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’s Disease

Definition

Description

Causes and symptoms

Demographics

Diagnosis

Treatments

Prognosis

Prevention

Resources

Definition

Alzheimer’s disease, or AD, is a progressive, incurable disease of the brain caused by the degeneration and eventual death of neurons (nerve cells) in several areas of the brain.

Description

Patients with AD first lose such mental functions as short-term memory and the ability to learn new things. In the later stages of AD they gradually lose control over their sense of orientation, their emotions, and other aspects of behavior. End-stage AD is characterized by loss of control of body functions, an increased likelihood of seizures, loss of the ability to eat or swallow, and eventual death from infection or malnutrition. Alzheimer’s disease is the most common cause of dementia (loss of cognitive abilities) in people aged 65 and older; it is thought to be responsible for 50%-70% of cases of dementia in the United States.

Alzheimer’s disease was first identified in 1906 by a German psychiatrist and neuroanatomist named Alois Alzheimer. He was studying slides prepared from the brain of a fifty-one-year-old woman, known as Frau D., who had died after several years of dementia with symptoms that did not fit the definition of any brain disorder known at the time. Alzheimer was the first to describe the plaques and neurofibrillary tangles that are now used to identify AD at autopsy. Plaques are clumps or clusters of dead or dying nerve cells and other cellular debris found in the brains of patients with Alzheimer’s disease. Neurofibrillary tangles are the accumulations of twisted protein fragments found inside nerve cells in the brains of patients with AD. Because dementia had been associated with elderly people and Frau D. had been middle-aged, AD was first known as presenile dementia, and was thought to be a very rare disorder. It was not until the early 1950s that researchers at St. Elizabeth’s Hospital in Washington, D.C., came to recognize that AD is the single most common cause of dementia in adults.

Alzheimer’s disease is now considered a very serious public health problem because of the growing numbers of people who are affected by it, the increasing length of their lives, and the direct and indirect costs of their care. It is estimated that 4.5 million people in the United States had AD as of 2006. About 5% of people between the ages of 65 and 74, and almost 50% of people aged 85 and older, have AD. The number of cases of AD is expected to more than triple by 2050. The direct and indirect costs of caring for Americans with AD is estimated to be at least $100 billion annually.

Types of Alzheimer’s disease

There are two different types of Alzheimer’s disease.

FAMILIAL AD

Familial AD is a rare form of Alzheimer’s disease found in fewer than 10% of AD patients. It develops before the age of 65, and is caused by gene mutations on chromosomes 1, 14 or 21.

SPORADIC OR LATE-ONSET AD

Sporadic or late-onset AD is the most common form of the disease; its symptoms usually begin to appear after age 65. The cause of this type of AD is unknown. Having a particular form of the APOE gene, located on chromosome 19, increases the risk of this type of AD.

Stages

Health care professionals use the term “insidious” to describe AD, which means that it is very gradual in onset. Many times people recognize the first symptoms of the disorder in a friend or family member only in hindsight. In addition, the present generation of people old enough to be at risk for AD is the first generation in history to know what the diagnosis means; there are therefore very powerful emotional reasons for attributing the early signs of AD to normal aging, job stress, adjusting to retirement, and other less troubling factors. The insidious onset of AD is a characteristic, however, that allows doctors to distinguish it from other causes of dementia, including vascular dementia.

EARLY-STAGE ALZHEIMER’S

Early-stage Alzheimer’s disease may begin almost imperceptibly. The first symptoms usually include short-term memory loss, temporary episodes of spatial disorientation, groping for words while one is speaking, minor problems with arithmetic, and small errors of judgment. For example, the person may light a stove burner under a saucepan before noticing that he has forgotten to put the food or water in the pan first, or he may have difficulty balancing a checkbook as quickly as he used to. At this stage in the disease, however, the patient can usually keep up with most activities of daily life. Although some persons at this point can still operate a motor vehicle safely, it is advisable to consult a physician about possible impairment behind the wheel. Many patients with early-stage AD voluntarily give up their driver’s licenses for their own safety and that of other drivers on the roads.

MIDDLE-STAGE ALZHEIMER’S

rsquo;s. In the middle stage, which typically begins two to three years after onset, the person begins to lose awareness of his or her cognitive deficits. Memory lapses are more frequent and the person begins to have more severe problems with language. Unlike early-stage AD, the problems caused by loss of cognitive functioning are impossible to ignore. The middle stage of AD is the point at which the behavioral and psychiatric symptoms that are so stressful to caregivers often begin—the agitation, wandering, temper outbursts, depression, and disorientation. The patient is at high risk for falls and similar accidents. In addition, the patient becomes increasingly unable to understand simple instructions or to follow a conversation, and begins to lose his or her basic sense of personal identity.

