characterized by loss of mental ability severe enough to interfere with normal activities of daily living, lasting at least six months, and not present from birth. AD usually occurs in old age, and is marked by a decline in cognitive functions such as remembering, reasoning, and planning.

Description

A person with AD usually has a gradual decline in mental functions, often beginning with slight memory loss, followed by losses in the ability to maintain employment, to plan and execute familiar tasks, and to reason and exercise judgment. Communication ability, mood, and personality also may be affected. Most people who have AD die within eight years of their diagnosis, although the interval may be as short as one year or as long as 20 years. AD 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 population ages. While a small number of people in their 40s and 50s develop the disease (called earlyonset AD), AD predominantly affects the elderly. AD affects 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, leaving a higher proportion of women in the most affected age groups.

The cost of caring for a person with AD is considerable. The annual cost of caring for one AD patient in 1998 was estimated as about $18,400 for a patient with mild AD, $30,100 for a patient with moderate AD, and $36,100 for a patient with severe AD. The annual direct and indirect costs of caring for AD patients in the United States was estimated to be as much as $100 billion. Slightly more than half of people with AD are cared for at home, while the remainder are cared for in a variety of health care institutions.

Causes and symptoms

Causes

The cause or causes of Alzheimer's disease are largely unknown, though some forms have genetic links. Some strong leads have been found through recent research, however, and these have given some theoretical support to several new experimental treatments.

At first AD destroys neurons (nerve cells) in parts of the brain that control memory, including the hippocampus, which is a structure deep in the deep that controls short-term memory. As these neurons in the hippocampus stop functioning, the person's short-term memory fails, and the ability to perform familiar tasks decreases. Later AD affects the cerebral cortex, particularly the areas responsible for language and reasoning. Many language skills are lost and the ability to make judgments is affected. Personality changes occur, which may include emotional outbursts, wandering, and agitation. The severity of these changes increases with disease progression. Eventually many other areas of the brain become involved, the brain regions affected atrophy (shrink and lose function), and the person with AD becomes bedridden, incontinent, helpless, and non-responsive.

Autopsy of a person with AD shows that the regions of the brain affected by the disease become clogged with two abnormal structures, called neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles are twisted masses of protein fibers inside nerve cells, or neurons. In AD, tau proteins, which normally help bind and stabilize parts of neurons, are changed chemically, become twisted and tangled, and no longer can stabilize the neurons. Amyloid plaques consist of insoluble deposits of beta-amyloid, (a protein fragment from a larger protein called amyloid precursor protein (APP), mixed with parts of neurons and non-nerve cells. Plaques are found in the spaces between the nerve cells of the brain. While it is not clear exactly how these structures cause problems, many researchers believe that their formation is responsible for the mental changes of AD, presumably by interfering with the normal communication between neurons in the brain and later leading to the death of neurons. By 2000, three drugs for the treatment of AD symptoms were approved by the U.S. Food and Drug Administration (FDA). They act by increasing the level of chemical signaling molecules in the brain, known as neurotransmitters, to make up for this decreased communication ability. All act by inhibiting the activity of acetyl-cholinesterase, which is an enzyme that breaks down acetylcholine, an important neurotransmitter released by neurons that is necessary for cognitive function. These drugs modestly increase cognition and improve one's ability to perform normal activities of daily living.

Exactly what triggers the formation of plaques and tangles and the development of AD is unknown. AD likely results from many interrelated factors, including genetic, environmental, and others not yet identified. Two types of AD exist: familial AD (FAD), which is a rare autosomal dominant inherited disease, and sporadic AD, with no obvious inheritance pattern. AD also is described in terms of age at onset, with early onset AD occurring in people younger than 65, and late-onset occurring in those 65 and older. Early onset AD comprises about 5-10 % of AD cases and affects people aged 30 to 60. Some cases of early onset AD are inherited and are common in some families. Early-onset AD often progresses faster than the more common late-onset type.

All cases of FAD, which is relatively uncommon, that have been identified to date are the early onset type. As many as 50% of FAD cases are known to be caused by three genes located on three different chromosomes. Some families have mutations in the APP gene located on chromosome 21, which causes the production of abnormal APP protein. Others have mutations in a gene called presenilin 1 located on chromosome 14, which causes the production of abnormal presenilin 1 protein, and others have mutations in a similar gene called presenilin 2 located on chromosome 1, which causes production of abnormal presenilin 2. Presenilin 1 may be one of the enzymes that clips APP into beta-amyloid; it also may be important in the synaptic connections between brain cells.

KEY TERMS

Acetylcholine —One of the substances in the body that helps transmit nerve impulses.

Dementia —Impaired intellectual function that interferes with normal social and work activities.

Ginkgo —An herb from the Ginkgo biloba tree that some alternative practitioners recommend for the prevention and treatment of AD.

Neurofibrillary tangle —Twisted masses of protein inside nerve cells that develop in the brains of people with AD.

Senile plaque —Structures composed of parts of neurons surrounding brain proteins called beta-amyloid deposits found in the brains of people with AD.

There is no evidence that the mutated genes that cause early onset FAD also cause late onset AD, but genetics appears to play a role in this more common form of AD. Discovered by researchers at Duke University in the early 1990s, potentially the most important genetic link to AD was on chromosome 19. A gene on this chromosome, called APOE (apolipoprotein E), codes for a protein involved in transporting lipids into neurons. APOE occurs in at least three forms (alleles), called APOE e2, APOE e3, and APOE e4. Each person inherits one APOE from each parent, and therefore can either have one copy of two different forms, or two copies of one. The relatively rare APOE e2 appears to protect some people from AD, as it seems to be associated with a lower risk of AD and a later age of onset if AD develops. APOE e3 is the most common version found in the general population, and only appears to have a neutral role in AD. However, APOE e4 appears to increase the risk of developing late onset AD with the inheritance of one or two copies of APOE e4. Compared to those without APOE e4, people with one copy are about three times as likely to develop late-onset AD, and those with two copies are almost four times as likely to do so. Having APOE e4 also can lower the age of onset by as much as 17 years. However, APOE e4 only increases the risk of developing AD and does not cause it, as not everyone with APOE e4 develops AD, and people without it can still have the disease. Why APOE e4 increases the chances of developing AD is not known with certainty. However, one theory is that APOE e4 facilitates beta-amyloid buildup in plaques, thus contributing to the lowering of the age of onset of AD; other theories involve interactions with cholesterol levels and effects on nerve cell death independent of its effects on plaque buildup. In 2000, four new AD-related regions in the human genome were identified, where one out of several hundred genes in each of these regions may be a risk factor gene for AD. These genes, which are not yet identified, appear to make a contribution to the risk of developing late-onset AD that is at least as important as APOE e4.

Other non-genetic factors have been studied in relation to the causes of AD. Inflammation of the brain may play a role in development of AD, and use of nonsteroidal anti-inflammatory drugs (NSAIDs) were once thought to reduce the risk of developing AD. Other agents once thought to reduce chances of dementia are now thought to increase its risk. In 2002, hormone replacement therapy (HRT), which combines estrogen and progestogen, was found to double the risk of developing dementia in postmenopausal women. Highly reactive molecular fragments called free radicals damage cells of all kinds, especially brain cells, which have smaller supplies of protective antioxidants thought to protect against free radical damage. Vitamin E is one such antioxidant, and its use in AD may be of possible theoretical benefit.

While the ultimate cause or causes of Alzheimer's disease still are unknown, there are several risk factors that increase a person's likelihood of developing the disease. The most significant one is, of course, age; older people develop AD at much higher rates than younger ones. There is some evidence that strokes and AD may be linked, with small strokes that go undetected clinically contributing to the injury of neurons. A 2003 Dutch study reported that symptomless, unnoticed strokes could double the risk of AD and other dementias. Blood cholesterol levels also may be important. Scientists have shown that high blood cholesterol levels in special breeds of genetically engineered (transgenic) mice may increase the rate of plaque deposition. There are also parallels between AD and other progressive neurodegenerative disorders that cause dementia, including prion diseases, Parkinson's disease, and Huntington's disease.

Numerous epidemiological studies of populations also are being conducted to learn more about whether and to what extent early life events, socioeconomic factors, and ethnicity have an impact on the development of AD. For example, a 2003 report showed that the more formal education a person has, the better his or her memory is, despite presence of AD. Other studies have related education level or participation in leisure activities such as playing cards or doing crossword puzzles to delayed onset of AD.

Many environmental factors have been suspected of contributing to AD, but epidemiological population studies have not borne out these links. Among these have been pollutants in drinking water, aluminum from commercial products, and metal dental fillings. 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 factors.

Symptoms

The symptoms of Alzheimer's disease begin gradually, usually with memory lapses. Occasional memory lapses are of course common to everyone, and do not by themselves signify any change in cognitive function. The person with AD may begin with only the routine sort of memory lapse—forgetting where the car keys are—but progress to more profound or disturbing losses, such as forgetting that he or she can even drive a car. Becoming lost or disoriented on a walk around the neighborhood becomes more likely as the disease progresses. A person with AD may 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 people with AD have trouble sleeping and may suffer from confusion or agitation in the evening ("sunsetting" or Sundowner's Syndrome). In some cases, people with AD repeat the same ideas, movements, words, or thoughts. In the final stages people may have severe problems with eating, communicating, and controlling their bladder and bowel functions.

The Alzheimer's Association has developed a list of 10 warning signs of AD. A person with several of these symptoms should see a physician for a thorough evaluation:

• memory loss that affects job skills
• difficulty performing familiar tasks
• problems with language
• disorientation of time and place

• poor or decreased judgment
• problems with abstract thinking
• misplacing things
• changes in mood or behavior
• changes in personality
• loss of initiative

Other types of dementia, including some that are reversible, can cause similar symptoms. It is important for the person with these symptoms to be evaluated by a professional who can weigh the possibility that his or her symptoms 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

Diagnosis of Alzheimer's disease is complex, and may require office visits to several different specialists over several months before a diagnosis can be made. While a confident provisional diagnosis may be made in most cases after thorough testing, AD cannot be diagnosed definitively until autopsy examination of the brain for plaques and neurofibrillary tangles.

The diagnosis of AD begins with a thorough physical exam and complete medical 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 drugs that can cause the same mental changes as AD, a careful review of the patient's drug, medicine, and alcohol use is important. AD-like symptoms also can 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), positron emission tomography (PET ) or single photon emission computed tomography (SPECT) scans, tests of the brain's electrical activity (electroencephalographs or EEGs), or other tests. Several types of oral and written 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 early stages.

One of the most important parts of the diagnostic process is to evaluate the patient for depression and delirium, since each of these can be present with AD, or may be mistaken for it. (Delirium involves a decreased consciousness or awareness of one's environment.) Depression and memory loss both are common in the elderly, and the combination of the often can be mistaken for AD. On the other hand, depression can be a risk factor for AD. A 2003 study showed that a history of depressive symptoms can be associated with nearly twice the risk of eventually developing AD. Depression can be treated with drugs, although some antidepressants can worsen dementia if it is present, further complicating both diagnosis and treatment.

An early and accurate diagnosis of AD is important in developing strategies for managing symptoms and for helping patients and their families planning for the future and pursuing care options while the patient can still take part in the decision-making process.

A genetic test for the APOE e4 gene is available, but is not used for diagnosis, since possessing even two copies does not ensure that a person will develop AD. In addition, access to genetic information could affect the insurability of a patient if disclosed, and also affect employment status and legal rights.

Treatment

Alzheimer's disease is presently incurable. Recent reports show that prompt intervention can slow decline from AD. The use of medications mentioned below as early as possible in the course of AD can help people with the disease maintain independent function as long as possible. The remaining treatment for a person with AD is good nursing care, providing both physical and emotional support for a person who is gradually able to do less and less for himself, and whose behavior is becoming more and more erratic. Modifications of the home to increase safety and security often are necessary. The caregiver also needs support to prevent anger, despair, and burnout from becoming overwhelming. 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. Regular medical care by a practitioner with a non-defeatist attitude toward AD is important so that illnesses such as urinary or respiratory infections can be diagnosed and treated properly, rather than being incorrectly attributed to the inevitable decline seen in AD.

People with AD often are depressed or anxious, and may suffer from sleeplessness, poor nutrition, and general poor health. Each of these conditions is treatable to some degree. It is important for the person with AD to eat well and continue to exercise. Professional advice from a nutritionist may be useful to provide healthy, easy-to-prepare meals. Finger foods may be preferable to those requiring utensils to be eaten. Regular exercise (supervised if necessary for safety) promotes overall health. A calm, structured environment with simple orientation aids (such as calendars and clocks) may reduce anxiety and increase safety. Other psychiatric symptoms, such as depression, anxiety, hallucinations (seeing or hearing things that aren't there), and delusions (false beliefs) may be treated with drugs if necessary.

Drugs

As of 2003, four drugs—tacrine (Cognex), donepezil hydrochloride (Aricept), and rivastigmine (Exelon)—have been approved by the FDA for its treatment. Tacrine has been shown to be effective for improving memory skills, but only in patients with mild-to-moderate AD, and even then in less than half of those who take it. Its beneficial effects are usually mild and temporary, but it may delay the need for nursing home admission. The most significant side effect is an increase in a liver enzyme known as alanine aminotransferase, or ALT. Patients taking tacrine must have a weekly blood test to monitor their ALT levels. Other frequent side effects include nausea, vomiting, diarrhea, abdominal pain, indigestion, and skin rash. The cost of tacrine was about $125 per month in early 1998, with additional costs for the weekly blood monitoring. Despite its high cost, tacrine appears to be cost-effective for those who respond to it, since it may decrease the number of months a patient needs nursing care. Donepezil is the drug most commonly used to treat mild to moderate symptoms of AD, although it only helps some patients for periods of time ranging from months to about two years. Donepezil has two advantages over tacrine: it has fewer side effects, and it can be given once daily rather than three times daily. Donepezil does not appear to affect liver enzymes, and therefore does not require weekly blood tests. The frequency of abdominal side effects is also lower. The monthly cost is approximately the same. Rivastigmine, approved for use in April of 2000, has been shown to improve the ability of patients to carry out daily activities, such as eating and dressing, decrease behavioral symptoms such as delusions and agitation, and improve cognitive functions such as thinking, memory, and speaking. The cost is similar to those of the other two drugs. However, none of these three drugs stops or reverses the progression of AD. Galantamine (Reminyl) works in the early and moderates stages of AD. It has fewer side effects than other drugs, with the exception of donepezil and must be taken twice a day. Three other drugs were being tested for AD treatment in mid-2003.

Estrogen, the female sex hormone, is widely prescribed for post-menopausal women to prevent osteoporosis. Studies once showed that estrogen was beneficial to women with AD, but in 2003, a large clinical trial called the Women's Health Initiative showed dementia among other negative effects of combined estrogen therapy.

Preliminary studies once suggested a reduced risk for developing AD in elderly people who regularly used nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen, and naproxen, although not acetaminophen. However, an important study published in 2003 showed that NSAIDs were not effective in preventing or slowing the progression of AD. The study authors recommended that people stop taking NSAIDs to slow dementia.

Antioxidants, which act to inhibit and protect against oxidative damage caused by free radicals, have been shown to inhibit toxic effects of beta-amyloid in tissue culture. Therefore, research is being conducted to see whether antioxidants may delay or prevent AD.

Another antioxidant, vitamin E, is also thought to delay AD onset. Hoever, it is not yet clear whether this is due to the specific action of vitamin E on brain cells, or to an increase in the overall health of those taking it.

Drugs such as antidepressants, anti-psychotics, and sedatives are used to treat the behavioral symptoms (agitation, aggression, wandering, and sleep disorders) of AD. Research is being conducted to search for better treatments, including non-drug approaches for AD patients.

Nursing care and safety

The person with Alzheimer's disease will gradually lose the ability to dress, groom, feed, bathe, or use the toilet by himself; in the later stages of the disease, he may be unable to move or speak. In addition, the person's behavior becomes increasingly erratic. A tendency to wander may make it difficult to leave him unattended for even a few minutes and make even the home a potentially dangerous place. In addition, some people with AD may exhibit inappropriate sexual behaviors.

The nursing care required for a person with AD is well within the abilities of most people to learn. The difficulty for many caregivers comes in the constant but unpredictable nature of the demands put on them. In addition, the personality changes undergone by a person with AD can be heartbreaking for family members as a loved one deteriorates, seeming to become a different person. Not all people with AD develop negative behaviors. Some become quite gentle, and spend increasing amounts of time in dreamlike states.

A loss of good grooming may be one of the early symptoms of AD. Mismatched clothing, unkempt hair, and decreased interest in personal hygiene become more common. Caregivers, especially spouses, may find these changes socially embarrassing and difficult to cope with. The caregiver usually will need to spend increasing amounts of time on grooming to compensate for the loss of attention from the patient, although some adjustment of expectations (while maintaining cleanliness) is often needed as the disease progresses.

Proper nutrition is important for a person with AD, and may require assisted feeding early on, to make sure the person is taking in enough nutrients. Later on, as movement and swallowing become difficult, a feeding tube may be placed into the stomach through the abdominal wall. A feeding tube requires more attention, but is generally easy to care for if the patient is not resistant to its use.

For many caregivers, incontinence becomes the most difficult problem to deal with at home, and is a principal reason for pursuing nursing home care. In the early stages, limiting fluid intake and increasing the frequency of toileting can help. Careful attention to hygiene is important to prevent skin irritation and infection from soiled clothing.