END-STAGE ALZHEIMER’S

End-stage Alzheimer’s disease is marked by the loss of the ability to walk and eventually even to sit up. Patients may be able to use a wheelchair for awhile, but eventually become completely bedridden. They lose bladder and bowel control. When the disease begins to affect the patient’s brain stem, the basic processes of digestion, respiration, and excretion shut down. Patients usually stop eating at this point and sleep most of the time. The hands and feet begin to feel cold, the breathing becomes shallow, and the patient is generally unresponsive to caregivers. Eventually the patient’s breathing simply stops.

Causes and symptoms

Causes

Evidence has accumulated that Alzheimer’s disease is multifactorial—that is, it is caused by a combination of several genetic and environmental factors.

GENETIC

Early-onset AD is caused by a defect in one of three genes known as APP, presenilin-1 (PS1 ), and presenilin-2 (PS 2). The APP gene is found on chromosome 21. People with Down syndrome, who have three copies of chromosome 21, develop an Alzheimer’s type dementia if they live longer than 40 years of age. A family history of Down syndrome is associated with a greater risk of developing early-onset AD. Mutations of the APP gene are associated with an onset of AD between the ages of 55 and 60.

The PS 1 gene is found on chromosome 14, and the PS2 gene is found on chromosome 1. Mutations in these genes are associated with an onset of AD between 30 and 50 years.

The APP, PS 1 and PS2 gene mutations are very rare, and only account for about 5% of all cases of AD.

Genetic research indicates that late-onset Alzheimer’s disease is a polygenic disorder; that is, its development is influenced by more than one gene. It has been known since 1993 that a specific form of a gene for apolipoprotein E (APOE4) on human chromosome 19 is a genetic risk factor for late-onset AD. People who inherit the APOE4 gene from both parents have a greater chance of developing AD than those who inherit the gene from only one parent. About 65% of people with AD have at least one copy of the APOE4 gene. One of the remaining puzzles about this particular gene, however, is that it is not a consistent marker for AD. In other words, some people who have the APOE4 gene do not develop AD, and some who do not have the gene do develop the disorder. Researchers are working on identifying other genes that may also influence people’s susceptibility to AD.

Familial Alzheimer’s disease appears to be related to abnormal genes on human chromosomes 21 and 14.

NEUROBIOLOGICAL

Investigators since Alois Alzheimer’s time have studied the abnormalities found at autopsy in the brains of patients with AD. One abnormality is plaques, or clumps, of a sticky protein called beta amyloid. Beta amyloid is formed when a substance called amyloid precursor protein, or APP, fails to be metabolized properly in the body. After beta amyloid is formed, pieces of it then stick to one another and gradually build up into plaques. The other abnormal finding is neurofibrillary tangles, which are twisted threads of a protein called tau that form inside nerve cells. If the tau protein is damaged by the addition of molecules of phosphorus, a process called hyperphosphorylation, it forms filaments that twist around each other to form the neurofibrillary tangles. Research suggests that the abnormal tau protein may be caused by increases in amyloid. As the plaques and tangles accumulate in the brain, they cause the nerve cells to wither and eventually die. As the nerve cells die, the affected parts of the brain start to shrink in size. It is still not known, however, whether the plaques and tangles are causes of AD or results of it.

Another nervous system abnormality in AD is the lowered level of neurotransmitters produced by the cells in the brain. Neurotransmitters are chemicals that carry nerve impulses across the small gaps (synapses) between nerve cells. The neurotransmitters affected by Alzheimer’s include serotonin, norepinephrine, and acetylcholine. Many of the behavioral and psychiatric problems associated with AD are thought to result from the inadequate supply of these neurotransmitters.

ENVIRONMENTAL

Researchers have been studying the possibility that certain chemicals or other toxins in the environment may have a role in causing or triggering AD. The environmental factors that have been considered include aluminum, zinc, toxins in contaminated food, viruses, and a history of head trauma.

RISK FACTORS

A number of factors have been identified that increase a person’s risk of developing Alzheimer’s:

• Age. The risk of developing AD rises after age 65, and rises sharply after age 75. While 1% of the population has AD at age 65, almost 50% of those over 85 have it.
• Sex. Women are more likely to develop AD than men. However, it is not known whether women are more susceptible to the disorder or more likely to develop it because they live longer than men, on average.
• Family history of AD.
• Having Down syndrome.
• History of head injury.
• Substances in the environment. Higher-than-average amounts of aluminum have been found in the brains of patients with AD. Some researchers in the late 1990s thought that exposure to aluminum might be a risk factor for the disorder. It now appears that the levels of aluminum in the brains of patients are a result rather than a cause of AD.
• Low occupational attainment and education level. Studies have found a clear correlation between employment in jobs that are not mentally challenging and an increased risk of AD. In addition, taking less rather than more challenging jobs as one grows older is associated with a higher risk of AD.
• High systolic blood pressure.
• High blood cholesterol levels. When both high systolic blood pressure and high cholesterol are present, the risk of developing AD increases by a factor of 3.5.
• Mild cognitive impairment (MCI). Mild cognitive impairment is a transitional decline in cognitive functioning that precedes the onset of AD. MCI is characterized primarily by memory loss while other cognitive functions remain intact. Persons with MCI are at higher risk for AD than people who do not develop the condition; 12% of people with mild cognitive impairment develop Alzheimer’s disease each year, compared with 1-2% per year of people without MCI. After four years, 40% of people diagnosed with mild cognitive impairment have clear symptoms of Alzheimer’s disease.
• Diet. Researchers suspect that a high-cholesterol, high-fat diet may be implicated in the onset of AD. High levels of an amino acid called homocysteine may also be a risk factor for late-onset AD.

Symptoms

The symptoms of AD can be grouped into three categories: cognitive deficits, or losses of brain function related to memory and learning; behavioral and psychiatric symptoms of dementia, or BPSD; and problems with activities of daily life, or ADLs.

COGNITIVE DEFICITS

There are four major symptoms of loss of cognitive capacities in AD:

• Amnesia. Amnesia refers to memory impairment; however, loss of short-term memory also means that the patient loses his or her sense of time as well.
• Aphasia. Aphasia refers to loss of language function. The person may not remember the names of objects and may use words like “thing” or “it” instead; they may echo what other people say or repeat a word or phrase over and over. On occasion the person may lose the ability to speak except for curse words.
• Apraxia. Apraxia is the loss of the ability to perform voluntary movements in the absence of paralysis. For example, person with apraxia may have trouble putting on a hospital gown or brushing his or her teeth.
• Agnosia. Agnosia comes from a Greek word that means “to not know”, and refers to inability to recognize familiar places and people. Patients with agnosia may even fail to recognize their own face in a mirror.

NEUROPSYCHIATRIC SYMPTOMS

Symptoms associated with BPSD include:

• Depression. Depression associated with AD is thought to result from the lowered production of the neurotransmitter serotonin. Depression in AD can be treated with medication, usually with one of the selective serotonin reuptake inhibitors, or SSRIs.
• Delusions. A delusion is a false belief that a person maintains even when presented with contrary evidence. For example, patients with AD may say that a person is stealing their things when they cannot remember where they have put them. Suspicions of other people caused by delusions can sometimes be treated with medication.
• Wandering. This behavior may result from becoming disoriented and getting lost, but sometimes people with AD wander for no apparent reason. The Alzheimer’s Association in Chicago has a Safe Return Hotline that can be contacted for information about registering a patient with AD. If the registered patient should wander from home, the Safe Return Hotline can help identify the patient and return him or her to their family or nursing home.
• Hallucinations. Like delusions, hallucinations in AD patients are thought to be related to the deterioration of the patient’s brain tissue. In a hallucination, the patient has a sensory experience that is real to him or her but not to other people. Hallucinations can affect any of the senses, but most are either visual or auditory. For example, a patient with AD may say that he or she sees little Martians in the corner of the room, or that he or she hears the voice of a long-dead parent calling to them. Hallucinations are sometimes caused by medications that the patient may be taking.
• Aggression. Aggression refers to hitting, shoving, pushing, or threatening behavior.
• Agitation. Agitation refers to emotionally excited behavior (screaming, shouting, cursing, pacing, fidgeting, etc.) that is disruptive or unsafe. Agitation may result from the changes in the patient’s brain tissue, or it may be a symptom of depression associated with Alzheimer’s disease.

For most of the twentieth century, studies of patients with AD focused on the cognitive symptoms of the disorder. It was not until the 1980s and 1990s that researchers began to look more closely at the behavioral and psychiatric symptoms of AD. Such methods of standardized assessment of these symptoms as the neuropsychiatric inventory are very recent developments.

PROBLEMS WITH ACTIVITIES OF DAILY LIVING (ADLS)

Needing help with ADLs, or personal care activities that are part of everyday living, is among the earliest symptoms of AD. The functions that are often affected include:

• eating, including simple cooking and washing dishes
• bathing, showering, or shaving
• grooming and dressing in clothing appropriate to the weather and activity
• toileting
• other aspects of personal hygiene (brushing teeth or cleaning dentures, washing hair, etc.)
• shopping for groceries and other necessary items

Health care professionals usually assess the ADLs of a patient diagnosed with AD in order to determine what type of care is needed.