Persons with dementia must deal with six basic safety concerns: injury from falls, injury from ingesting dangerous substances, leaving the home and getting lost, injury to self or others from sharp objects, fire or burns, and the inability to respond rapidly to crisis situations. In all cases, a person diagnosed with AD should no longer be allowed to drive, because of the increased potential for accidents and the increased likelihood of wandering very far from home while disoriented. In the home, simple measures such as grab bars in the bathroom, bed rails on the bed, and easily negotiable passageways can greatly increase safety. Electrical appliances should be unplugged and put away when not in use, and matches, lighters, knives, or weapons should be stored safely out of reach. The hot water heater temperature may be set lower to prevent accidental scalding. A list of emergency numbers, including the poison control center and the hospital emergency room, should be posted by the phone. As the disease progresses, caregivers need to periodically reevaluate the physical safety of the home and introduce new strategies for continued safety.

Care for the caregiver

Family members or others caring for a person with AD have an extremely difficult and stressful job, which becomes harder as the disease progresses. Dementia caregivers spend significantly more time on caregiving than do people providing care for those with other types of illnesses. This type of caregiving also has a greater impact in terms of employment complications, caregiver strain, mental and physical health problems, time for leisure and other family members, and family conflict than do other types of caregiving. It is common for AD caregivers to develop feelings of anger, resentment, guilt, and hopelessness, in addition to the sorrow they feel for their loved one and for themselves. Depression is an extremely common consequence of being a full-time caregiver for a person with AD. Support groups are an important way to deal with the stress of caregiving. Becoming a member of an AD caregivers' support group can be one of the most important things a family member does, not only for him or herself, but for the person with AD as well. The location and contact numbers for AD caregiver support groups are available from the Alzheimer's Association; they also may be available through a local social service agency, the patient's physician, or pharmaceutical companies that manufacture the drugs used to treat AD. Medical treatment for depression may be an important adjunct to group support.

Outside help, nursing homes, and governmental assistance

Most families eventually need outside help to relieve some of the burden of around-the-clock care for a person with AD. Personal care assistants, either volunteer or paid, may be available through local social service agencies. Adult daycare facilities are becoming increasingly common. Meal delivery, shopping assistance, or respite care may be available as well.

Providing the total care required by a person with late-stage AD can become an overwhelming burden for a family, even with outside help. At this stage, many families consider nursing home care. This decision often is one of the most difficult for the family, since it is often seen as an abandonment of the loved one and a failure of the family. Careful counseling with a sympathetic physician, clergy, or other trusted adviser may ease the difficulties of this transition. Selecting a nursing home may require a difficult balancing of cost, services, location, and availability. Keeping the entire family involved in the decision may help prevent further stress from developing later on.

Several federal government programs may ease the cost of caring for a person with AD, including Social Security Disability, Medicare, and Supplemental Security Income. Each of these programs may provide some assistance for care, medication, or other costs, but none of them will pay for nursing home care indefinitely. Medicaid is a state-funded program that may provide for some or all of the cost of nursing home care, although there are important restrictions. Details of the benefits and eligibility requirements of these programs are available through the local Social Security or Medicaid office, or from local social service agencies.

Private long-term care insurance, special "reverse mortgages," viatical insurance, and other financial devices are other ways of paying for care for those with the appropriate financial situations. Further information on these options may be available through resources listed below.

Alternative treatment

Several substances are currently being tested for their ability to slow the progress of Alzheimer's disease. These include acetylcarnitine, a supplement that acts on the cellular energy structures known as mitochondria. Ginkgo extract, derived from the leaves of the Ginkgo biloba tree, appears to have antioxidant as well as anti-inflammatory and anticoagulant properties. Ginkgo extract has been used for many years in China and is widely prescribed in Europe for treatment of circulatory problems. A 1997 study of patients with dementia seemed to show that ginkgo extract could improve their symptoms, though the study was criticized for certain flaws in its method. Large scale follow-up studies are being conducted to determine whether Ginkgo extract can prevent or delay the development of AD. Ginkgo extract is available in many health food or nutritional supplement stores. Some alternative practitioners also advise people with AD to take supplements of phosphatidylcholine, vitamin B₁₂, gotu kola, ginseng, St. Johnõs Wort, rosemary, saiko-keishi-to-shakuyaku (A Japanese herbal mixture), and folic acid.

Prognosis

While Alzheimer's disease may not be the direct cause of death, the generally poorer health of a person with AD increases the risk of life-threatening infection, including pneumonia. In addition, other diseases common in old age—cancer, stroke, and heart disease—may lead to more severe consequences in a person with AD. On average, people with AD live eight years past their diagnosis, with a range from one to 20 years.

Prevention

Currently, there is no sure way to prevent Alzheimer's disease. treatments discussed above may eventually be proven to reduce the risk of developing the disease. Avoiding risks such as hormone replacement therapy may help prevent development of AD.

Research on the prevention of AD is focusing on blocking the production of amyloid in the brain as well as breaking down beta-amyloid once it is released from cells but before it has a chance to aggregate into insoluble plaques. There also are promising studies being conducted to develop an AD vaccine, where immune responses may result in the elimination of the formation of amyloid plaques.

The Alzheimer's Disease Research Centers (ADCs) program promotes research, training and education, technology transfer, and multicenter and cooperative studies in AD, other dementias, and normal brain aging. Each ADC enrolls and performs studies on AD patients and healthy older people. Persons can participate in research protocols and clinical drug trials at these centers. Data from the ADCs as well as from other sources are coordinated and made available for use by researchers at the National Alzheimer's Coordinating Center, established in 1999.

Resources

BOOKS

Cohen, Donna, and Carl Eisdorfer. The Loss of Self: A Family Resource for the Care of Alzheimer's Disease and Related Disorders. Revised. NewYork: W.W. Norton & Company, 2001.

Geldmacher, David S. Contemporary Diagnosis and Management of Alzheimer's Disease. Newtown, PA: Associates in Medical Marketing Co., Inc., 2001.

Gruetzner, Howard. Alzheimer's: A Caregiverõs Guideand Sourcebook. 3rd ed. New York: John Wiley & Sons, 2001.

Mace, Nancy L., and Peter V. Rabins. The 36-Hour Day: A Family Guide for Caring with Persons with Alzheimer Disease, Related Dementing Illnesses, and MemoryLoss in Later Life. New York: Warner Books, 2001.

Teitel, Rosette, and Marc L. Gordon. The Handholderõs Handbook: A Guide for Caregivers of Alzheimerõs and other Dementias. NewBrunswick, NJ: Rutgers University Press, 2001.

PERIODICALS

"Alzheimer's Could be Linked to Depression." GP (May 26, 2003): 4.

"Alzheimer's Could Reduced by Education." The Lancet (June 28, 2003): 2215.

"Contrary to Some Earlier Results, New Study Shows NSAIDs Do Not Slow Progression of Alzheimer's Disease." The Brown University Geriatric Psychopharmacology Update (July 2003): 1.

Gitlin, L.N., and M. Corcoran. "Making Homes Safer: Environmental Adaptations for People with Dementia." Alzheimer's Care Quarterly 1 (2000): 50-58.

Helmuth, L. "Alzheimer's Congress: Further Progress on aB-Amyloid Vaccine." Science 289, no. 5476 (2000): 375.

Josefson, Deborah. "Latests HRT Trial Results Show Risk of Dementia." British Medical Journal (June 7, 2003): 1232.

McReady, Norah. "Prompt Intervention May Slow Alzheimer's Decline." Family Practice News (May 1, 2003): 32-41.

Naditz, Alan. "Deeply Affected: As the Nation Ages, Alzheimer's Will Strike More People Close to Us." Contemporary Long Term Care (July 2003): 20-23.

"Researchers Believe "Silent" Strokes Boost Risk." GP (April 14, 2003): 9.

OTHER

Alzheimer's Disease Books and Videotapes. 〈http://www.alzheimersbooks.com〉.

National Institute on Aging, National Institutes of Health. 2000: Progress Report on Alzheimer's Disease—Taking the Next Steps. NIH Publication No. 4859 (2000). 〈http://www.alzheimers.org/pubs/prog00.htm#References〉.

Alzheimer disease

Definition

Alzheimer disease is a neurological disorder characterized by slow, progressive memory loss due to a gradual loss of brain cells. Alzheimer disease significantly affects cognitive (thought) capabilities and, eventually, affected individuals become incapacitated. Alzheimer-related issues can cause emotional and financial upheaval for both the individuals with the disease and their families. Alzheimer disease is the most common form of dementia (loss of intellectual function) and, according to the National Institutes of Health (NIH), it is the fourth leading cause of death in adults.

Description

The condition was first described in 1906 by Alois Alzheimer, a German physician. Alzheimer characterized two abnormal structures in the brain of a woman with dementia that are now considered the hallmarks of the disease: amyloid plaques and neurofibrillary tangles. The nature of Alzheimer disease is progressive. Initially, dementia is manifested by barely noticeable memory deficits. Eventually, the memory loss becomes more severe until it is incapacitating. Other symptoms such as confusion, the inability to articulate words correctly, and hallucinations occur with varying degrees. Emotional problems such as easy agitation, poor judgment, and feelings of withdrawal are also common in the early stages. Affected individuals are also likely to develop seizures , hypertonicity (increased muscle movements), and incontinence. Without treatment or supervision, death often results from malnutrition or pneumonia. From the initial symptoms, disease progression can last up to 25 years, although typically the duration ranges from eight to 10 years.

Demographics

Dementia is thought to affect between 25–50% of individuals 85 years or older. The risk of developing Alzheimer disease increases with age and is independent of sex or geographical location (although there are environmental toxic agents that can impair various cognitive functions, including memory loss). A genetic association has been found for higher risk of developing Alzheimer disease in individuals with mutations in a particular gene who are also African American or Caribbean Hispanics. This association is greatest in individuals with a positive family history of dementia.

Approximately 10% of people 65 years or older are at risk for developing significant memory loss. More than half of these individuals (5% of all individuals 65 years or older) have Alzheimer disease. Approximately four in 10,000 individuals between the ages of 40 and 60 are at risk for having Alzheimer disease.

Causes and symptoms

Although there are several known causes of Alzheimer disease, about 75% of cases are sporadic and occur without a clear cause; this percentage represents people without a family history of the disorder. Scientists assume that these cases are due to a combination of unknown genetic predisposing factors and environmental exposures. Although various narcotics, therapeutic drugs, viruses, and toxins have been implicated in the etiology of the disease, there is currently no proof that they can cause Alzheimer disease.

Genetic basis for Alzheimer disease

Of all persons with Alzheimer disease, up to 25% of cases are thought to be part of a familial-based inheritance pattern and therefore are only determined based on family history or genetic test results. In general, these forms of Alzheimer disease are inherited as an autosomal dominant disorder, meaning that affected individuals have a 50% chance of passing on the mutated gene to their offspring in each pregnancy. There is a late-onset familial form (AD2), three early-onset familial forms (AD1, AD3, AD4), and a form of Alzheimer disease associated with Down syndrome.

Down syndrome and Alzheimer disease

Less than 1% of all cases of Alzheimer disease are due to a chromosomal defect called trisomy 21 (also known as Down syndrome). This occurs when there are three copies of genes found on chromosome 21, usually due to a person having an extra chromosome 21. These individuals usually develop Alzheimer disease after the age of 40. The APP gene, which encodes the amyloid precursor protein and is implicated in the pathogenesis of Alzheimer disease, is localized to chromosome 21; it is felt that people with Down syndrome overproduce this protein, resulting in its accumulation in the brain. The excess protein is thought to cause the disease.

Early-onset familial Alzheimer disease

A low percentage (2%) of Alzheimer cases results from a familial form of the disease in which there is an early onset of symptoms (AD1, AD3, and AD4), usually occurring before the age of 60. Age of onset usually occurs around 40–50 years, but can occur as early as 30 years. The majority of these persons have family members that are also affected. The clinical manifestations are similar to the adult-onset form, with loss of memory and cognitive ability. In this form of Alzheimer disease, there are several chromosomal locations of genes implicated in causing the disease.

AD1 accounts for approximately 10–15% of earlyonset Alzheimer disease and involves a protein called presenilin 1 that has a mutation in the gene that encodes it called PSEN1, which is found on chromosome 14. AD3 accounts for 20–70% of the early-onset familial form and is caused by mutations in APP found on chromosome 21, which encodes a protein called amyloid beta A4. AD4 is extremely rare and is caused by mutations in PSEN2, localized to chromosome 1, and encodes a protein called presenilin 2.

Late-onset familial Alzheimer disease

The late-onset familial form of Alzheimer disease (AD2) accounts for approximately 15–25% of all cases. These familial cases are seemingly indistinguishable from sporadic cases when observed clinically, but can be recognized based on molecular genetic testing. However, there is no clear chromosomal location for a gene directly responsible for the disease. Therefore, this complex type may involve many susceptibility genes. These familial cases are most likely due to multiple genes that make these individuals susceptible to developing the disease. For example, the APOE e4 gene on chromosome 19 associated with late-onset Alzheimer disease reduces the age in which symptoms develop by an unknown mechanism. There are many other candidate genes that are thought to modify Alzheimer disease risks and these genes, with various chromosomal locations, have been linked to the disease in different families.

Development (pathogenesis) of Alzheimer disease

Although scientists know how brain cells of persons with Alzheimer disease are affected, and additionally understand some of the genetic explanations of the disease, the precise cause of Alzheimer disease is still unclear. For example, it is known that accumulations of clumps of proteins called amyloid plaques outside brain cells and accumulation of altered proteins inside the cells called neurofibrillary tangles are characteristic of Alzheimer disease; however, it is unclear how these accumulated proteins cause brain cells to die.

According to the Alzheimer's Disease and Related Disorders Association, Inc., there are seven stages that characterize the disease:

• Stage 1: No decline in function is yet noted. This group includes individuals who may carry predictive gene mutations but have no symptoms, or those who will be affected by other unknown mechanisms.
• Stage 2: Normal function in general, although the person is aware of a subtle cognitive decline.
• Stage 3: Early Alzheimer disease. Persons experience difficulty in performing complex tasks that require cognitive skills.
• Stage 4: Mild Alzheimer disease. Persons require assistance with common tasks such as paying bills and balancing a checkbook.
• Stage 5: Moderate Alzheimer disease. Persons require assistance in making personal everyday decisions such as choosing appropriate clothing for the weather or ordering from a menu.
• Stage 6: Moderately severe Alzheimer disease. Persons require assistance dressing, bathing, and using the toilet. Urinary and bowel incontinence may be present.
• Stage 7: Severe Alzheimer disease. The vocabulary shrinks to only a few words; then little or no verbal communication is heard. The ability to walk is lost, followed by an inability to maintain a sitting posture in a chair. Eventually, the person experiences profound lack of purposeful muscle control, is totally dependent for care, and cannot smile or hold up his or her head.

Diagnosis

Alzheimer disease is diagnosed clinically by a physician, postmortem by a histopathologist (a scientist who studies diseased tissues by their various staining patterns), or genetically by identifying mutations in genes associated with the disease.

The gold standard for diagnosis of Alzheimer disease is through autopsy examination by an experienced pathologist. Detection of amyloid plaques in the brain by histopathology is the most conclusive diagnostic tool. This is performed using antibodies that bind to the particular amyloid proteins and can be visualized by microscopic evaluation, as the antibodies are tagged with a fluorescent or colorimetric molecule. A positive result would involve a significantly greater number of plaques compared to agematched controls. Other brain defects that characterize the disease, such as abnormal nerve cell configurations called intraneuronal neurofibrillary tangles, can also be detected by histopathology by the same methods. A clinical diagnosis by a physician accounts for 80–90% of patients diagnosed with Alzheimer disease.

Clinical diagnosis

A physician can use a number of different tests to assess memory skills, and, combined with any observed changes in the individual's behavior, they can help make a diagnosis of Alzheimer disease. Other tests that are important in diagnosing the disorder can involve laboratory tests that require blood and urine or imaging studies of the

brain. By using neuroimaging studies such as magnetic resonance imaging (MRI) scans, physicians have found that patients with Alzheimer disease often have diffuse atrophy (weakening or decrease in size) in a specific area of the brain called the cerebrum.

Genetic diagnosis

It has been shown that there is a significant association of a specific gene called APOE e4 with the development the early-onset form of the disease. There are three different types of Alzheimer disease that have been shown to be caused by mutations in three distinct genes known as APP, PSEN1, and PSEN2. However, determining the genotype (whether a patient carries this associated mutation) is not entirely conclusive. Currently, although APOE e4 mutation analysis can help in diagnosing a patient suspected of having Alzheimer disease, it is not used for predictive testing of these individuals.

Biochemical markers

Although there are no tests to definitively diagnose Alzheimer disease, there are useful biochemical markers that can help distinguish Alzheimer disease from other disorders that involve dementia, including dementia caused by vascular disorders, drugs, or thyroid disease. Fluid that is found in the brain and spinal cord called cerebrospinal fluid can be tested for levels of two proteins, Tau and A[.beta]42, in patients that develop symptoms of dementia. A[.beta]42 accumulation in the brain is associated with reduced levels in the cerebrospinal fluid. Accumulation of the Tau protein in the brain is associated with Alzheimer disease. Therefore, increased Tau protein levels and decreased A[.beta]42 in the cerebrospinal fluid can pinpoint which persons have Alzheimer disease, regardless of the cause or the age of onset.