Demographics

Some demographic statistics in the developed countries have already been cited in the context of risk factors for AD and public health concerns related to the disorder.

AD is thought to be less prevalent in non-Western developed countries such as Japan, and in less industrialized countries such as India and Nigeria. However, relatively little is known about the demographics of AD and other forms of dementia in the developing countries. Alzheimer’s Disease International, which is based in London, supports a group of researchers called the 10/66 Dementia Research Group. The 10/66 group is trying to correct the global imbalance of AD research; as of 2001, fewer than 10% of all population-based research studies of AD and related forms of dementia have been directed toward the 66% of people with these disorders who live outside the developed countries.

Diagnosis

Currently, the diagnosis of AD is essentially a process of exclusion. A skilled physician can diagnose probable AD with 90% accuracy, but the diagnosis can only be confirmed post mortem (after death), by performing an autopsy and examining the patient’s brain tissue.

Diagnostic evaluation of AD

At present, the diagnostic process includes the following components:

• Clinical interview. In the absence of laboratory tests or imaging studies that can provide definite diagnoses, the physician must rely on his or her clinical judgment. In evaluating the patient, the doctor will assess signs of cognitive impairment other than short-term memory loss. In most cases, the doctor will ask a family member or close friend of the patient about the suddenness of symptom onset and the length of time that the patient seems to have been impaired.
• Physical examination. The patient will be given a complete physical and have blood and urine samples taken to rule out vitamin deficiencies, head trauma, tertiary syphilis, thyroid disorders, and other possible causes of dementia. The doctor will also review all the medications that the patient is taking (including alternative remedies) in order to exclude reversible dementia caused by drug interactions.
• Neurological examination. In early AD, the neurological findings are usually normal. If the patient appears to have had a stroke, he or she will be referred for a more thorough assessment by a neurologist.
• Tests of cognitive function. The patient will be given the mini-mental status examination (MMSE) and such other tests of cognitive function as the clock test or verbal fluency tests. The MMSE is a screening test and should not be used by itself to make the diagnosis of AD. In addition, the MMSE is not very sensitive in detecting cognitive impairment in people who previously functioned at a high level and were well educated. It is possible for a well-educated person to score a perfect 30 on the MMSE and still have cognitive impairment. The clock test is a test in which patients are asked to draw a clock face. Sometimes, patients will also be asked to include a specific time on the clock, such as 3:20. Patients with AD often draw the face of the clock with numbers out of order, or all of the hour markers in a portion of the clock face instead of evenly spaced around the face, and often have difficulty adding the clock hands.
• Neuropsychiatric evaluation. A neuropsychiatric examination may be given to determine the pattern of the patient’s cognitive impairment and probe his or her level of functioning more deeply. The patient may be asked to write a sample check, to describe how they answer the phone, to interpret sample traffic signs, and to look at a shopping list and pick out the items on the list from a display.
• Diagnostic imaging. Imaging studies are useful in detecting such causes of dementia as a previously undiagnosed brain tumor or abnormal brain structure. Scans can show doctors that certain areas of the brain have lost tissue (as happens in AD), and can strengthen a physician’s suspicion of a patient’s AD diagnosis, but scans cannot diagnose AD on their own. Scans are used more to rule out other possible diagnoses and to confirm a suspected diagnosis. CT (computed tomography) scans are commonly performed, as well as MRI (magnetic resonance imaging) scans in patients who are having problems with gait or balance. PET (positron emission tomography) and SPECT (single photon emission computed tomography) scans can be used to evaluate patterns of glucose (sugar) metabolism in the brain and to differentiate the patterns that are characteristic of Alzheimer’s from those associated with vascular dementia and Pick’s disease. PET scans are more precise than SPECT scans, but their cost may be prohibitive.

Ethical considerations

A blood test can determine whether a person has the APOE4 gene. However, since APOE4 is only a risk factor for AD rather than a cause, the test cannot determine whether a person will develop AD. The National Institute on Aging does not recommend using the test to screen people for AD. One reason is that the test results are not conclusive—some people who eventually develop AD do not carry this gene, and some people who carry the gene do not develop AD. Another important reason is that there are ethical implications of testing for a disease that presently has no cure, in terms of the psychological consequences for patients and their families and the possible loss of health insurance and job opportunities for people found to be carrying the gene. These considerations may change, however, if researchers discover better treatments for

KEY TERMS

Acetylcholine —A naturally occurring chemical in the body that transmits nerve impulses from cell to cell. Generally, it has opposite effects from dopamine and norepinephrine; it causes blood vessels to dilate, lowers blood pressure, and slows the heartbeat. Central nervous system well-being is dependent on a balance among acetylcholine, dopamine, serotonin, and norepinephrine.

Agitation —Excessive restlessness or emotional disturbance that is often associated with anxiety or psychosis. Agitation may be associated with middle-stage Alzheimer’s disease.

Agnosia —Loss of the ability to recognize familiar people, places, and objects.

Amygdala —An almond-shaped brain structure in the limbic system that is activated in stressful situations to trigger the emotion of fear. It is thought that the emotional overreactions in Alzheimer’s patients are related to the destruction of neurons in the amygdala.

Amyloid —A waxy translucent substance composed mostly of protein, that forms plaques (abnormal deposits) in the brain during the progression of Alzheimer’s disease.

Aphasia —Loss of language abilities.

Apolipoprotein E —A protein that transports cholesterol through the body. One form of this protein, APOE4, is associated with a 60% risk of late-onset AD.

Apraxia —Inability to perform purposeful movements that is not caused by paralysis or loss of feeling.

Beta amyloid protein —A starchy substance that builds up in the brains of people with AD to form the plaques that are characteristic of the disease. Beta amyloid is formed when amyloid precursor protein, or APP, is not broken down properly by the body.

Bleomycin hydrolase —An enzyme involved in the body’s processing of amyloid precursor protein. If the gene that governs production of BH mutates, the APP accumulates, producing the plaques in the brains of patients with AD.

Brain stem —The part of the brain that is continuous with the spinal cord and controls most basic life functions. It is the last part of the brain that is destroyed by Alzheimer’s disease.

Cholinesterase inhibitors —A group of medications given to slow the progression of Alzheimer’s disease.

Delirium —A disturbance of consciousness marked by confusion, difficulty paying attention, delusions, hallucinations, or restlessness. It can be distinguished from dementia by its relatively sudden onset and variation in the severity of the symptoms.

Dementia —A group of symptoms (syndrome) associated with a progressive loss of memory and other intellectual functions that is serious enough to interfere with a person’s ability to perform the tasks of daily life. Dementia impairs memory, alters personality, leads to deterioration in personal grooming, impairs reasoning ability, and causes disorientation.

primary dementia, more effective preventive methods, or more reliable genetic markers for AD.

Treatments

At present the mainstay of Alzheimer’s treatment is medication, both to slow symptom progression and to manage the behavioral and psychiatric symptoms of AD.

Medications to slow symptom progression

The medications most commonly given to delay the progression of symptoms in AD are a group of drugs called cholinesterase inhibitors. These drugs were approved by the FDA over a decade ago. They work by slowing down the body’s destruction of the neurotransmitter acetylcholine.

The cholinesterase inhibitors include:

• Tacrine (Cognex). This drug is the oldest cholinesterase inhibitor in use. It is used less often than newer agents because it must be taken four times a day and may cause liver damage.
• Donepezil (Aricept). This drug is the one used most commonly as of 2002 to treat AD. It has fewer side effects than tacrine and can be given in one daily dose.
• Rivastigmine (Exelon). This drug is taken twice daily.
• Galantamine (Reminyl). This is the newest cholinesterase inhibitor, approved in late 2001. It acts on an additional acetylcholine receptor.

None of these medications provides more than modest benefits to patients with AD: they slow the progression of symptoms for about six months to a year in one-third to one-half of patients with AD. In addition, the cholinesterase inhibitors have side effects, most commonly nausea, vomiting, diarrhea, muscle cramps, and sleep disturbances.

Another medication that has recently been approved for AD is memantine (Namenda). Memantine

Down syndrome —A genetic disorder characterized by an extra chromosome 21 (trisomy 21), mental retardation, and susceptibility to early-onset Alzheimer’s disease.

Gingko —A shade tree native to China with fan-shaped leaves and fleshy seeds with edible kernels. Gingko extract is being studied as a possible complementary or adjunctive treatment for Alzheimer’s disease.

Hallucination —False sensory perceptions. A person experiencing a hallucination may “hear” sounds or “see” people or objects that are not really present. Hallucinations can also affect the senses of smell, touch, and taste.

Hippocampus —A part of the brain that is involved in memory formation and learning. The hippocampus is shaped like a curved ridge and belongs to an organ system called the limbic system.

Insidious —Proceeding gradually and inconspicuously but with serious effect.

Mild cognitive impairment (MCI) —A transitional phase of memory loss in older people that precedes dementia or Alzheimer’s disease.

Neurofibrillary tangles —Accumulations of twisted protein fragments found inside the nerve cells in the brains of patients with Alzheimer’s disease.

Neurotransmitters —Chemicals that carry nerve impulses from one nerve cell to another. Alzheimer’s disease causes a drop in the production of several important neurotransmitters.

Plaques —Clumps or clusters of beta amyloid fragments, dead or dying nerve cells, and other cellular debris, found in the brains of patients with Alzheimer’s disease.