The score for these tests is numerical and relies heavily on a reference range determined by a patient's age, sex, and the type of equipment used to perform the test. A positive result will only indicate that a patient is at high risk of having Alzheimer disease and requires further analysis for an accurate diagnosis. This test has yet to be widely performed and is, therefore, only available in certain reference laboratories.

Treatment team

Initially, a physician usually recommends counseling by a psychologist or a support group experienced with this disease. After the diagnosis, visits to the physician focus on treating mild behavioral changes such as depression . Eventually, treatment requires 24-hour supervision and nursing care. The caretakers are mostly nurses or professionals who are part of various assisted-living programs.

Treatment

Pharmacological treatment

Treatment of Alzheimer disease is mainly palliative (given for comfort) and focuses on mitigating symptoms. Each symptom is treated based on its severity and the other symptoms that are affecting the individual. Most affected individuals will eventually need professional care in assisted living or nursing homes. They require constant supervision as memory loss becomes incapacitating. There are several pharmacological interventions and treatment regimens that are suggested. Patients who have depression are treated with antidepressants. Tacrine is often prescribed to help with some of the behavioral problems and provides modest cognitive benefits in a small percentage of patients. Aricept, Galantamine, and Exelon are more recent drugs used for a similar purpose, and are not believed to cause liver toxicity; the liver must be monitored in those taking Tacrine. Non-steroidal anti-inflammatory drugs (NSAIDs) are currently being investigated for their use in treating patients with Alzheimer disease.

Coping with the disorder

There are strategies to cope with this disorder and these should be considered in the beginning stages of the disease. Coping mechanisms depend on whether there are family members available for support. If an individual is without family members, relying on community support through neighbors or volunteers of Alzheimer disease organizations will be necessary.

Many precautions can be made early on to avoid difficult or life-threatening situations later, while maintaining everyday activities in the home environment. Dealing with a person with Alzheimer disease with patience is important. Daily tasks should be performed when the person with Alzheimer disease feels best. Informing neighbors of the person's condition is an important first step. Arranging for assistance, depending on the stage of the disorder, will become necessary. As the ability to drive may be compromised fairly early in the disorder, transportation may need to be arranged. There are local chapters of the Alzheimer's Association that offer help with transportation requirements.

In the early period of the disease when memory loss is minimal, it is helpful for family and friends to interact with the affected person, reminding him or her to take medication, eat, keep appointments, and so forth. Family and friends can help sustain the Alzheimer patient's daily living activities. Keeping records is also helpful, particularly if several people are overseeing the patient's care. Additionally, organizing the household so that it is easy to find important items is recommended.

Other helpful coping mechanisms include posting signs to remind patients of important phone numbers, to turn off appliances, and to lock doors. It is important that all electrical cords and appliances are arranged to minimize distraction, and to prevent danger of falling or misuse. Assistance in handling finances is usually necessary. Providing an extra house key for neighbors and setting up a schedule to check on persons with Alzheimer disease is very helpful for both the patient and the family. By utilizing these and other family, neighborhood, and community resources, many people with early Alzheimer disease are able to maintain a successful lifestyle in their home environment for months or years.

Recovery and rehabilitation

For a person with Alzheimer disease, emphasis is placed on maintaining cognitive and physical function for as long as possible. Currently, there is no cure for Alzheimer and, once the symptoms develop, patients do not recover. Instead, they progressively worsen, usually over a period of years. This has many psychosocial and financial ramifications for the patient and the patient's caretakers. Social service workers can help families plan for long-term care, as persons with Alzheimer disease most often eventually require 24-hour assistance with feeding, toileting, bathing, personal safety, and social interaction. Taking care of patients in the later stages can be financially and psychologically draining. Various support systems are available through community mental health centers and national support organizations.

Clinical trials

There are currently many clinical trials for the treatment or prevention of Alzheimer disease sponsored by the National Institutes of Health (NIH). Large multi-center clinical trials such as a Phase III clinical trail are aimed at determining whether anti-inflammatory drugs delay agerelated cognitive decline. (Contact information: UCLA Neuropsychiatric Institute, Los Angeles, California, 90024. Recruiter: Andrea Kaplan, (310) 825-0545 or her email: akaplan@mednet.ucla.edu.) A Phase III clinical trial is also organized to test the drug Risperidone for the treatment of agitated behavior in Alzheimer's patients. (Contact information: Palo Alto Veterans Administration Health Care System, Menlo Park, California, 94025. Recruiter: Erin L. Cassidy, PhD, (650) 493-5000, ext.27013 or her email: ecassidy@stanford.edu.)

Other trials include:

• A study on Valproate to prevent cognitive and behavioral symptoms in patients. Contact information: Laura Jakimovich, RN, MS, (585) 760-6578 or her email: laura_jakimovich@urmc.rochester.edu.
• The drug Simvastatin, a cholesterol-lowering medication, is being studied to learn if it slows the progression of Alzheimer disease. Contact information: Stanford University, Palo Alto, California, 94304. Recruiter: Lisa M. Kinoshita, PhD, (650) 493-0571 or her email: lisakino@stanford.edu.
• A study of the efficacy and dose of the drug NS 2330 to improve cognition. Contact information: Peter Glassman, MD, PhD, (800) 344-4095, ext. 4776 or his email: pglassma@rdg.boehringer-ingelheim.com.
• A study of investigational medications for the treatment of Alzheimer patients. Contact information: Eli Lilly and Company, (877) 285-4559.

There are also many other studies that are investigating various other pharmacological agents such as vitamin E and other currently available drugs.

Prognosis

There is considerable variability in the rate of Alzheimer disease progression. The Alzheimer Disease Association claims that the time from the onset of clinical symptoms to death can range from three to 20 years, with an average duration of eight years. There are probably many environmental and genetic factors that play a role in the progression of the disease. The accumulation of damage and loss of brain cells eventually results in the failure of many different organ systems in the body. According to the National Institute of Neurological Disorders and Stroke, the most common cause of death is due to infection.

Special concerns

Alzheimer disease should be distinguished from other forms of dementia. In some cases, depression can result in dementia-like symptoms. Other examples include chronic drug use, chronic infections of the central nervous system , thyroid disease, and vitamin deficiencies. These causes of dementia can often be treated. It is, therefore, important to obtain an accurate diagnosis to avoid complications associated with the inappropriate treatment and long-term care of these patients. There are also several genetically based syndromes in which dementia plays a role.

Genetic counseling

Genetic counseling is important for family members biologically related to patients with Alzheimer disease because each first-degree relative has as much as a 20% lifetime risk of also being affected. The risk to immediate relatives increases as more family members develop the disease. In the early-onset form of the disease, the inheritance pattern is thought to be autosomal dominant. This means that a carrier (who will eventually be affected) has a 50% chance of passing on the mutated gene to his or her offspring.

The general consensus in the scientific and medical community is to not test children or adolescents in the absence of symptoms for adult-onset disorders. There are many problems associated with predictive testing of asymptomatic individuals who are not yet adults. Children who undergo predictive testing lose the choice later in life (when they are capable of understanding the full ramifications of the disease) to know or not to know this information. It is, therefore, an important consideration that involves ethical and psychological implications.

Resources

BOOKS

Bird, T. D. "Memory Loss and Dementia." In Harrison's Principles of Internal Medicine, 15th ed. Edited by A. S. Franci, E. Daunwald, and K. J. Isrelbacher. New York: McGraw Hill, 2001.

Castleman, Michael, et al. There's Still a Person in There: The Complete Guide to Treating and Coping with Alzheimer's. New York: Perigee Books, 2000.

Mace, Nancy L., and Peter V. Rabins. The 36-Hour Day: A Family Guide to Caring for Persons with Alzheimer Disease, Related Dementing Illnesses, and Memory Loss in Later Life. New York: Warner Books, 2001.

PERIODICALS

Campion, D., et al. "Early-onset Autosomal Dominant Alzheimer Disease: Prevalence, Genetic Heterogeneity, and Mutation Spectrum." Am J Hum Genet 65 (1999): 664–70.

Green, R.C. "Risk Assessment for Alzheimer's Disease with Genetic Susceptibility Testing: Has the Moment Arrived?" Alzheimer's Care Quarterly (2002): 3,208–14.

Rogan, S., and C. F. Lippa. "Alzheimer's Disease and Other Dementias: A Review." Am J Alzheimers Dis Other Demen (2002) 17: 11–7.

Romas, S. N., et al. "Familial Alzheimer Disease among Caribbean Hispanics: A Reexamination of Its Association with APOE." Arch Neurol (2002) 59: 87–91.

Rosenberg, R. N. "The Molecular and Genetic Basis of AD: The End of the Beginning: The 2000 Wartenberg Lecture." Neurology 54 (2000): 2045–54.

OTHER

ADEAR Alzheimer Disease Education and Referral Center. National Institute on Aging about Alzheimer's Disease—General Information. February 10, 2004 (March 30, 2004). <http://www.alzheimers.org/generalinfo.htm>.

National Institutes of Health. Alzheimer's Disease. February 10, 2004 (March 30, 2004). <http://health.nih.gov/result.asp?disease_id=28>.

National Library of Medicine. Alzheimer's Disease. MED-LINE plus Health Information. February 10, 2004 (March 30, 2004). <http://www.nlm.nih.gov/medlineplus/alzheimersdisease.html>.

ORGANIZATIONS

Alzheimer's Association. 919 North Michigan Avenue, Suite 1000, Chicago, IL 60611-1676. (312) 335-8700 or (800) 272-3900; Fax: (312) 335-1110. info@alz.org. <http://www.alz.org>.

Alzheimer's Education and Referral Center. PO Box 8250, Silver Springs, MD 20907-8250. (800) 438-4380. adear@alzheimers.org. <http://www.alzheimers.org>.

National Institute on Aging. Building 31, Room 5C27, 31 Center Drive, MSC 2292, Bethesda, MD 20892. (301) 496-1752. <http://www.nia.nih.gov>.

Bryan Richard Cobb, PhD

DEMENTIA: ETHICAL ISSUES

There has been much progress in the ethics of dementia care. Dementia is a syndrome (i.e., a cluster of symptoms) that can be caused by a myriad of diseases. The most common disease cause of irreversible, progressive dementia is Alzheimer's disease, which this article will frequently allude to.

Moral progress is evident in the fact that the use of physical restraints is diminishing in nursing homes. By the mid-1990s, ample evidence had accumulated that "minimal restraint" or "no restraint" policies actually keep persons with dementia safest, for otherwise they can choke to death on strapped chairs, or fail to thrive as a direct result of physical coercion. Increasingly, architects have focused on how to design long-term care facilities that maximize the freedom to wander while minimizing environmental obstacles or hazards. Similarly, psychiatrists have become more adept at setting clear therapeutic goals for behavioral medications, monitoring for outcome, and using the smallest doses necessary. This avoids the problem of polypharmacy (prescription of large numbers of drugs, many of which are unnecessary and cause harm), which can further harm cognition in people with dementia who have problems with agitation, paranoia, hallucination, and the like. Increasing attention is being given to the fact that people with dementia can experience physical pain, especially in the end stage, and may require pain-relieving medications (palliative care). Professionals and family members are realizing that in the advanced stage of this disease, assisted oral feeding ensures a better quality of life than artificial nutrition and hydration (Post, 2000).

Dementia and moral standing

Persons with cognitive deficits such as those brought about by dementia eventually will no longer be intellectually or economically productive. The term "hypercognitivist" was coined in 1995 by Stephen Post to describe a value system that focuses on rational decisional capacity as the marker for moral standing under the protective umbrella of the principle of nonmaleficence (i.e., "do no harm"). In the absence of the ability to make plans and implement them, the person with dementia becomes a "nonperson," who, even if still treated with a degree of care, has a diminished moral standing. In contrast, focus group studies show that most family and professional caregivers hold a diametrically opposite view: they see the person with dementia in terms of remaining capacities, and in terms of emotional and relational well-being despite cognitive losses (Post and Whitehouse, 1995). The philosopher Alasdair MacIntyre (1999) points out that contrary to dominant schools of ethics, the classical Western tradition of moral thought refuses to devalue the cognitively imperiled.

In the wider culture, the criteria of rationality and productivity may blind many to other ways of thinking about the meaning of one's humanity and the nature of humane care in the context of dementia. Many people simply cannot handle being around someone who is mentally and emotionally disabled. People with the diagnosis of dementia often complain of a sense of social diminution, of a negative social psychology in which they no longer get the respect that they once enjoyed. They typically ask to be more included in conversations, decisions, and activities. A fuller attention to emotional and relational well-being may in some cases offset some of the adverse behavioral impact of neurological impairment. Any tendency to treat someone with dementia as though he or she counts less than, or has a different status than, other human beings should be discouraged (Kitwood, 1997).

Truth telling

There is a consensus among medical ethicists that patients should be told the truth about a diagnosis of Alzheimer's disease or any other dementing illness. This is also their legal right. By the late 1990s, especially with the advent of new treatments for the cognitive symptoms of Alzheimer's disease, and with more accurate diagnosis, nearly all clinicians informed patients of their diagnosis. The discovery of inheritance patterns, emerging treatments, and the general public awareness of Alzheimer's disease contributed to a noticeable swing toward diagnostic truth telling.

The question now is not whether to tell the truth, but how to tell it in a sensitive and supportive manner that does not create unnecessary despair and that, as far as possible, maintains hope. Professionals should assure patients that there are many ways to ensure good care and the treatment of the symptoms of dementia throughout its progression (Zarit and Downs, 1999).

Truth telling allows the person with the diagnosis to plan for optimal life experiences in remaining years of intact capacities, prepare a durable power of attorney for health care decisions—some may also prepare a living will —to be implemented upon eventual incompetence, and participate actively in Alzheimer's disease support groups, to which referrals should always be made.

Autonomy

Patient autonomy (i.e., self-determination) cannot exist without truth. Autonomy can be extended through advance directives (i.e., living wills and durable power of attorney for health care), and few question the importance of such documents. The durable power of attorney for health care allows the person, while still competent, to designate a trusted individual (usually a family member with whom he or she has had ample conversation) who will make medical treatment decisions once the person becomes unable to do so. This allows the surrogate decision maker to be attentive to the person's values and wishes, and to make decisions as needed. A living will, coupled with the durable power of attorney for health care, is usually recommended by lawyers. In the absence of legal documentation, all states allow the surrogate decision maker to proceed de facto, based on the sate statutes, although some states may try to interfere with surrogate control in designated areas, such as the refusal of a feeding tube.

The still competent self may not know what the experience of moderate dementia is like, nor be privy to the forms of well-being to be facilitated for such a self, but he or she surely knows the meaning of incontinence of bowel or bladder, repeated majors infections, and severe dysfunction. The best mechanism for empowering the intact self is the implementation of a durable power of attorney for health care, which is, paradoxically, the act of relinquishing control by placing oneself in the loving hands of another, with certain broad parameters spelled out as desired.

New medications

Medical science is likely to develop treatments for Alzheimer's disease and other causes of dementia that slow the progression of the disease. Patients, while competent, and surrogates will need to reflect carefully on the ethics of altering the course of progressive dementia. It is difficult to imagine that any reasonable person would want his or her disease progression slowed in the advanced stage, which is replete with severe dysfunction. Most, it can be assumed, would prefer a comfortable death in a hospice-like setting of palliative care. A drug to slow progression would, however, be most welcome prior to onset of symptoms, or in the mild and even moderate stages, in order to avoid the indignities of advanced dementia (Post, 2000). The ethical maxim is this: prevent or delay onset of symptoms, mitigate symptoms insofar as possible, but never purposefully prolong life in the advance stage of severe dysfunction.

As for the cognitive enhancing drugs, which do not slow the progression of dementia but mitigate some symptoms for limited periods of time, the absence of clear data on outcomes necessitates caution when addressing the ethical implications. Some major ethical quandaries are, however, identifiable. The introduction of acetylcholinesterase inhibitors for treatment of mild to moderate Alzheimer's disease is, on the one hand, promising. There is anecdotal evidence of its effectiveness: a mildly demented woman insisted that, with the help of donepezil, she can now find her words; a woman who was too forgetful to cook anymore regained sufficient memory to begin cooking again in relative safety. But patients and caregivers who have already navigated certain crises of cognitive decline may have to repeat the process. The individual who has lost insight into his or her losses may regain insight, along with renewed anxiety. New cognitive enhancing compounds should not be prescribed without attention to individual cases. Each patient's response must be carefully monitored with regard to quality of life. Every caregiver should know that the use of these compounds is a deeply personal and value-laden decision requiring the careful exercise of compassion and good judgment. There is nothing wrong with withdrawing an antidementia treatment that does not seem to have a positive result. Modest improvement or temporary stabilization of cognitive decline will be viewed by some caregivers as gratifying—but certainly not by all.

A natural dying

In general terms, no caregiver should feel that the technological extension of the life of a loved one with advanced Alzheimer's disease is necessary. One clear marker of the severe stage is the loss of the capacity to swallow. Artificial nutrition and hydration are generally not a solution because such intrusion is almost invariably unwelcome to the patient. Physical discomfort and complications are equally serious considerations. No wonder the person with Alzheimer's repeatedly pulls out feeding tubes. The Alzheimer's Association guidelines for the treatment of patients with severe dementia are clear: "Severely and irreversibly demented patients need only care given to make them comfortable. If such a patient is unable to receive food and water by mouth, it is ethically permissible to choose to withhold nutrition and hydration artificially administered by vein or gastric tube. Spoon feeding should be continued if needed for comfort" (1994).

In case consultations, caregivers who have already rejected the use of a feeding tube ask how aggressively to encourage eating and drinking by mouth in patients who are losing these capacities. As long as a person retains the capacity, food and water should be offered, and the taking of them encouraged by spoon feeding. A baby bottle can be helpful because the sucking reflex is often retained. But when the person no longer is able to swallow, it is of no benefit to fill the mouth with food and water.

After the capacity for natural eating and drinking has been lost, it should be firmly understood that a decision against artificial nutrition must also be a decision against artificial hydration (a fluid IV). Families need to be informed that their loved one will likely die within one or two weeks, and that dehydration is known to have sedating effects that ensure a more peaceful dying.

The clinician should proactively clarify for caregivers the burdens of invasive treatments in order to spare them the sense of guilt associated with not doing everything to prolong life. Chaplains should advise caregivers that their love is better expressed through compassion, commitment, and humble entry into the culture of dementia.

The right to well-being

It is morally imperative to build on the remaining capacities of persons with dementia. The well-being available to people with dementia is obvious to anyone who has watched art or music therapy sessions. In some cases, a person with advanced Alzheimer's disease may still draw a valued symbol, as though through art a sense of self is retained. The abstract expressionist painter Willem de Kooning painted his way through much of his struggle with Alzheimer's disease. Some critics commented that his work, though not what it had been, was nevertheless impressive. Kay Larson, former art critic for New York magazine wrote, "It would be cruel to suggest that de Kooning needed his disease to free himself. Nonetheless, the erosions of Alzheimer's could not eliminate the effects of a lifetime of discipline and love of craft. When infirmity struck, the artist was prepared. If he didn't know what he was doing, maybe it didn't matter—to him. He knew what he loved best, and it sustained him" (Larson, p. 298). DeKooning, like all persons with dementia, retained some strengths and abilities that he was able to capitalize on. It is important to look at what the person with dementia can do, rather than at what he or she cannot do.

In addition to self-expression through the arts, many persons with dementia enjoy the smell and look of fall leaves, or the sounds of birds singing, and they can appreciate the "wonder of it all" through such small gratifications. The losses associated with dementia must be placed within the context of losses associated with aging in general. As horizons of experience narrow, small pleasures in life become more and more important. In dementia care, pleasures and gratifications that are small loom especially large. Many of the better assisted living facilities are single-story campuses with access to rubberized pathways in garden areas surrounded by attractive fencing to prevent wandering off.

Justice for persons with dementia

While we can all agree that services for persons with dementia should be better and more plentiful, who should pay for them, and are there limits? The American health care system is oriented to pay for "rescue" medicine that pulls persons in any condition from the jaws of death, but it provides very little to support the expense of chronic and long-term care.

It is easy to reject the notion of categorical age-based rationing of life-extending health care associated with Daniel Callahan (1987), for age alone is never a fair basis for allocating lifesaving. Elderly persons are remarkably heterogeneous, and age is a notoriously poor indicator of outcome in almost all medical circumstances (Binstock and Post, 1991). Yet Callahan succeeded in forcing the question and spurring a moment of debate among intellectuals. On his side of the argument is the reality that overtreatment of older adults is rampant in American medicine, and a source of wide public concern. If the autonomy model cannot solve the problem of overtreatment, then perhaps rationing must. It might be possible for society, by some means of consensus, to arrive at the notion of categorically limiting purposeful efforts to extend the lives of persons in the advanced stage of Alzheimer's disease. This would not be based on age, however, but on the gravity of the condition and its discomforts and burdens to the patient. It would be altogether fitting for policymakers, in dialogue with informed constituencies and through democratic action, to determine that while hospice-oriented long-term care will be paid for with public funds, efforts to rescue a person in advanced and terminal dementia would not be, nor would the protracted expense of long-term care that results from such rescue. In essence, if there were a practical trade-off possible within the health care system, emphasis should be placed on everything but technological rescue efforts for persons beyond the moderate stage of Alzheimer's disease and for whom quality of life, but not quantity of life, should be enhanced.

American society is still not quite at the point of consensus. Yet in the future, policies may be constructed on a majority basis that would in fact limit rescue efforts, at least with respect to dialysis, mechanical ventilators, and cardiopulmonary resuscitation. Perhaps artificial nutrition and hydration in the terminal stage could also be deleted from public funding once the society realizes the burdens this creates (Gillick, 2000).

Stephen G. Post

See also Advance Directives for Health Care; Alzheimer's Disease; Autonomy; Competency; Dementia; Refusing and Withdrawing Medical Treatment.

BIBLIOGRAPHY

Alzheimer's Association Public Statement on Tube Feeding (press release). Chicago, 1994.

Binstock, R. H., and Post, S. G., eds. Too Old for Health Care? Controversies in Medicine, Law, Economics, and Ethics. Baltimore: Johns Hopkins University Press, 1991.

Callahan, D. Setting Limits: Medical Goals in an Aging Society. New York: Simon and Schuster, 1987.

Gillick, M. R. "Rethinking the Role of Tube Feeding in Patients with Advanced Dementia." New England Journal of Medicine 342 (2000): 206–210.

Kitwood, T. Dementia Reconsidered: The Person Comes First. Buckingham, U.K., and Philadelphia: Open University Press, 1997.

Klepper, H., and Rorty, M. "Personal Identity, Advance Directives, and Genetic Testing for Alzheimer Disease." Genetic Testing 3 (1999): 99–106.

Larson, K. "DeKooning and Alzheimer's." The World & I 12 (1997): 297–299.

MacIntrye, A. Dependent Rational Animals: Why Human Beings Need the Virtues. Chicago: Open Court Press, 1999.

Post, S. G. The Moral Challenge of Alzheimer Disease. Baltimore: Johns Hopkins University Press, 1995.

Post, S. G. The Moral Challenge of Alzheimer Disease: Ethical Issues from Diagnosis to Dying, 2d ed., rev. Baltimore: Johns Hopkins University Press, 2000.

Post, S. G., and Whitehouse, P. J. "Fairhill Guidelines on Ethics of the Care of People with Alzheimer's Disease: A Clinician's Summary." Journal of the American Geriatrics Society 43 (1995): 1423–1429.

Zarit, S. H., and Downs, M. G., eds. Generations: State of the Art for Practice in Dementia (a special issue of Generations ) 23, no. 3 (Fall 1999).

ALZHEIMER'S DISEASE

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Because its incidence and prevalence increase with age, more and more people are expected to be affected by this common condition with the increasing longevity of populations and the large cohort of baby boomers coming to maturity. Fortunately there has been a rapid increase in understanding of the clinical presentation, natural history, and pathophysiology of AD. Furthermore, there are encouraging results in symptomatic therapy and there is hope for long-term stabilization and preventive treatment.

Clinical presentation

In 1982 Professor Barry Reisberg proposed a Global Deterioration Scale that summarizes seven steps in the progression of AD and serves as an excellent means to describe its natural history (see Table 1).

The symptoms of AD are thus a combination of progressive decline in intellectual abilities and functional autonomy, very often with psychiatric features such as anxiety and depression (mostly in stages 3 and 4), followed by delusions, hallucinations, and wandering (mostly in stages 5 and 6). The latter symptoms cause a severe burden for the families and lead to nursing home placement in most countries. In the final stage of AD (stage 7), there are changes in motor tone and walking ability similar to those in Parkinson's disease. Death occurs within six to eight years after diagnosis, usually from pneumonia.

There is currently a great interest in the very early symptoms of AD, since early treatment with agents that modify the disease process can significantly delay progression from normal (stage 1) to minimal symptoms (stages 2 and 3), or from minimal symptoms to diagnosable AD (stage 4 and beyond). It appears that late onset depression with loss of interest, energy, or concentration; a long postoperative delirium; or subjective memory complaints with changes in abilities to handle finances, medication, phone, or transportation suggests the possibility of incipient AD.

Diagnosis

Most commonly family members initiate the diagnostic process by bringing the affected person to the attention of the family doctor. The progressive loss of memory for current or recent events is highlighted, with examples of missed appointments, bills paid late, and repeating stories on the phone. A decreased initiative and planning ability is often quite striking, with reduced participation in conversation. The diagnosis of AD is done primarily by a structured history with the patient and a knowledgeable informant. In addition to memory decline, the diagnosis of dementia requires a change in one other intellectual domain (such as language, recognizing objects and people, using tools, planning and adjusting to circumstances) that interferes with daily life and represents a decline from a previous level of functioning. The typical progression of AD as described in the previous section and a normal neurologic examination strongly support the diagnosis of probable AD (90 percent probability if a microscopic examination of the brain is made from a biopsy or autopsy, in which case the diagnosis can be definite). Other features can be found through history and physical examination that suggest alternative diagnosis: history of strokes or high blood pressure with asymmetric reflexes (vascular dementia or mixed AD and vascular dementia), visual hallucinations and gait instability early in the course (dementia with Lewy bodies), social disinhibition and loss of speech early in the course (fronto-temporal dementia). A concomitant disorder, such as depression, malnutrition, or hypothyroidism, would change the diagnosis of AD to "possible."

A mental status assessment is required when AD is suspected, and can range from the simple but short and reliable Mini Mental State Examination of Martial, Folstein, et al. to a structured and complete neuropsychological examination performed by a psychometrician. This may be required in highly educated individuals suspected of early stage AD, for whom the diagnosis is of some urgency because of occupational or social responsibility. Most often these tests need to be repeated within six to twelve months in order to conclusively demonstrate a decline in two cognitive domains.

The laboratory assessment of AD is currently done to support the clinical impression based on a careful history and physical examination. A minimum workup includes blood count of red and white cells; markers of thyroid, liver, and renal function; and blood sugar levels. In some countries routine additional tests include markers of nutritional deficiencies (B12, folic acid) and of previous infection with syphilis. Brain imaging using computer tomography or magnetic resonance imaging without infusion is most often performed in order to demonstrate brain atrophy and rule out tumors, blood clots, and strokes large or small. It is unusual for a brain scan to change the clinical diagnosis or management.

A number of putative biological markers of AD are under study as adjuncts to the clinical diagnosis. The best known are the blood apolipoprotein E genotype and spinal fluid levels of beta-amyloid fragments and tau. None of these markers has the specificity and sensitivity required for routine use, but this research is important for the day when individuals at risk of AD who are in presymptomatic stages will seek advice for preventive therapy.

Pathophysiology

The core pathology of AD was described by Alois Alzheimer early in 1907: extracellular senile or neuritic plaques made up of an amyloid core, surrounded by cell debris, and intracellular neurofibrillary tangles. More recently Robert Terry has emphasized the importance of neuronal cell loss, and Patrick McGeer has documented a strikingly enhanced cellular immune response in the brain of persons with AD. Peter Whitehouse has demonstrated a relatively selective loss of cholinergic neurons in basal forebrain structures, particularly the nucleus basalis of Meynert. This observation, coupled with the reduction in levels of the acetylcholinesynthesizing enzyme choline acetyltransferase, suggested a neurotransmitter deficiency amenable to pharmacotherapy, similar to dopamine deficiency in Parkinson's disease.

Genetic factors clearly play a major role in AD. Presenilin genes carried on chromosomes 1 and 14, and genes on chromosome 21 modifying beta-amyloid metabolism, cause AD at relatively young ages in a Mendelian dominant pattern. Other genes, such as apolipoprotein E on chromosome 19, increase the risk of AD but do not cause it. Many other genes related to late-onset AD (the most common type) remain to be identified.

Acquired factors over a lifetime can positively or negatively modify the genetic risks. Epidemiological studies have confirmed and found risk factors (see Table 2) and protective factors for AD (see Table 3). Caution should be exerted, since the relative importance of such factors varies between studies. For instance, smoking was considered alternatively a risk and a protective factor; it is now considered neutral as far as AD (but a major risk factor for many other health conditions). High aluminum water content and closed head trauma have been considered risk factors, but the current consensus is that this is not the case. There is currently uncertainty as to the preventive value of hormone replacement therapy (HRT) in postmenopausal women.

Some of these factors clearly make biological sense: systolic hypertension increases the risk of strokes, an additional burden to the aging brain with plaques and tangles; apolipoprotein E4 carriers have a reduced ability to maintain synaptic plasticity (or repair) abilities; NSAIDs suppress the chronic brain inflammatory response associated with neuronal loss; higher education increases the density of synaptic connections; red wine contains a natural antioxidant. Some of these factors interact: higher education and longer HRT (if confirmed to be of value in ongoing randomized studies) will lead to a reduction in the risk of AD associated with female gender. It is hypothesized that a careful weighing of these risk and protective factors for individuals could lead to a preventive strategy in which advice would be proportional to the risk. For example, a person carrying a double apolipoprotein E4 mutation (from both parents) and a positive family history of AD may want to take NSAIDs chronically. Other risk factors can be modified for all individuals, such as systolic hypertension. This strategy needs to be validated in prospective studies but offers hope of delaying onset of symptoms of AD by five to ten years for the population as a whole, thus significantly reducing the prevalence of AD within one generation.

Treatments

The global management of AD includes a number of steps (see Table 4). In most countries the family practitioner handles them all, in consultation with a variety of health professionals and other community resources throughout the course of AD. For instance, an atypical presentation or pattern of progression may suggest a diagnosis of dementia other than AD, and an expert diagnostic opinion may be needed. Depression or cognitive or behavioral symptoms unresponsive to standard pharmacotherapy may require a trial of another class of drug, with input from experienced clinicians.

Many patients in early stages of AD require treatment with an antidepressant, preferably of the selective serotonin reuptake inhibitor class, for six to twelve months. Most will want to try a cholinesterase inhibitor (CI) in an attempt to increase brain acetylcholine levels and improve symptoms. Randomized clinical trials and clinical experience have shown that in mild to moderately severe stages of AD (stages 3 to 6), therapeutic doses of CI cause an initial improvement, variable between individuals. After nine to twelve months the improvement above the starting point is followed by a slower decline in cognition and functional autonomy relative to patients not on CI, for periods lasting up to three years. It is likely but not yet fully established that CI delays the emergence of neuropsychiatric symptoms seen in stages 5 and 6. There has been some disappointment at the modest size of improvement, the relatively short duration of benefit, and the lack of predictability of who will improve. A more realistic expectation is a delay in progression of symptoms until drugs (currently in various phases of experimental testing) acting on the pathophysiology of AD are proven safe and effective, leading to a combination of symptomatic and stabilization therapy.

A number of possible treatments to delay progression of AD, based on data generated from large-scale epidemiological studies, human brain banks, and the transgenic animal models of AD (see Table 6), are available for evaluation. Largescale randomized studies are required to test these, some as long as five years, depending on the therapeutic target (for instance, delaying emergence of cognitive symptoms in healthy elderly persons, or conversion from mild cognitive impairment to diagnosable AD).

Conclusion

Although the human and societal cost of AD is staggering, there is hope that earlier and better diagnosis, increased knowledge of its natural history with support of the patient and family throughout the disease stages, effective symptomatic drugs, and potentially effective disease modification strategies will have a dramatic impact on the number of persons affected in the future, and the quality of life of persons currently affected. The fast pace of research and development in AD is unique in neurological history, and should lead to a better future for aging populations.

Serge Gauthier

See also Brain; Dementia; Dementia, Ethical Issues; Dementia with Lewy Bodies; Estrogen; Fronto-Temporal Dementia; Memory; Memory Dysfunction, Drug Treatment; Retrogenesis; Vascular Dementia.

BIBLIOGRAPHY

Breintner, J. C. S. "The End of Alzheimer's Disease?" International Journal of Geriatric Psychiatry 14 (1999): 577–586.

Gauthier, S. Alzheimer's Disease in Primary Care, 2d ed. Martin Dunitz, 1999.

Gauthier, S. "Managing Expectations in the Long-Term Treatment of Alzheimer's Disease." Gerontology 45 (1999): 33–38.

Mayeux, R., and SANO, M. "Treatment of Alzheimer's Disease." New England Journal of Medicine 341 (1999): 1670–1679.

McKhann, G.; Drachman, D.; Folstein, M.; Katzman, R.; Price, D.; and Stadlan, E. M. "Clinical Diagnosis of Alzheimer's Disease: Report of the NINCDS-ADRDA Work Group Under the Auspices of Department of Health and Human Services Task Force on Alzheimer's Disease." Neurology 24 (1984): 939–944.

MeGeer, P.; Schulzer, M.; and McGeer, E. "Arthritis and Anti-Inflammatory Agents As Possible Protective Factors for Alzheimer's Disease: A Review of 17 Epidemiological Studies." Neurology 47 (1996): 425–432.

Reisberg, B.; Ferris, S. H.; De Leon, M. J.; and Crook, T. "The Global Deterioration Scale for Assessment of Primary Degenerative Dementia." American Journal of Psychiatry 139 (1982): 1136–1139.

Rosenberg, R. N. "The Molecular and Genetic Basis of AD: The End of the Beginning." Neurology 54 (2000): 2045–2054.

Terry, R. D.; Masliah, E. E.; Salmon, D. P.; Butters, N.; DeTeresa, R.; Hill, R.; Hansen, L. A.; and Katzman, R. "Physical Basis of Cognitive Alterations in Alzheimer's Disease: Synapse Loss is the Major Correlate of Cognitive Impairment." Annals of Neurology 30 (1991): 572–580.

Thal, L. "Potential Prevention Strategies for Alzheimer's Disease." Alzheimer Disease and Associated Disorders 10, suppl. 1 (1996): 6–8.