Polygenic —A trait or disorder that is determined by a group of genes acting together. Most human characteristics, including height, weight, and general body build, are polygenic. Schizophrenia and late-onset Alzheimer’s disease are considered polygenic disorders.

Post mortem —After death. The definitive diagnosis of Alzheimer’s disease can be made only after the patient’s death.

Presenile dementia —An older name for Alzheimer’s disease.

Pseudodementia —A term for a depression with symptoms resembling those of dementia. The term “dementia of depression” is now preferred.

Systolic —Referring to the rhythmic contraction of the heart (systole), when the blood in the chambers of the heart is forced out. Systolic blood pressure is blood pressure measured during this phase.

Tau protein —A protein that is involved in maintaining the internal structure of nerve cells. The tau protein is damaged in Alzheimer’s disease and ends up forming the neurofibrillary tangles.

tine is thought to regulate the activity of a neurotransmitter called glutamate. When used alone or together with donezapil, it appears to help AD patients to function better cognitively.

Because brain inflammation may contribute to AD, researchers are studying nonsteroidal anti-inflammatory drugs, such as celecoxib (Celebrex) and naproxen (Aleve), to see whether they can slow the onset of AD. Recent studies have shown that naproxen and another anti-inflammatory nonsteroid drug, rofecoxib (Vioxx) do not, however, slow the progression of AD in people who have already developed AD.

Medications for BPSD

Medications are also prescribed to manage the behavioral and psychiatric symptoms of AD, which are often quite stressful for caregivers if the patient is being cared for at home. These medications are usually prescribed for specific symptoms:

• Delusions: Antipsychotic drugs, usually haloperidol (Haldol) or risperidone (Risperdal).
• Agitation: Short-term anti-anxiety drugs, usually lorazepam (Ativan) or buspirone (BuSpar).
• Depression: One of the selective serotonin reuptake inhibitors (SSRIs), at half the dosage for a young adult.
• Pain: Acetaminophen or a very low dose of codeine.

In general, older patients require lower dosages than those given to younger adults. Patients with AD are also more susceptible to the side effects of medications. For these reasons, physicians often recommend making changes in the patient’s environment to reduce the behavioral symptoms before trying medications.

Alternative and complementary treatments

Some complementary therapies have been shown to benefit patients with Alzheimer’s.

NATUROPATHY

A naturopathic approach to AD includes supplementing antioxidant vitamins (vitamins A, E, and C) in the patient’s diet, along with adding carotenoids, small amounts of selenium and zinc, and thiamine. Research shows that vitamin E can slow the progression of some symptoms of AD by about seven months. Currently, research is being done to find out whether vitamin E can prevent or delay AD in patients who have MCI. Botanical supplements that have been said to improve cognitive function include an extract made from Gingko biloba, a tree that is native to China. GBE, or gingko biloba extract, is the most frequently used herbal medicine in Europe. It is available in Germany by prescription and in an over-the-counter form, and has been approved by the German Commission E for dementia-related memory loss. Gingko extract is thought to work in a manner similar to the cholinesterase inhibitors. At present, the National Center for Complementary and Alternative Medicine (NCCAM) is conducting studies of gingko extract as a treatment for Alzheimer’s.

MUSIC THERAPY

Music therapy has been found to calm agitated patients with AD, to improve mood, and to enhance long-term memory. Old familiar songs are particularly effective in improving recall. In other studies, music therapy has been shown to reduce sensations of chronic pain in patients with AD.

Prognosis

There is no cure for Alzheimer’s disease. The prognosis is progressive loss of mental and bodily functions leading to death within seven to ten years. Some patients, however, die within three years of diagnosis and others may survive for as long as fifteen.

Prevention

Researchers are considering several different strategies to prevent AD. A vaccine to prevent the formation of beta amyloid plaques was initially tested in animals, but clinical trials in humans were stopped because of dangerous side effects. Research on new treatment approaches continues.

See alsoDementia; Mini mental state examination (MMSE).

Resources

BOOKS

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th edition, text revised. Washington, DC: American Psychiatric Association, 2000.

Butcher, James N., Susan Mineka, and Jill M. Hooley, Abnormal Psychology. Boston, MA: Pearson Education, Inc., 2007.

Keck, David. Forgetting Whose We Are: Alzheimer’s Disease and the Love of God. Nashville, TN: Abingdon Press, 1996.

Mace, Nancy L., and Peter V. Rabins. The 36-Hour Day. Revised and updated edition. New York: Warner Books, Inc., 2001; by arrangement with The Johns Hopkins University Press.

Pelletier, Kenneth R., MD. The Best Alternative Medicine. Part II. “CAM Therapies for Specific Conditions: Alzheimer’s Disease.” New York: Simon and Schuster, 2002.

Shenk, David. The Forgetting: Alzheimer’s: Portrait of an Epidemic. New York: Doubleday, 2001.

PERIODICALS

Aisen, P. S., J. Schmeidler, and G. M. Pasinetti. “Randomized Pilot Study of Nimesulide Treatment in Alzheimer’s Disease.” Neurology 58 (April 9, 2002): 1050–1054.

Bone, Kerry. “Gingko and Alzheimer’s Disease.” Townsend Letter for Doctors and Patients (January 2001): 27.

Delargarza, V.W., MD. “Pharmacologic Treatment of Alzheimer’s Disease: An Update.” American Family Physician 68, no. 7 (October 1, 2003): 1365–1372.

Desai, P. P., H. C. Hendrie, R. M. Evans, and others. “Genetic Variation in Apolipoprotein D Affects the Risk of Alzheimer’s Disease in African Americans.” American Journal of Human Genetics 69 (October 2001): 416.

Editorial Commentary. “Neuropsychiatric Phenomena in Alzheimer’s Disease.” Journal of Neurology, Neurosurgery and Psychiatry 71 (December 2001): 715.

“Head Injury Linked to Increased Risk of Alzheimer’s Disease.” FDA Consumer 35 (January-February 2001): 8.

Holmes, C., H. Smith, R. Ganderton, and others. “Psychosis and Aggression in Alzheimer’s Disease: The Effect of Dopamine Receptor Gene Variation.” Journal of Neurology, Neurosurgery and Psychiatry 71 (December 2001): 777-779.

in’t Veld, Bas A., Annemieke Ruitenberg, Albert Hofman, and others. “Nonsteroidal Anti-inflammatory Drugs and the Risk of Alzheimer’s Disease.” New England Journal of Medicine 345 (November 22, 2001): 1515–1521.

Khosh, Farhang. “Naturopathic Approach to Alzheimer’s Disease.” Townsend Letter for Doctors and Patients (July 2001): 22–24.

Kim, S. Y., J. H. Karlawish, E. D. Caine. “Current State of Research on Decision-Making Competence of Cognitively Impaired Elderly Persons.” American Journal of Geriartic Psychiatry 10 (March-April 2002): 151-165.

Kivipelto, M., and others. “Midlife Vascular Risk Factors and Alzheimer’s Disease in Later Life: Longitudinal, Population-Based Study.” British Medical Journal 322 (June 16, 2001): 1447–1451.

Langbart, C. “Diagnosing and Treating Alzheimer’s Disease: A Practitioner’s Overview.” Journal of the American Academy of Nurse Practitioners 14 (March 2002): 103-109.

Luedecking-Zimmer, E., S. T. DeKosky, M. I. Kamboh. “Candidate Genes for Late-Onset Alzheimer’s Disease on Chromosome 12.” American Journal of Human Genetics 69 (October 2001): 518.

Olin, J. T., I. R. Katz, B. S. Meyers, and others. “Provisional Diagnostic Criteria for Depression of Alzheimer Disease: Rationale and Background.” American Journal of Geriatric Psychiatry 10 (March-April 2002): 129-141.

Shigenobu, K., M. Ikeda, R. Fukuhara, and others. “Reducing the Burden of Caring for Alzheimer’s Disease Through the Amelioration of ‘Delusions of Theft’ by Drug Therapy.” International Journal of Geriatric Psychiatry 17 (March 2002): 211-217.

Silverman, Daniel H. S., Gary W. Small, Carol Y. Chang, and others. “Positron Emission Tomography in Evaluation of Dementia: Regional Brain Metabolism and Long-Term Outcome.” Journal of the American Medical Association 286 (November 7, 2001): 2120.

Sloane, P. D., S. Zimmerman, C. Suchindran, and others. “The Public Health Impact of Alzheimer’s Disease, 2000-2050: Potential Implication of Treatment Advances.” Annual Review of Public Health 23 (2002): 213-231.

Walsh, D. M., I. Klyubin, J. V. Fadeeva, and others. “Naturally Secreted Oligomers of Amyloid Beta Protein Potently Inhibit Hippocampal Long-Term Potentiation in Vivo.” Nature 416 (April 4, 2002): 535-539.

ORGANIZATIONS

Alzheimer’s Association. 919 North Michigan Avenue, Suite 1100, Chicago, IL 60611-1676. Telephone: (800) 272-3900 or (312) 335-8700. Fax: (312) 335-1110. <http://www.alz.org>.

Alzheimer’s Disease Education and Referral (ADEAR) Center. P. O. Box 8250, Silver Spring, MD 20907-8250. Telephone: (800) 438-4380. <http://www.alzheimers.org>.