Whitehouse, P.; Price, D. L.; Clark, A. W.; Coyle, J. T.; and DeLong, M. R. "Alzheimer Disease: Evidence for Selective Loss of Cholinergic Neurons in the Nucleus Basalis." Annals of Neurology 10 (1981): 122–126.

Alzheimer's Disease

Alzheimer's disease (AD) is a diagnosis applied to a group of degenerative brain disorders with similar clinical and pathological characteristics. It is the most common cause of dementia, with onset of symptoms after the age of fifty-five years. It is recognized as a major public health concern in societies with an aging population. AD affects four million people in the United States. At least 90 percent of those affected are over sixty-five years of age. In 1998 direct health care costs were estimated to be $50 billion. Indirect costs, such as lost productivity and absences from work, were estimated to be $33 billion.

First Description of AD

In 1907, Alois Alzheimer, a German physician from Bavaria, published the case of one of his patients. The patient, Mrs. Auguste D., at the age of fifty-one years developed an unfounded jealousy regarding her husband. This behavioral change was followed closely by a subtle and slow decline in other cognitive abilities, including memory, orientation to time and to physical location, language, and the ability to perform learned behaviors. All of her difficulties gradually progressed in severity. Within three years, the patient did not recognize her family or herself, could not maintain her self-care, and was institutionalized. She died a short four and a half years after her illness began. Her brain was removed at autopsy. Using a novel (at the time) silver stain to highlight changes in brain sections, Dr. Alzheimer viewed the tissue under his microscope. He described what are now the pathologic lesions of the disease that bears his name: loss of neurons , senile plaques found in the brain substance but outside of the neurons, and neurofibrillary tangles found inside neurons.

Dr. Alzheimer's patient had developed dementia. Dementia is an acquired and continuing loss of thinking abilities in three or more areas of cognition (which include memory, language, orientation, calculation, judgment, personality, and other functions) severe enough that the individual can no longer function independently at work or in society. There is no decrease in level of consciousness. Early in the illness, physical strength is maintained, though later the individual may "forget" how to perform certain physical functions, such as using tools or utensils, dressing, or performing personal hygiene activities. Onset of dementia may occur over days, months, or years. Its course may be static or progressive. Causes of dementia, other than AD, include other neurodegenerative disease, central nervous system infection, brain tumor, metabolic disease, vitamin deficiency, and cerebrovascular disease .

An Evolving Understanding of Dementia

Within three years of the publication of Dr. Alzheimer's first case, the term "Alzheimer's disease" was applied to patients who developed significant difficulty in memory and other areas of cognition at an age less than sixty-five years. Individuals who developed such symptoms later in life, generally after the age of sixty-five, were said to be suffering from senility, a process considered a normal part of aging. The phrase "hardening of the arteries," implying narrowing of arterial size with a reduction in blood flow to the brain, was used by physicians and by laypersons to designate the reason for senility. However, a causal relationship between arterial narrowing and senility had not been established scientifically.

Critical research reports were published in 1968 and 1970 providing evidence that senility and the disease Alzheimer described were similar both clinically and pathologically. Patients in each category developed similar and multiple cognitive deficits. Patients in each category developed plaques and tangles, and the majority of those diagnosed with senility did not have evidence of "hardening of the arteries." Over the next decade senile dementia, Alzheimer's type, would replace senility as the accepted common cause of late-life dementia.

In 1984, consensus criteria for a clinical diagnosis of AD were established. Cardinal features include the insidious onset of decline in at least two areas of cognition, gradual progression of severity in these spheres resulting in dementia, onset of symptoms between the ages of forty and ninety years (most often after age sixty-five), and absence of another medical condition that by itself could cause dementia. Pathological study of tissue after death should reveal the characteristic findings of senile plaques in age-associated numbers (numbers larger than expected for the individual's age) and of neurofibrillary tangles. Using these criteria, both Alzheimer's disease as a presenile disorder and senile dementia, Alzheimer type, are subsumed into the broader diagnosis, Alzheimer's disease.

Genetics of Alzheimer's Disease

There are three areas of evidence that indicate a genetic basis for AD. First, it occurs as a Mendelian, autosomal dominant disease of early onset (occurring before the age of sixty) in multiple families. However, the number of such families with autosomal dominant inheritance is small. Second, it is generally the case that if an individual has a first-degree relative (parent or sibling) with AD, he or she has a greater risk of developing the disease than a person with no affected first-degree relative. Finally, AD is more likely to occur in each of a pair of identical twins than it is to occur in a pair of fraternal twins .

Recognizing these observations, in the mid-1980s researchers initiated scientific efforts to identify genes of importance in the disease, using the then-emerging recombinant DNA technology. By 1995, three causative genes and one susceptibility gene had been identified: APP, PS1/2, and APOE.

APP.

In 1991, a British research group identified mutations in the APP gene that occurred only in patients with AD in very rare families. (Less than twenty such families have been reported in the medical literature.) The mutations were not found in family members who did not have AD. The APP gene codes for amyloid precursor protein, one of whose degradation products is a main constituent of the senile plaques of AD.

PS1 and PS2.

In 1992, using linkage analysis of data from early-onset, autosomal-dominant families, researchers in Seattle, Washington; Jacksonville, Florida; and Antwerp, Belgium, almost simultaneously determined

that a then-unknown gene for early-onset AD was located on chromosome 14. In 1995, a research scientist in Toronto, Canada, identified this gene as PS1, which codes for the protein called presenilin1. Individuals who have mutations in the gene consistently develop AD. Also in 1995, using comparative genomic techniques, the Seattle research group cited above identified the PS2 gene, which codes for the protein termed presenilin 2. Using data from a few large, genetically isolated families with early-and late-onset disease, they determined that mutations in the gene consistently occur only in patients with AD.

APP, PS1, and PS2 are causative genes: When mutated, each causes AD. If a person has a mutated gene, he or she will develop the disease at about the same age as others who have the same mutation. The risk of developing the disease approaches 100 percent.

APOE.

In 1993 researchers in Durham, North Carolina, reported that one form (allele ) of the APOE gene occurred more commonly in patients with late onset AD than was expected given its occurrence in the population as a whole. Numerous additional research groups corroborated the finding. The APOE gene occurs in three forms (alleles), determined by the DNA sequence. The three forms are termed APOEε2, APOEε3, and APOEε4, and they code for apolipoprotein E molecules differing from one another by only one or two amino acids. APOE is a susceptibility gene; it imparts an increased risk of disease occurrence but by itself does not cause the disease. The presence of the ε4 form (APOEε4 ) in either one or two copies in an individual increases the likelihood that the individual will develop AD. Occurrence may depend on other genetic factors or environmental factors or some combination from each category.

Additional families exist with early-onset, autosomal-dominant AD with no APP, PS1, or PS2 mutations. Such families provide evidence that there may be additional causative genes. Whole-genome-scan analyses reported in the late 1990s provide evidence of additional susceptibility genes on chromosomes 9, 10, and 12. The genes located on these chromosomes have yet to be identified.

Rationale for a Genetic Approach to Alzheimer's Disease

Alzheimer's disease, broadly defined, is a complex genetic disorder: Multiple causative and susceptibility genes acting singly or in concert produce similar symptoms and pathologic changes in patients. In each of its forms, it manifests age-dependent penetrance, meaning that the older an individual becomes, the more likely it is that he or she will develop the disease. Disease manifestations (such as age of onset or rate of progression) may be influenced by environmental exposures (alcohol use, head injury) or other health conditions (such as cerebrovascular disease). Identification of AD genes will lead to a better understanding of the cellular processes that cause dementia.

Currently, amyloid production from amyloid precursor protein is the focus of much research, although debate continues about its role. Amyloid production and deposition in the brain are affected by each of the four known AD genes. Decrease in amyloid production or increase in amyloid metabolism with a resulting decrease in deposition may result in delayed age of onset or slower progression of disease. Thus, alteration of amyloid processing of sufficient magnitude might result in disease prevention. Once process-altering treatments become available, knowing who is at risk for the disease will be important.

Genetic Testing and Alzheimer's Disease

DNA testing can be performed to determine whether an individual has a mutation in one of the causative genes and/or whether he or she carries one or two copies of the APOEε4 susceptibility gene. Whether to test and which test to perform will depend on three conditions: family history of dementia, age of onset of disease, and clinical status of the individual. If a person has dementia, the test result could be useful in determining that the cause of the dementia is a form of AD. If a person has no symptoms of dementia, an estimate of the individual's risk could be developed, using the test. In the case of such estimates, both the actual accuracy of the test and the tested individual's understanding of its accuracy are of concern. While the consensus is that presymptomatic testing for causative mutations may be performed with appropriate counseling, debate over the safety and utility of APOE testing for individuals who do not show symptoms of Alzheimer's is ongoing.

In 2001, there was no treatment that prevented, much less cured, AD. Information regarding the risk of developing AD is useful only in life planning activities (such as purchasing or offering health insurance coverage or long-term care insurance coverage, or choosing retirement age) or in family planning. An individual's ability to cope with either an increased or a decreased risk may vary. Misuse of the information resulting in insurance or employment discrimination is possible. Absence of a causative gene mutation or of an APOEε4 susceptibility gene in either symptomatic or presymptomatic disease does not preclude AD as the cause of dementia or mean that the individual has no risk of developing AD in later years.

see also Complex Traits; Disease, Genetics of; Gene Discovery; Genetic Testing; Inheritance Patterns; Psychiatric Disorders.

P. C. Gaskell Jr.

Bibliography

Mace, Nancy L., and Peter V. Rabins, eds. The 36-Hour Day, 3rd ed. Baltimore: The Johns Hopkins University Press, 1999.

St. George-Hyslop, Peter H. "Piecing Together Alzheimer's." Scientific American (Dec. 2000): 76-83.

Terry, Robert D., et al., eds. Alzheimer Disease, 3rd ed. Philadelphia, PA: Lippincott, Williams & Wilkins, 1999.

Internet Resources

"Ethical, Legal, and Social Issues." Human Genome Project, U.S. Department of Energy Office of Science. <http://www.ornl.gov/TechResources/Human_Genome/home.html>.

"Progress Report on Alzheimer's Disease, 1999." National Institute on Aging. Bethesda: National Institutes of Health, 1999. <http://www.nih.gov/nia/>.

The first preimplantation testing for the APP mutation was announced in February 2002. Four gene-negative embryos from a gene-positive woman were selected and implanted, and she gave birth to one child who was free of the gene mutation, which causes early-onset Alzheimer's disease.

Alzheimer's Disease

Alzheimer's disease (AD) is a progressive and irreversible neurological disorder that results in significant memory loss and behavioral and personality changes. It is the most common form of dementia, which is a category of diseases characterized by serious memory loss and other neurological symptoms. The two hallmarks of Alzheimer's disease are the amyloid plaques and neurofibrillary tangles that are found in the brain cells of those with a diagnosis of Alzheimer's disease. The amyloid plaques are abnormal clusters of dead nerve cells and amyloid proteins. The neurofibrillary tangles are twisted protein fragments inside the nerve cells. These plaques and tangles "clog" the messaging system in the brain and prevent neurons from communicating with each other and, hence, prevent the brain from functioning normally.

Symptoms

The Alzheimer's Association (2001) has developed a document entitled the 10 Warning Signs of Alzheimer's Disease. Forgetting names or past events is not necessarily a sign of Alzheimer's disease. However, when the memory loss is significant, such as familiar names or frequently used telephone numbers, then it may be a sign of illness. A person with Alzheimer's disease may find even the easiest tasks, such as tying one's shoes or setting the table for dinner, too hard to complete. Similarly, difficulty may arise with job performance, even if the person has been working in the same job for many years.

Word-finding difficulties or becoming easily tongue-tied are characteristics of Alzheimer's disease. Moreover, new nonsense words may be used when the correct words cannot be remembered. Having Alzheimer's disease may mean becoming easily lost, even in one's own neighborhood, or not knowing the accurate day of the week. Someone with Alzheimer's disease may wear winter clothes in the summer or make poor decisions regarding money, such as entrusting a total stranger with large sums of cash.

It is very easy to lose eyeglasses or misplace keys. However, individuals with Alzheimer's disease will lose many items, often placing them in inappropriate places, such as clothes in the freezer or milk in the cedar chest. Mood swings are common in individuals with Alzheimer's disease and often occur for no apparent reason. Someone may become quickly enraged and then immediately calm down.

Perhaps one of the most disturbing symptoms of Alzheimer's disease is the change that may occur in personality. A normally happy person may become chronically depressed or a mild-mannered person may become rude and easily agitated. Another symptom of Alzheimer's disease is excessive sleeping or unusual passivity. The individual may become chronically fatigued and uncooperative.

Causes

The cause of Alzheimer's disease remains a mystery. However, on-going research has provided clues as to possible underlying causes of the disease. Alzheimer's disease is usually categorized into two types: familial and sporadic onset (National Institute on Aging 2000). Familial Alzheimer's disease, where the cause of the disease is linked to heredity, is most often associated with an early onset of symptoms (under the age of sixty-five). Early onset cases only account for about 5 to 10 percent of the total number of Alzheimer's cases. Defects in three different genes have been linked to familial Alzheimer's disease: chromosomes 21, 14, and 1.

The most prevalent type of Alzheimer's disease is sporadic onset, which is often linked to an onset of symptoms beginning after the age of sixty-five. Indeed, increased age is one of the largest risk factors of developing Alzheimer's. During the aging process, neurons in the brain may die or shrink and lose their ability to maintain functioning. Ongoing research is looking for reasons why these changes in the brain lead to Alzheimer's disease in some people but not others. Other risk factors associated with sporadic onset Alzheimer's disease are head trauma and lesions on the brain.

Diagnosis

It is important to note that Alzheimer's disease is not a normal part of the aging process—it is a disease. Moreover, many illnesses that cause symptoms similar to Alzheimer's are treatable. Clinical depression, for example, will cause dementia-like symptoms, but is an illness that can be treated effectively with medication and other types of therapy. Consequently, it is vitally important to receive a complete neurological examination as soon as symptoms arise.

No one test serves as a definitive indicator for Alzheimer's disease. However, when administered together, a full medical history, a mental status examination, physical and neurological examinations, neuropsychology tests, and laboratory tests help physicians determine a diagnosis with a high rate of accuracy. The only way to be one hundred percent certain that a person has Alzheimer's disease is to examine brain tissue at autopsy.

When receiving a diagnosis of Alzheimer's disease, individuals are usually placed in one of two categories: probable AD and possible AD. Probable AD is an indication that the physician has eliminated other possible causes of dementia and that the symptoms are most likely caused by Alzheimer's disease. Possible AD implies that although Alzheimer's is most likely the primary reason for the dementia, other disorders, such as Parkinson's disease, may be affecting the disease's progression.

Treatments

Although there is, at present, no cure for Alzheimer's disease, a class of medications has been approved for the treatment of Alzheimer's disease in the United States, Japan, England, Italy, Canada, and many other countries. These medications are known as cholinesterase inhibitors. They improve memory by increasing levels of the chemical acetylcholine, which helps transmit messages in the brain. Another treatment for Alzheimer's disease is Vitamin E. In a widely cited study (Sano et al. 1997), results suggest that Vitamin E helps to delay the onset of symptoms. Research is also looking into the roles that other drug therapies may play in treating Alzheimer's disease, such as hormone replacement therapy and anti-inflammatory medications. The results of these research studies, however, have been inconclusive.

There are nonpharmacological treatments that can help both the person diagnosed with Alzheimer's disease and family members. These include personal and family counseling, making modifications to living arrangements, and remaining active. There is evidently some truth to the old "use it or lose it" adage. Research has consistently shown that maintaining mental activity can help stave off Alzheimer's disease. For example, in a study of older nuns (Wilson et al. 2002), results suggest that active participation in cognitively stimulating activities reduces the risk of developing Alzheimer's disease.

World Prevalence

The worldwide rates of Alzheimer's disease continue to rise. Alzheimer's Disease International, a voluntary health organization that supports a network of member associations from fifty countries, estimates that over 18 million people worldwide have dementia; two-thirds of those cases are likely Alzheimer's disease. It is projected that by 2025, 34 million will develop dementia. Of that number, over two-thirds will be from developing countries—countries that will have poor access to treatments and adequate health care.

Impact on the Family

Research has consistently shown that providing care for a family member with Alzheimer's disease is one of the most stressful of life events, particularly for women, who are more likely than men to be primary caregivers. The majority of people with Alzheimer's disease are cared for in the home, which may affect the work situation of the caregivers, their own health, and their finances. In the United States alone, direct-care costs for people with Alzheimer's disease are over $50 billion per year (Leon, Cheng, and Neumann 1998). That figure does not include billions of dollars that businesses lose each year because of productivity losses and absenteeism of caregivers.

Further Information

Several organizations are focused on providing support and education to the topic of Alzheimer's disease. Three of the most prominent are the Alzheimer's Association, Alzheimer's Disease International (ADI), and the Alzheimer's Disease Education and Referral Center (ADEAR).

Alzheimer's Association. Through its national network of chapters, the Alzheimer's Association offers a broad range of programs and services for diagnosed persons, their families, and caregivers. The Association is also the largest private funder of research directed at the cause and cure of Alzheimer's disease.

Alzheimer's Disease International. ADI is an umbrella organization for Alzheimer's Associations throughout the word. The essential role of ADI is to strengthen this network of associations so that each is better able to support families living with dementia.

Alzheimer's Disease Education and Referral Center. ADEAR is an official site of the National Institute on Aging of the U.S. Department of Health and Human Services. ADEAR provides information about the latest research breakthroughs in federally funded Alzheimer's research and about ongoing clinical trials. It is also a resource for family caregivers.

See also:Caregiving: Formal; Caregiving: Informal; Chronic Illness; Dementia; Disabilities; Elders; Health and Families; Respite Care: Adult

Bibliography

alzheimer's association. (2001). 10 warning signs ofalzheimer's disease. chicago: author.

leon, j.; cheng, c.; and neumann, p. (1998). "alzheimer'sdisease care: costs and potential savings." health affairs 17: 206–216.

national institute on aging. (2000). progress report onalzheimer's disease. bethesda, md: national institutes of health.

sano, m.; ernesto, c; thomas, r. g.; klauber, m. r.; schaffer, k.; grundman, m.; woodbury, p.; growdon, j.; cotman, c. w.; pfeiffer, e.; schneider, l. s.; thal, l. j.; and member of the alzheimer's disease cooperative study. (1997). "a controlled trial of selegiline, alpha-tocopherol, or both as treatment for alzheimer's disease." new england journal of medicine 336: 1216–1222.

shirey, l.; summer, l; and o'neill, g. (2000). alzheimer'sdisease and dementia: a growing challenge. washington, dc: national academy on an aging society.

wilson, r. s.; mendes de leon, c. f.; barnes, l. l.; schneider, j. a.; bienias, j. l.; evans, d. a.; and bennett, d. a. (2002). "participation in cognitively stimulating activities and risk of incident alzheimer disease." journal of the american medical association 287: 742–748.

other resources

alzheimer's association. available from http://www.alz.org.

alzheimer's disease education and referral center. available from http://www.alzheimers.org.

alzheimer's disease international. available from http://www.alz.co.uk.

jon c. stuckey

ALZHEIMER'S DISEASE

Alzheimer's disease is a neurodegenerative disorder characterized by loss of memory along with other cognitive changes, including aphasia (language impairment), apraxia (difficulty carrying out motor activities despite intact motor function), and agnosia (difficulty recognizing or identifying objects despite intact sensory function). There is a significant impairment in social and occupational functioning, as well as a behavioral disturbance commonly occurring in the disorder that may include apathy, loss of interest in daily activities, delusions, hallucinations, preservation, disinhibition, and depression. The cognitive, functional, and behavioral components have different manifestations at different stages of the disease, and the course of the disease is characterized by gradual onset and continuing cognitive decline.

The functional change is generally hierarchical, beginning with changes in instrumental activities of daily living (using the telephone, shopping, food preparation, housekeeping, accessing transportation, taking medications, handling finances) and later affecting the basic activities of daily living (toiletting, feeding, dressing, grooming, physical ambulation, and bathing). The onset of the disorder is insidious, and the disease progresses over ten to twenty years. In the early stages the individual may require supervision or assistance for activities such as managing finances and shopping. In the later stages, 24-hour help may be required. Social skills are often preserved until the later stages, and individuals may be very impaired or be at significant risk before the disease is recognized.

CAUSES

The cause of Alzheimer's disease is not understood completely. Age is the biggest risk factor, but other risk factors may be involved, including a low level of education and significant head injury. A family history of the disease also increases the risk. With familial Alzheimer's the inheritance is autosomal dominant, and chromosomes 1, 14, 19, and 21 have been identified as important in the inheritance. It appears that individuals with the gene apolipoprotein E4 have an increased risk, while the genes apoE2 and apoE3 may have a protective function. ApoE status, however, is not considered a part of predictive testing and apoE4 is not considered a cause of the disease. The genetics of Alzheimer's disease suggest a heterogeneous disorder, and several other genes are being investigated.

Alzheimer's disease is the most common type of dementia in older people. Prevalence estimates of dementia in Canada suggest that 8 percent of all Canadians age 65 and over have some type of dementia. Of these, 5.1 percent have Alzheimer's disease. In the larger population, rate for Alzheimer's disease was 1 percent in the 65 to 74 age group and 26 percent in those over 85 years. For all types of dementia the rates were 2.4 percent and 34.5 percent respectively. These rates are comparable to those found in incidence studies conducted in New York.

DIAGNOSIS AND TREATMENT

The diagnosis of Alzheimer's disease is made by taking a history documenting the changes in capacity compared with previous abilities. It is usually necessary to obtain collateral information from a close relative or friend in order to ascertain changes, particularly in the early stages of the disorder. An individual's general medical and surgical histories also need to be reviewed, including neurological and psychiatric histories. A complete physical examination, including a neurological examination, is imperative, along with a mental status screening test and blood work. A computed tomographic scan of the head may be helpful in some cases, particularly in patients under sixty years of age, or when there is rapid unexplained decline in cognition or function, a duration of dementia of less than two years, recent and significant head trauma, unexplained neurologic symptoms such as new onset of severe headache or seizures, and in various other instances. Other radiologic evaluations may be done, as well as certain specialized evaluations not usually part of routine clinical practice, including functional MRI and proton emission tomography (PET).

Management of Alzheimer's disease includes attention to specific problems such as safety, driving capacity, medication compliance, managing finances, and nutrition. Assistance by family members, friends, and professional persons such as lawyers and accountants can be very helpful, as can access to support services such as adult day centers and local Alzheimer's support groups. Identifying and specifically treating depression, agitation, and sleeplessness with medication and environmental modification is also important.

Judicious use of certain drugs to treat various symptoms of the disease can be undertaken as appropriate. These often include cholinesterase inhibitors such as donepezil, revistigmin, and taccine. In addition, some individuals advocate up to 2000 IU of vitamin E per day, gingko biloba, and other compounds. These therapies tend to provide symptomatic treatment and potential stabilization of the disorder for a period of time. Future therapies may include biomedical engineering for beta amyloid protein and immunization.

A diagnosis of Alzheimer's disease can be confirmed only with a brain biopsy, or through microscopical study of the brain after death. The typical lesions found include neurofibrillary tangles, senile (amyloid) plaques, and neuritic plaques. The latter is composed of a central core of homogeneous material, primarily beta amyloid, and a reactive outer zone with fibrillary and cellular material. Tau protein is the main constituent of the paired helical filaments of the neurofibrillary tangles. Other constituents include ubiquitin, a widely distributed protein. Attempts to standardize neuropathological diagnosis of Alzheimer's disease have been undertaken by Zaben Khachaturian and by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD).

Diagnosis can be confusing because there are other disorders that cause dementia, including multiple strokes, Pick disease, Lewy body dementia, and disorders associated with other neurodegenerative diseases such as progressive palsy (PSP), Parkinson's disease, and Huntington's disease. Differential diagnosis is therefore an important consideration.

As with many diseases, a number of ethical and legal issues are raised when dealing with those afflicted with Alzheimer's disease. These issues revolve around questions of daily living, such as whether it is safe for an individual to drive, to continue to live at home, and to handle financial responsibilities; and around scientific questions, particularly how cognitively impaired persons can take part in research programs. Disclosing the diagnosis of Alzheimer's disease to family members and others also causes concerns. Disclosure of the diagnosis should include a discussion of prognosis, advance planning, treatment options, support groups, and future plans.

B. Lynn Beattie

(see also: AARP; Dementia; Geriatrics; Gerontology; National Institute on Aging )

Bibliography

Canadian Study of Health and Aging Working Group (1994). "The Canadian Study of Health and Aging: Risk Factors for Alzheimer's Disease in Canada." Neurology 44:2073–2080.

—— (1994). "Canadian Study of Health and Aging: Study Methods and Prevalence of Dementia." Canadian Medical Association Journal 150:899–912.

—— (2000). "The Incidence of Dementia in Canada." Neurology 55:66–73.

Folstein, M. F.; Folstein, S. E.; and McHugh, P. R. (1975). "Mini Mental State: A Practical Method for Grading the Cognitive State of Patients for the Clinician." Journal of Psychological Research 12:189–198.

Gauthier, S., ed. (1999). Clinical Management and Diagnosis of Alzheimer's Disease, 2nd edition. London: Martin Dunitz.

Khachaturian, Z. S. (1985). "Diagnosis of Alzheimer's Disease." Archives of Neurology 42:1097–1105.

Mayeux, R., and Sano, M. (1999). "Drug Therapy: Treatment of Alzheimer's Disease." New England Journal of Medicine 341:1670–1679.

Mirra, S. S. et al. (1991). "The Consortium to Establish a Registry for Alzheimer's Disease (CERAD): Standardization of the Neuropathologic Assessment of Alzheimer's Disease." Neurology 41:479–486.

Patterson, C. J. S. et al. (1999). "Management of Dementing Disorders: Conclusions from the Canadian Consensus Conference on Dementia." Canadian Medical Association Journal 160.

Alzheimer's disease

Alzheimer's is a brain disease in which damaged and dying brain cells cause devastating mental deterioration over a period of time. Often confused with senility (mental and physical deterioration associated with old age), its symptoms include increasingly poor memory, personality changes, and loss of concentration and judgment. The disease affects approximately four million people in the United States. Although most victims are over age 65, Alzheimer's disease is not a normal result of aging. Medication can relieve some symptoms in the early stages of the disease, but there is no effective treatment or cure. Its exact cause remains unknown.

History

Alzheimer's disease is named after German neurologist Alois Alzheimer (1864–1915), who was the first to describe it. In 1906, he studied a 51-year-old woman whose personality and mental abilities were obviously deteriorating: she forgot things, became paranoid, and acted strangely. After the woman's death, Alzheimer examined her brain at autopsy (examination of a dead body to find the cause of death or investigate the damage produced by disease) and noted an unusual thickening and tangling of the organ's nerve fibers. He also found that the cell body and nucleus of nerve cells had disappeared. Alzheimer noted that these changes indicated some new, unidentified illness. More than seven decades would pass before researchers again turned their attention to this puzzling, destructive disease.

Words to Know

Beta amyloid protein: A protein that accumulates in the brains of Alzheimer's disease victims.

Neocortex: The deeply folded outer layer of the cerebrum, controlling higher brain functions such as memory, speech, and thought.

Neurofibrillary tangle: An abnormal collection of bunched and twisted fibers found in dying neurons.

Proteins: Large molecules that are essential to the structure and functioning of all living cells.

Senility: Mental and physical deterioration of old age once considered a normal process of aging.

A progressive disorder

Alzheimer's is a tragic disease that slowly destroys its victim's brains, robbing them of the thoughts and memories that make them unique human beings. Patients with Alzheimer's typically progress through a series of stages that begin with relatively minor memory loss of recent events. Gradually, loss of memory is accompanied by forgetfulness, inattention to personal hygiene, impaired judgment, and loss of concentration. Later symptoms include confusion, restlessness, irritability, and disorientation. These conditions worsen until patients are no longer able to read, write, speak, recognize loved ones, or take care of themselves. Survival after onset of symptoms is usually five to ten years but can be as long as twenty years. Persons with Alzheimer's are especially vulnerable to infection (particularly pneumonia), which is the usual cause of death.

Changes in the brain

A healthy brain is composed of billions of nerve cells (neurons), each consisting of a cell body, dendrites, and an axon. Dendrites and axons together are called nerve fibers and are extensions of the cell body. Nerve messages enter a neuron by way of the dendrites and leave by way of the axon. Neurons are separated from one another by narrow gaps called synapses. Messages traveling from one neuron to another are carried across these narrow gaps by chemicals called neurotransmitters. This highly organized system allows the brain to recognize stimuli and respond in an appropriate manner.

In Alzheimer patients, this orderly system becomes damaged to such a degree that it no longer works. The brains of Alzheimer's patients examined at autopsy show two hallmark features: (1) a mass of fibrous structures called neurofibrillary tangles and (2) plaques consisting of a core of abnormal proteins embedded in a cluster of dying nerve endings and dendrites. Lowered levels of the neurotransmitter acetylcholine (pronounced uh-seh-tuhl-KOH-leen) are also observed. The brains of Alzheimer's disease victims appear shrunken, particularly in large parts of the neocortex, the outer layer of gray matter responsible for higher brain functions such as thought and memory. Much of the shrinkage of the brain is due to loss of brain cells and decreased numbers of connections, or synapses, between them.

Diagnosing Alzheimer's disease. There is no simple procedure, such as a blood test, to diagnose Alzheimer's. A definitive diagnosis can only be made by examining brain tissue after death. Diagnosis in a live patient is based on medical history, physical examination, laboratory tests to rule out other possible causes of symptoms, and neurological exams to test mental performance. Using these methods, physicians can accurately diagnose 90 percent or more of cases.

Risk factors for Alzheimer's disease. The specific cause of Alzheimer's disease remains unknown, although risk factors include advanced age, trauma such as head injury, and gene mutations. (Genes are the units of inheritance, and mutations are permanent changes to them.) When the disorder appears in a number of family members, it is called familial Alzheimer's disease and is thought to be caused by an altered gene. Scientists are exploring the metal aluminum as a possible toxic agent involved in the development of Alzheimer's. Also being studied is the role of the neurotransmitter acetylcholine, as declining levels of this chemical result in more severe symptoms of the disease. Some scientists believe the abnormal proteins found in plaques in the brains of Alzheimer's victims may be the key to understanding the disease. Yet another factor being studied as a possible cause is a slow-acting virus.

A growing problem

The Alzheimer's Association, a nonprofit research and support organization based in Chicago, estimates that more than 100,000 Americans die of Alzheimer's each year, making it the fourth leading cause of death among adults in the United States (after heart disease, cancer, and stroke). The cost of caring for Alzheimer's patients is projected to be $80 to $90 billion per year. As more and more citizens live into their eighties and nineties, the number of Alzheimer's disease cases could reach 14 million or more before the middle of the twenty-first century.

[See also Aging and death; Brain; Dementia; Nervous system ]

ALZHEIMER'S DISEASE

More than Simple Forgetfulness

Do you ever leave the house and wonder if you remembered to turn off the iron or the water? All people experience this occasional absentmindedness, but for some it is the beginning of the loss of their minds—and a long, wasting death. In November 1989 researchers at Boston's Brigham and Women's Hospital found that more than 10 percent of people sixty-five years old and older, and nearly half of those older than eighty-five, suffered from "probable" Alzheimer's disease. This new information almost doubled previous estimates, raising the number to as many as 4 million victims nationwide. With predictions of 14 million victims by the year 2050, Alzheimer's was becoming "one of the biggest public health dilemmas we've ever encountered," according to the National Institute on Aging's deputy director, Gene Cohen. Before 1980 many Americans had never heard of Alzheimer's disease, described by some as "a living death," or "the long goodbye." Although many families watched their loved ones succumb to the disease, it did not become generally familiar to the public until the news broke that film star Rita Hayworth suffered from Alzheimer's disease.

The Long Good-Bye

Senility was long seen as an inevitable consequence of getting old. But it is not an inescapable aspect of old age; there are many reversible dementias that can be successfully treated. But Alzheimer's, a neurological condition that impairs the brain's functioning, is an irreversible disease. It is diagnosed through a process of elimination of other disorders. Neurofibrillary tangles and senile plaques in the brain characteristic of Alzheimer's disease could only prove the disease in autopsies of victims. It was the fourth leading killer of adults, causing more than one hundred thousand deaths a year. Researchers did not know the cause of the disease, although genetics was thought to play a role. Other theories suggested a slow virus, a disorder in the immune system, or excessive amounts of aluminum in the brain. First recognized in 1906 by the German neurologist Alois Alzheimer, it was marked by early forgetfulness. Within three to ten years the disease progressed through severe losses of intellectual functioning, and painful personality and physical changes. Patients were unable to speak, think, or care for themselves. Death usually occurred within ten years after diagnosis. "The emotional impact of watching a parent or spouse deteriorate is devastating," said Johns Hopkins psychiatrist Peter Rabins.

Victims and Their Families

Families bore most of the burden of care, with about 70 percent of Alzheimer's victims remaining at home. In the earlier stages of the disease, some victims were prone to wander or have out-bursts of violence and anger; in the later stages they became incontinent and could not dress or feed themselves. The twenty-four-hour needs of the Alzheimer's sufferer often severely taxed the physical and psychological stamina of caregivers and caused breakdowns in their own immune systems. Health concerns for the caregiver could begin to rival those of the patient. Alzheimer's also came to be known as "the survivor's disease." Nursing-home costs of caring for Alzheimer's sufferers ranged from $22,000 to $30,000 a year and were not covered by Medicare or by many private health insurance companies. For families to become eligible for Medicaid funds, they had to run through their savings. Community resources were important since social support was an important way for caregivers to provide for the increasing needs of their loved ones and themselves. Day-care centers for the elderly were few in 1989, and most only took Alzheimer's victims in the early stages. For "difficult" patients who needed constant watching or restraints, there was almost nothing. Neither nursing homes nor day-care centers would take these patients.

Elusive Treatments

Finding treatments were even more elusive than finding the cause. No "wonder drug" existed for the disease, nor even a clear and consistent treatment approach. Researchers found that some drugs helped some of the people some of the time, but there were puzzling inconsistencies in response from one patient to the next. Sadly, even once diagnosed, a person inevitably got worse, and as knowledge of the puzzling disease spread, sufferers had a frantic awareness in the early stages—they had it and could not do anything about it. By 1989 much was known about the symptoms of the disease, but little was known of the causes. Ongoing research attempted to unlock the secrets of the disease, but neither a full scientific understanding nor a cure existed. Before the 1980s Alzheimer's was thought to be a rare disease and few Americans had heard of it. Alzheimer's disease received considerable public attention during the 1980s. The media emphasized the impact the illness had on both its victims and their families. Most communities did not have services or care facilities developed specifically for the long-term needs of Alzheimer's patients, nor did they provide support services for the caregivers. But many communities did have agencies that provided for the various needs of the elderly, and by decade's end many of these agencies often provided support and service to both patients and care-givers. The next decade and the increased aging of America would see an increase in care facilities and other social supports for both Alzheimer's victims and their families.

Sources:

David Gelman, Mary Hager, and Vicki Quade, "The Brain Killer," Newsweek (18 December 1989): 54-56;

Howard Gruetzner, Alzheimers. A Caregivers Guide and Sourcebook (New York: John Wiley & Sons, 1988);

Abigail Trafford and Joseph Carl, "Behind Spreading Fear of Two Modern 'Plagues,'" U.S. News & World Report (12 August 1985): 46-47.

Alzheimer’s Disease

BIBLIOGRAPHY

Alzheimer’s disease (AD) constitutes about two-thirds of all dementia cases. Dementia is defined as cognitive impairment of sufficient severity to interfere with daily functioning. AD currently affects twelve million people worldwide, including over four million in the United States. These numbers could triple by 2050 due to increasing life expectancies. The prevalence of AD is approximately 1 percent among those under 70 years and increases with age to about 40 percent in those 85 years and older. It is the fourth-leading cause of death in the United States among persons older than 65 years. The term senility was used in the past to indicate severe age-related cognitive changes. It is now recognized that subtle cognitive changes do occur with aging, but very marked changes are unexpected unless there is an underlying disease process. The recognition of AD as a disease syndrome has transformed cognitive impairment from an expected stage of life to a medical problem, prompting public concern, new policies, and advocacy.

AD is characterized by a subtle onset and gradual decline. The most prominent early symptom is memory impairment, particularly the ability to remember recent events or names of familiar people or objects. This is accompanied by other, initially subtle, cognitive deficits, such as impaired verbal, spatial, or problem-solving skills. Other symptoms may include disorientation, increased irritability, mood lability, depression, anxiety, and sleep disturbance. Delusions are common, as are behavior problems (e.g., aggression, wandering, disregard for normative social conduct). As the disease progresses, basic activities of daily living, such as eating and dressing, become impaired. Late-stage AD is marked by the loss of recognizable speech and the inability to control bodily functions, leaving patients completely dependent on caregivers. Death occurs approximately eight to ten years after diagnosis (range three to twenty years).

The causes of AD are currently not fully understood. The most evident brain abnormalities are neuritic plaques (clumps of beta amyloid protein) and neurofibrillary tangles (Tau protein strands). Soluble forms of these abnormalities may be toxic to the brain. There is also a deficiency in the neurotransmitter acetylcholine, clogging of the NMDA-glutamate receptor, and considerable brain atrophy (shrinkage).

AD can be familial (inherited) or sporadic. Familial AD is rare and begins earlier in life (age 30 to 60 years). There are at least three genes that can cause familial AD: presenilin 1, presenilin 2, or the amyloid precursor protein gene. Sporadic AD typically occurs after age 65 and accounts for 90 percent of all AD cases. The primary risk factor for sporadic AD is age. Others include a family history of AD, carrying the E4 allele (variant) of the apolipoprotein E (ApoE) gene, being female, Down syndrome, head injury, a prolonged loss of consciousness, diabetes, and cardiovascular disease. Compared to Americans of European descent, African and Hispanic Americans are at greater risk for AD, whereas Asians and Native Americans are at lower risk. It is unclear whether these differences are due to genetic heritage, health, or social or cultural differences between ethnic groups. Protective factors include higher occupational attainment, education, literacy, physical exercise, and engagement in socially and intellectually stimulating leisure activities.

Current drug treatments of AD consist of cholinesterase inhibitors, which increase the neurotransmitter acetylcholine, and NMDA receptor antagonists, which block glutamate from activating NMDA receptors. There is some evidence that antioxidants (vitamins E), anti-inflammatory agents (ibuprofen, aspirin), and estrogen may slow the progression of AD. All current treatments are symptomatic and only marginally helpful. There is weak support for the effectiveness of cognitive interventions in improving cognitive and emotional health during early AD.

The burden of AD is enormous, both to society and to individual caregivers, who suffer from financial and emotional distress. Lack of effective treatment, high health care costs, and increasing numbers of patients make AD one of the most challenging medical conditions.

SEE ALSO Dementia; Disease; Medicine; Mental Health; Mental Illness

BIBLIOGRAPHY

Emilien, Gérard, Durlach, Cécile, Minaker, Kenneth L., et al., eds. 2004. Alzheimer Disease: Neuropsychology and Neuropharmacology. Basel, Switzerland: Birkhäuser Verlag.

Whitehouse, Peter J., Maurer, Konrad, and Ballenger, Jesse F., eds. 2000. Concepts of Alzheimer Disease: Biological, Clinical, and Cultural Perspectives. Baltimore, MD: Johns Hopkins University Press.

Anja Soldan

Yaakov Stern

Alzheimer's Disease, a progressive neural disorder that gradually degrades the cognitive system and culminates in death.Once considered a rare disease of middle age, Alzheimer's came to be viewed in the 1970s as a major public‐health problem in the United States, estimated to be the fourth or fifth leading cause of death in those over sixty‐five.

Alois Alzheimer of Munich first described the disease in 1906, after dissecting the brain of a woman who had died in her fifties from a progressive dementia and observing cortical atrophy, cellular plaques, and neurofribrillary “tangles.” Other physicians who verified these lesions in similar patients recognized the disease as a cause of dementia and premature senility. Nevertheless, for decades thereafter, most physicians continued to believe that memory loss and functional deterioration in the elderly were characteristic of the normal aging process. However, electron‐microscopic studies at Albert Einstein College of Medicine, by Robert Terry in the 1960s and Robert Katzman in the 1970s, identified Alzheimer's plaques and tangles in the brains of 50 to 60 percent of all elderly patients suffering from progressive dementia. In a brief but influential editorial in the Archives of Neurology in April 1976, Katzman argued that senility should be recognized not as normal aging, but as an organic disease that would significantly impact American families financially and emotionally as more of the population lived past the age of seventy.

In 1977, Katzman and Terry wrote to Donald Tower, director of the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS), explaining the need for further research on Alzheimer's disease. Tower collaborated with Robert Butler, director of the newly created National Institute on Aging (NIA), collaborated with staff of the National Institute of Mental Health in sponsoring a major Alzheimer's conference, which presented current research findings and encouraged scientists to develop new projects. Establishing a Neurobiology on Aging program within the NIA in 1977, Butler and others successfully promoted the funding and expansion of Alzheimer's research. The Health Research Services Act of 1985 established ten Centers of Excellence across the country to define diagnostic standards for the disease and to coordinate basic, clinical, and social research projects. By 1993, federal grant support for Alzheimer's research had grown from less than $5 million to more than $300 million a year.

Butler, Tower, and Katzman sought grassroots support from lay groups across the country, formed by relatives and caregivers of Alzheimer's patients. Local groups met in Washington, DC, in 1979 to organize the Alzheimer's Disease and Related Disorders Association (ADRDA). In the years that followed, ADRDA lobbied actively for federal research funding and significantly increased public interest in and concern about Alzheimer's disease.

Although the cause of Alzheimer's disease remains unknown, some researchers have hypothesized that chemical changes in certain proteins found in the brain, perhaps the result of genetic mutations or brain injury, may be the keys to its etiology. Despite significant research progress, Alzheimer's disease remains a tragic scourge and public‐health challenge, as families watch beloved relatives deteriorate, while struggling to find the resources for their care.

Bibliography

Patrick Fox , From Senility to Alzheimer's Disease: The Rise of the Alzheimer's Disease Movement, Milbank Quarterly 67 (1989): 58–102.
Robert Katzman , Current Research on Alzheimer's Disease in a Historical Perspective, in Alzheimer's Disease: Causes, Diagnosis, Treatment, and Care, eds. Zaven S. Khachaturian and Teresa Radebaugh, 1996, pp.15–29.

Marcia Meldrum

ALZHEIMER'S DISEASE

ALZHEIMER'S DISEASE, the most common cause of dementia in the United States, is characterized by a slowly progressive mental deterioration. It is named for Dr. Alois Alzheimer, a German doctor who, in 1906, noticed unusual patterns in the brain of a woman who had died of a perplexing mental illness. Alzheimer's disease is not only a problem for those afflicted but is also of great consequence for their families and society; since 1980 it has been the subject of intensive medical research. The first symptom is usually loss of ability to remember new information. The abilities to speak, dress, and be oriented to time, along with loss of old memories ensue, and ultimately even loss of memory of one's own identity occurs. The onset is usually after age sixty-five, and the disease can progress over a period of just a few years to up to two decades. Alzheimer's disease is extremely common, with conservative estimates of 5 percent of the population over age sixty-five affected. The incidence rises with increasing age, so that at least 15 to 20 percent of all individuals over age eighty are afflicted.

Changes in mental abilities are associated with three neuropathological changes in the brain: the formation of abnormal tangles within nerve cells; the widespread deposition of a characteristic protein (amyloid); and the death of nerve cells important for communicating between one brain area and another. A small percentage of individuals with Alzheimer's have inherited one of several mutant genes, each of which appears to be able to cause the disease. One such cause of Alzheimer's disease is a mutation in the gene responsible for making the amyloid protein, which accumulates in the brain of patients with Alzheimer's disease as senile plaques. Another gene partly responsible for the disease (whose specific identity is still unknown) has been found to be located on chromosome 14. Yet another genetic influence on risk of developing Alzheimer's disease, probably present in half of all cases, is inheritance of the E4 allele of apolipoprotein E. Scientists are also studying education, diet, environment, and viruses to learn what role they might play in the development of Alzheimer's disease.

A number of drugs have been used to treat Alzheimer's disease. The U.S. Food and Drug Administration (FDA) approved the first, Cognex (tacrine) in 1993. Aricept (donepezil) became available in 1996.The FDA approved Exelon (rivastigmine) in 2000 and Reminyl (galantamine) in 2001. Each of these drugs increases the amount of acetylcholine available in the brain. Of the four drugs, Cognex has the most adverse side effects.

Although treatment and knowledge of Alzheimer's disease has improved dramatically, the cause of the disease remained unknown at the beginning of the twenty-first century.

BIBLIOGRAPHY

Mace, Nancy L., and Peter V. Rabins. The 36-Hour Day: A Family Guide to Caring for Persons with Alzheimer's Disease, Related Dementing Illnesses, and Memory Loss in Later Life. Baltimore: Johns Hopkins University Press, 1981. 3d ed. 1999.

Schneider, Edward L., and John W. Rowe, eds. Handbook of the Biology of Aging. 3d ed. San Diego: Academic Press, 1990.

Whitehouse, Peter J., Konrad Maurer, and Jesse F. Ballenger, eds. Concepts of Alzheimer Disease: Biological, Clinical, and Cultural Perspectives. Baltimore: Johns Hopkins University Press, 2000.

BradleyHyman/f. b.

See alsoHuman Genome Project ; Mental Illness ; Old Age .

Alzheimer's disease , degenerative disease of nerve cells in the cerebral cortex that leads to atrophy of the brain and senile dementia. The disease is characterized by abnormal accumulation of plaques and by neurofibrillary tangles (malformed nerve cells), changes in brain tissue first described by Alois Alzheimer in 1906. The plaques result from the release and accumulation of excessive amounts of amyloid-beta (or beta-amyloid) proteins, normal proteins whose function in the body is not known. The neurofibrillary tangles prevent transportation of synthesized products within the cell body to organelles and target sites. The plaques and neurofibrillary tangles prevent proper transmission of electrochemical signals necessary for information processing and retrieval. The plaques also suffocate neurons by inhibiting proper blood supplies from reaching them.

Alzheimer's disease usually affects people over age 65, although it can appear in people as young as 40, especially in some familial forms of the disease. A condition called mild cognitive impairment, in which a person experiences an inability to form memories for events that occurred a few minutes ago, typically is the first sign of the disease. Although other conditions may cause mild cognitive impairment, if no identifiable cause is present, it leads to Alzheimer's in some 80% of the cases. As the disease progresses, a variety of symptoms may become apparent, including loss of memory, anxiety, confusion, irritability, and restlessness, as well as disorientation, impaired judgment and concentration, and more severe emotional and behavioral disorders.

The cause of Alzheimer's is unknown, but a number of genes appear to be associated with the disease. Mutations in a gene on chromosome 21, which is also associated with Down syndrome , and another gene on chromosome 14 have been found in early-onset cases. Late-onset cases, which are the vast majority, may be caused by a combination of genetic and environmental factors. In 1999 scientists discovered an enzyme, named beta-secretase, that begins the process in the brain leading to Alzheimer's disease. One study has suggested that the buildup of amyloid-beta protein in some patients is due to slower than normal clearance of the protein from the brain.

There is as yet no known cure. Genetic screening for families with a history of early Alzheimer's is sometimes advised. Treatment includes relieving the patient's symptoms and alleviating stress on caregivers through support groups and counseling services. Donepezil (Aricept), rivastigmine (Exelon), and other acetylcholinesterase inhibitors provide temporary improvement for some patients with mild to moderate Alzheimer's. Memantine (Namenda), which appears to protect against damage from the effects of excess glutamate, slows the progression of the disease in some patients in the late stage of Alzheimer's.

Bibliography: See study by D. Shenk (2001).

ALZHEIMER'S DISEASE

DEFINITION

Alzheimer's (pronounced ALTS-hih-merz) disease (AD) is the most common form of dementia (pronounced dih-MEN-sha). Dementia is a disease of the nervous system characterized by loss of certain mental abilities. This loss is severe enough to interfere with normal activities and lasts at least six months. AD is not present at birth but usually develops during old age. It is marked by a decline in mental functions such as memory, reasoning, and the ability to plan.

DESCRIPTION

A person with AD usually has a gradual decline in mental functions. The first stages include a slight loss in memory, such as the inability to remember the names of people or objects. As the disease develops, a person loses the ability to carry out familiar tasks, to reason, and to exercise judgment. Moods, personality, and ability to communicate may also be affected.

People with AD typically die within eight years of their diagnosis. Some individuals may die within a year of diagnosis, others may live as long as twenty years. AD is the fourth leading cause of death among adults in the United States after heart disease, cancer, and stroke.

Between two and four million Americans have AD. That number is expected to reach fourteen million by the middle of the twenty-first century. The reason for this growth is that the U.S. population as a whole is aging (there are more older people than younger people).

One form of AD, called early-onset AD, affects people in their forties and fifties. But the majority of AD patients are older than sixty-five. About 3 percent of those between ages sixty-five and seventy-four have the disease compared to 19 percent of those between ages seventy-five and eighty-four, and 47 percent of those over the age of eighty-four.

Alzheimer's Disease: Words to Know

Dementia:

Impaired intellectual function that interferes with normal social and work activities.

Donepezil hydrochloride (Aricept):

A drug approved for use with AD patients that increases brain activity.

Ginkgo:

An herb obtained from the ginkgo tree, thought by some alternative practitioners to be helpful in treating AD patients.

Neurofibrillary tangle:

Twisted masses that develop inside brain cells of people with AD.

Senile plaque:

Deposits that collect inside the brain cells of people with AD.

Tacrine (Cognex):

A drug that may help improve memory in people with mild to moderate cases of Alzheimer's disease.

CAUSES

The causes of AD are currently not known. Research has produced some strong leads, however, and made possible the development of some promising experimental treatments. This research has been based largely on autopsies of people who have died from AD. These autopsies show that brain cells responsible for learning, reasoning, and memory have been damaged. They have become clogged with two kinds of abnormal structures known as neurofibrillary (pronounced noor-o-FIB-ruhl-ary) tangles and senile plaques.

No one knows how these structures cause AD, but researchers have some theories. They think the structures keep brain cells from functioning normally, which prevents the transmission of brain signals from one cell to another.

This discovery has led to the development of one class of drugs for the treatment of AD. These drugs increase the amount of neurotransmitters produced in the brain. Neurotransmitters are chemicals that carry signals between brain cells. The first two drugs of this kind were approved for use by the U.S. Food and Drug Administration (FDA) in January 1998.

What triggers the formation of tangles and plaques is not known. But researchers are pursuing some possible leads. First, inflammation in the brain may be a factor. A class of drugs known as nonsteroidal anti-inflammatory drugs (NSAIDs) may prevent inflammation and reduce the risk of AD.

Free radicals are another factor in the formation of tangles and plaques. Free radicals are very active chemicals that form in the brain and damage brain cells. Chemicals known as antioxidants react with and destroy free radicals. Vitamin E is a naturally occurring antioxidant.

Genetic factors seem to be important in the development of AD. Scientists have discovered certain gene defects that appear to be related to the disease. They have found that mutations (changes) in certain genes are connected with some forms of AD. However, research in this area is at a very early stage. Little information that can be used for treatment of the disease has been uncovered.

The Alzheimer's Association has developed a list of ten warning signs of AD:

• Memory loss that affects job skills.
• Difficulty in performing familiar tasks.
• Problems with language.
• Confusion about time and place.
• Poor or diminished judgment.
• Problems with abstract thinking.
• Misplacing of things.
• Changes in mood or behavior.
• Changes in personality.
• Loss of initiative.

In spite of how little is known about the causes of AD, a number of risk factors have been identified. The most obvious of these factors is age. The older a person is, the more likely he or she will be to develop AD. Another risk factor is heredity. People whose family members have had AD, Down's syndrome (see down's syndrome entry), or Parkinson's disease (see Parkinson's disease entry) are more likely to develop Alzheimer's disease than those whose families do not have this history. People who have hypothyroidism (reduced levels of thyroid in the blood) or have experienced head injuries are also at relatively high risk for AD.

Environmental factors have sometimes been proposed as possible causes for AD. For example, the ingestion of aluminum was once thought to be a possible factor in the disease. So far, scientific studies have not been able to confirm the role of any environmental factor in causing AD.

SYMPTOMS

The earliest symptom of Alzheimer's disease is memory loss. Older people often worry that they may have AD because they forget more easily. But memory loss by itself is not an indication that a person has Alzheimer's disease. Some memory loss is a natural part of growing old.

With AD patients, however, memory loss is progressive and, eventually, so serious that they cannot function normally. In the early stages, memory loss may simply mean that the person has forgotten where he or she left the

car keys. Over time, the problem becomes so serious that he or she can no longer remember where the car is parked or how to drive it.

As AD progresses, other symptoms appear. Patients can no longer perform routine tasks, like tying shoes or eating. Many patients develop sleep disorders or become confused or disturbed in the evening. These symptoms are sometimes referred to as "sunsetting." In the final stages of the disease, patients have problems eating, communicating with others, and controlling their bladder or bowels.

Other forms of mental disorders can cause any of these symptoms. In fact, about 20 percent of those who are first suspected of having AD turn out to have some other disorder. For that reason, it is essential that a person who experiences any of the symptoms discussed see a doctor for a thorough examination.

DIAGNOSIS

Diagnosis of AD is difficult. Its symptoms are similar to those of other diseases and to those of the normal aging process. For example, loss of memory and depression (see depressive disorder entry) are symptoms of AD, but they are also typical changes that take place as a person gets older.

The only way to be absolutely sure that a person has AD is to perform an autopsy of the brain after death. The autopsy will reveal tangles and plaques that characterize AD. But this method of diagnosis is of no value to a living person.

The main approach used in diagnosing AD is to rule out other disease possibilities. To do so, a doctor uses three methods: physical examination, medical history, and a variety of tests. A physical examination is used to make sure the patient is not suffering from some other medical problem, such as an infection or a mild stroke (see stroke entry). A medical history reveals changes in the patient's behavior. It also includes questions about drugs the patient is taking and other factors that may account for AD-like symptoms. Blood and urine tests, brain scans, and other tests are used to find out if other medical conditions exist that are causing the patient's abnormal behavior.

TREATMENT

There is currently no cure and virtually no medical treatment for Alzheimer's disease. Steps can be taken, however, to make an AD patient more comfortable and to protect him or her from potential dangers posed by the disease. Both physical and emotional support can be provided for the patients who are able to do less and less for themselves.

Caregivers also need assistance. Looking after a person with AD can be discouraging and exhausting. The caregiver needs support to prevent anger, despair, and burnout. Provisions also need to be made for the financial and legal problems that arise as an AD patient is less able to think and plan clearly.

Drugs

The two drugs currently approved for use with AD patients are tacrine (pronounced tak-REEN, trade name Cognex) and donepezil (pronounced do-NEP-uh-zil) hydrochloride (trade name Aricept). Both are neurotransmitters, which increase the ability of brain cells to communicate with each other. In this way, they provide some help in improving a person's ability to think and to perform normal daily activities.

Tacrine has limited effects on patients in the early stages of AD. While it may delay their admission to a nursing homes by a few months, it is quite expensive and has side effects such as nausea, vomiting, diarrhea, stomach pain, indigestion, and skin rash. Donepezil has two advantages over tacrine: it has fewer side effects and has to be taken only once a day rather than three times a day.

Doctors sometimes prescribe other drugs for AD patients. Several preliminary studies have been made on older women who take the hormone estrogen, which is used to prevent osteoporosis (pronounced OSS-tee-o-puh-ROS-sis; see osteoporosis entry), or weakening of the bones. These studies show that women who take estrogen have lower rates of AD, and that those who do develop AD have slower disease progression and less severe symptoms.

Other early studies show promise in delaying the onset and even the risk of developing AD. The regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of developing AD. Two antioxidants, selegiline and vitamin E, are also thought to delay the onset (beginning) of AD in some people.

Care and Safety of Individuals with Alzheimer's

As the course of AD develops, individuals require more and more care. At first, the problems are relatively simple. Perhaps they lose the ability to select appropriate clothing or comb their hair. Gradually, however, they may not be able to eat, wash, or otherwise take care of themselves.

Ensuring that people with AD eat properly is one problem. Sometimes they may simply not feel hungry or forget how to prepare foods for themselves. In advanced stages of the disease, they may have difficulty in swallowing, which means they ultimately will require the use of a feeding tube.

Eventually, many people with AD become incontinent, that is, they lose control of their bowels and bladder. Problems with incontinence are among the most difficult for family members to deal with, often convincing the family to have the AD patient moved to a nursing home where regular, professional care is available.

If a person with AD remains in the home, they should be provided with a calm, non-threatening environment. Regular exercise is also important. Professional help may be necessary to deal with emotional problems, such as anxiety, depression, and hallucinations.

AD patients must also be protected from a variety of physical hazards. They usually can no longer take long walks by themselves or drive a car. Safety devices such as grab bars in the bathroom, bed rails on the bed, and wider door openings may be needed. Electrical appliances may have to be unplugged when not in use, and the hot water heater thermostat adjusted to prevent the individual from being burned.

Care for the Caregiver

Family members and others who care for a person with AD have a difficult and stressful job that becomes even harder over time. It is not unusual for caregivers to develop feelings of anger, resentment, guilt, and hopelessness. Depression is a common problem among caregivers.

For many caregivers, the most helpful way of dealing with these feelings is a support group. Support groups consist of other AD caregivers and professional counselors. Caregivers have an opportunity to discuss their thoughts and feelings with others in the same situation. Contact numbers of AD support groups can be obtained from the Alzheimer's Association and from local social service agencies, the patient's physician, or drug companies that supply medications used to treat AD.

Outside Help, Nursing Homes, and Government Assistance

The problems of caring for an AD patient often become too much for family members. In such cases, a variety of outside care is usually available. For example, some local community agencies will bring a hot meal to the patient's home each day. Some adult day-care businesses exist where the patient can spend the day under professional supervision.

Eventually, temporary outside help may not be enough. In such cases, the family may decide to move the patient to a nursing home. This decision is usually extremely hard for both the patient and the family. It can also be very expensive. In addition, the most suitable home for the patient may be located at some distance from the family home, making regular visits difficult.

Several federal governmental programs can help with the cost of care for an AD patient. These include Social Security Disability, Medicare, and Supplemental Security income. These programs do not pay for long-term nursing home stays, but they may help with the cost of care, medication, and other expenses. Information about these programs can be obtained from local Social Security and Medicare offices.

Nursing home care can also be paid for through a variety of private insurance programs. In general, these programs tend to be expensive and are not available to many people with limited incomes.

Alternative Treatment

Ginkgo extract has been suggested as a possible treatment for AD patients. Some people think the herb may help relieve the symptoms of dementia. A natural product called acetylcarnitine (pronounced uh-setl-KAR-nuh-teen) has also been proposed as a method for improving the function of brain cells. At present, there is little scientific evidence for the effectiveness of either product. Other nutritional supplements, such as vitamin B₁₂, and folic acid have been recommended for the maintenance of good mental health.

PROGNOSIS

Alzheimer's is sometimes the immediate and direct cause of death. More often, patients die from conditions that result from their generally poor and deteriorating health. Pneumonia, cancer (see cancer entry), stroke, and heart disease (see heart attack and atherosclerosis entries) are the most common of these conditions. On average, people with AD live eight years beyond their diagnosis. Some die as soon as a year after diagnosis, while others survive up to twenty years.

PREVENTION

There is currently no approved method for preventing Alzheimer's disease. There is some hope that some of the drugs mentioned, such as estrogen, NSAIDs, and vitamin E, may be useful. Additional research is being conducted to provide more information.

FOR MORE INFORMATION

Books

Gillick, Muriel R. Tangled Minds: Understanding Alzheimer's Disease and Other Dementias. New York: E. P. Dutton, 1998.

Gray-Davidson, Frena. The Alzheimer's Sourcebook for Caregivers: A Practical Guide for Getting Through the Day. Los Angeles, CA: Lowell House, 1996.

Larkin, Marilynn. When Someone You Love Has Alzheimer's: What You Must Know, What You Can Do, What You Should Expect. New York: Dell Publishing, 1995.

Nelson, James Lindemann, and Hilde Lindemann Nelson. Alzheimer's: Answers to Hard Questions for Families. San Diego, CA: Main Street Books, 1997.

Powell, Lenore S., with Katie Courtice. Alzheimer's Disease: A Guide for Families. Reading, MA: Addison-Wesley Publishing Company, 1993.

Williams, Carol Lynch. If I Forget, You Remember. New York: Delacorte Press, 1998.

Organizations

Alzheimer Association. 919 North Michigan Avenue, Suite 1000, Chicago, IL 60611. (800) 272–3900. (312) 335–8882. http://www.alz.org.

National Institute of Aging. Alzheimer's Education and Referral Center. (800) 438–4380.

Web sites

Alzheimers.com [Online] http://www.alzheimers.com (accessed on June 15, 1999).

Alzheimer Disease

Alzheimer Not Oldtimer’s

Causes, Diagnosis, and Treatment of Alzheimer Disease

Resources

Alzheimer (ALTS-hy-mer) disease (commonly called Alzheimer’s disease) is a condition in which abnormal structures (called plaques and tangles) form in the brain, accumulating over time and interfering with nerve cell connections. The disease leads to problems with memory and thinking and to changes in personality and behavior, called dementia (de-MEN-sha).

KEYWORDS

for searching the Internet and other reference sources

Dementia

Memory loss

Alzheimer Not Oldtimer’s

Alzheimer disease is named after Alois Alzheimer, the German physician who first described it in the early part of the twentieth century. Some people mistakenly call this condition “oldtimer’s disease.” Their mistake reflects the fact that it usually affects people age 65 and older, with advancing age being the single biggest risk factor for the disease. (There is an early-onset form of Alzheimer disease that strikes middle-aged adults in their thirties, forties, or fifties, often affecting several members of the same family. This form of the disease is much less common.) Experts estimate that 1 in 10 to 1 in 20 Americans over age 65 have Alzheimer disease, which translates to about 4 million people. Since people are living

ALOIS ALZHEIMER

In 1907, the German physician Alois Alzheimer published an article on what he called a “new disease of the [brain] cortex.” Little did he know that it would be named after him! In that article, he described the increasingly bizarre behavior of a 51-year-old patient and went on to describe what he found upon examining her brain after death. Here are Alzheimer’s key observations, in his own words:

“The woman, 51 years of age, showed as her first symptom a jealousy towards her husband. Soon she showed a rapidly increasing amnesia; she became lost in her own apartment, carried objects about aimlessly, hid them, sometimes believed she was to be murdered, and had spells of unrestrained screaming. . . . The autopsy showed a diffusely atrophied brain . . . remarkable changes of the neurofibrillae. In place of a normal cell, one or several fibrillae, which ran parallel to each other, were altered in a similar fashion. Over the entire brain, and especially in the upper layers, miliary centers appear, which were caused by an unusual substance . . . The glia became fibrous, and many glia cells showed fatty deposits. . . . Apparently we are dealing with an unidentified illness.”

longer than ever, as many as 14 million Americans may have this disease by the year 2050.

These positron emission tomography (PET) scans show the dramatic difference in brain activity between a healthy person (left ) and a person with Alzheimer disease (right ). Brain activity, indicated by red and yellow, has been greatly reduced in the brain at right. Photo Researchers, Inc.

In Alzheimer disease, structures called plaques and tangles form in the cerebral (se-REE-bral) cortex (KOR-teks), which is the outer surface of the brain, as well as in the brain matter just under the cortex. The cortex has several functional areas, including those involved with vision, hearing, speech understanding, and bodily awareness. These structures interfere with the normal functioning of the neurons (NU-rons), or nerve cells, and the transmission of messages between the brain and other parts of the body. Although these plaques and tangles occur to some extent with normal aging, they are much more prevalent in people who have Alzheimer disease. It is important to keep in mind that this disease is not a normal part of getting older.

At first, the condition usually hinders certain aspects of immediate memory. For example, a person might consistently forget where certain key possessions are, leave a boiling pot or kettle on the stove, or repeat the same stories. Gradually, symptoms worsen, affecting a greater portion of a person’s memory and then, quite often, personality, decision-making abilities, and language skills. Everyday activities, such as working at a job, driving a car, keeping house, balancing a checkbook, and participating in social activities, become impossible. As the disease advances, people who have it seem less and less “like themselves,” often showing drastic mood swings, unpredictable changes in temperament, inability to recognize loved ones, and increasing helplessness. At this point, people with Alzheimer disease usually need full-time care.

Causes, Diagnosis, and Treatment of Alzheimer Disease

Doctors are not sure what causes Alzheimer disease, and they do not have a simple test for diagnosing it. No treatments have proved effective in curing it. Neuroscience researchers are actively investigating these areas. They have discovered certain therapies that appear to help with the symptoms of Alzheimer disease. For example, the Food and Drug Administration has approved drugs that help slow memory loss and lessen other disease symptoms. These drugs increase the brain’s level of acetycholine [a-see-til-KO-leen], a brain chemical involved in sending messages from nerve cell to nerve cell to allow the brain to function normally.

At present, Alzheimer disease is diagnosed based on a person’s symptoms and by ruling out other possible causes. While there is no single test to show that a person has the disease, doctors now have access to technological methods that may prove very useful in diagnosing it. Using computerized tomography* scans and other special brain imaging techniques, doctors can examine the structure, blood flow, and metabolic activity* of the brain. These tests can help show the presence of Alzheimer disease.

* computerized tomography (CT)

also called computerized axial tomography, is a computer imaging technique using x-rays. These CT scans take images of “slices” of the body and brain (which do not involve actual cutting). Doctors can view these detailed images to find out what is going on inside a person.

* metabolic activity

refers to the process in the body that converts food into energy and waste products.

The causes of Alzheimer disease largely remain a mystery, except in the less common early-onset form of the disease, which is clearly linked to genes*. For the more common form of the disease, researchers have not been able to trace a clear link to heredity or to other factors, such as dietary habits, occupation, personality type, or environmental factors. Researchers are working to identify how a person’s genetic makeup and environmental factors might interact to cause this condition. At present, there is nothing a person can do to prevent Alzheimer disease, nor are there any tests available to predict whether someone will get the disease. Research in these areas may yield useful treatments for Alzheimer disease and maybe even a vaccine to prevent the disease.

* genes

are chemicals in the body that help determine a person’s characteristics, such as hair or eye color. They are inherited from a person’s parents and are contained in the chromosomes, threadlike structures inside the cells of the body.

See also

Dementia

Memory

Resources

Books

Klein, Norma. Going Backwards. New York: Scholastic, 1986. In this novel for young adults, family dynamics are strained when Grandmother Gustel, who has Alzheimer disease, moves in. Although Charles, a high school senior, tries to cope with his grandmother’s disease, his father refuses to recognize the problem.

Wilkinson, Beth. Coping When a Grandparent Has Alzheimer’s Disease. New York: Rosen Publishing Group, 1995.

Organizations

Alzheimer’s Association, 919 North Michigan Avenue, Suite 1100, Chicago, IL 60611-1676. This health organization funds research into the causes, treatment, and prevention of Alzheimer disease and provides education and support to people affected with the disease and their families through a national network of chapters. Telephone 800-272-3900 http://www.alz.org

Alzheimer’s Disease Education and Referral Center, National Institute on Aging, National Institutes of Health, P.O Box 8250, Silver Spring, MD 20907-8250. This center, a service of the U.S. government, provides research updates and referrals on its website. 800-438-4380http://www.alzheimers.org

Neuroscience for Kids is a website maintained by Associate Professor Eric Chudler at the University of Washington, Seattle. It features easy-to-understand information on a range of topics related to the brain and nervous system, including Alzheimer disease. The website gives an extensive bibliography of readings for children and teens. http://faculty.washington.edu/chudler/alz.html

Alzheimer's disease A neurological disease characterized by progressive loss of intellectual ability. The disease, which is named after German physician Alois Alzheimer (1864–1915), is associated with general shrinkage of the brain tissue, with deposits of β-amyloid protein and abnormal filaments composed of tau protein in the brain, and changes in the neurotransmitter systems within the brain that include a loss in the activity of cholinergic neurons. Some inherited forms are associated with a genetic locus on chromosome 21.

Alzheimer's disease (alts-hy-merz) n. a progressive form of dementia occurring in middle age or later, characterized by loss of short-term memory, deterioration in both behaviour and intellectual performance, and slowness of thought. It is associated with damage to cholinergic pathways in the brain and the presence of excess amyloid protein in brain tissue.[ A. Alzheimer (1864–1915), German physician]

Alzheimer's disease Degenerative condition characterized by memory loss and progressive mental impairment; it is the commonest cause of dementia. Sometimes seen in the middle years, Alzheimer's becomes increasingly common with advancing age. Many factors have been implicated, but the precise cause is unknown.