Alzheimer’s Disease International. 45-46 Lower Marsh, London SE1 7RG, UK. Telephone: (+44) 20-7620-3011. Fax: (+44) 20-7401-7351. <http://www.alz.co.uk>.

National Center for Complementary and Alternative Medicine (NCCAM) Clearinghouse. P.O. Box 7923, Gaithersburg, MD 20898. Telephone: (888) 644-6226. TTY: (866) 464-3615. Fax: (866) 464-3616. <http://www.nccam.nih.gov>.

National Institute of Mental Health. 6001 Executive Boulevard, Room 8184, MSC 9663, Bethesda, MD 20892-9663. Telephone: (301) 443-4513. <http://www.nimh.nih.gov>.

National Institute of Neurological Disorders and Stroke (NINDS). Building 31, Room 8A06, 9000 Rockville Pike, Bethesda, MD 20892. Telephone: (301) 496-5751. <http://www.ninds.nih.gov>.

OTHER

Alzheimer’s Association. Alzheimer’s Disease Fact Sheet. (June 2, 2004).

Alzheimer’s Disease Education and Referral (ADEAR) Center. Alzheimer’s Disease Genetics Fact Sheet NIH Publication No. 03-3431. (August, 2004).

Alzheimer’s Disease Education and Referral (ADEAR) Center. Alzheimer’s Disease Fact Sheet NIH Publication No. 06-3431. (July, 2006).

Safe Return Hotline. (888) 572-8566. This hotline provides information about registering a patient with AD with the Alzheimer’s Association as a means of identification in the event that he or she wanders away from home.

Rebecca Frey, Ph.D.
Ruvanee Pietersz Vilhauer, PhD

Alzheimer's disease

Definition

Alzheimer's disease, or AD, is a progressive, incurable disease of the brain caused by the degeneration and eventual death of neurons (nerve cells) in several areas of the brain.

Description

Patients with AD first lose such mental functions as short-term memory and the ability to learn new things. In the later stages of AD they gradually lose control over their sense of orientation, their emotions, and other aspects of behavior. End-stage AD is characterized by loss of control of body functions, an increased likelihood of seizures , loss of the ability to eat or swallow, and eventual death from infection or malnutrition. Alzheimer's disease is the most common cause of dementia (loss of cognitive abilities) in the elderly; it is thought to be responsible for 50%–70% of cases of dementia in the United States.

Alzheimer's disease was first identified in 1906 by a German psychiatrist and neuroanatomist named Alois Alzheimer. He was studying slides prepared from the brain of a fifty-one-year-old woman, known as Frau D., who had died after several years of dementia with symptoms that did not fit the definition of any brain disorder known at the time. Alzheimer was the first to describe the plaques and neurofibrillary tangles that are now used to identify AD at autopsy. Plaques are clumps or clusters of dead or dying nerve cells and other cellular debris found in the brains of patients with Alzheimer's disease. Neurofibrillary tangles are the accumulations of twisted protein fragments found inside the nerve cells in the brains of Alzheimer's patients. Because dementia had been associated with elderly people and Frau D. had been middle-aged, AD was first known as presenile dementia and was thought to be a very rare disorder. It was not until the early 1950s that researchers at St. Elizabeth's Hospital in Washington, DC, came to recognize that AD is the single most common cause of dementia in adults.

Alzheimer's disease is now considered a very serious public health problem because of the growing numbers of people who are affected by it, the increasing length of their lives, and the direct and indirect costs of their care. It is estimated that four million people in the United States had AD as of 2000, with 360,000–400,000 new cases identified every year. One person in ten over the age of 65 has AD, and nearly 50% of those over 85 have the disease. Unless a cure or preventive treatment is discovered, 14 million Americans will have Alzheimer's by 2050. Very few people are wealthy enough to cover the cost of caring for an Alzheimer's patient in the seven–10 years that typically extend between the beginning of the person's dependency and death. The average lifetime cost of caring for one patient with AD is estimated at $174,000. The costs of laboratory tests, physicians' visits, medications, nursing services, home care, and adult day care come to $114.4 billion per year in the United States alone. This sum is greater than the combined annual budgets of six Federal departments (Commerce, Education, Justice, Labor, Energy, and Interior).

The problem is expected to be complicated in future years by the fact that the so-called "baby boomer" generation is better nourished and better educated than the generation now at risk for AD. When the baby boomers are old enough to be at risk for late-onset Alzheimer's, they are expected to live longer than the average Alzheimer's patient does in 2002. Public health researchers who are making future projections about the impact of AD in the mid-twenty-first century point out that a treatment that would delay the onset of the disease would reduce the overall prevalence of AD. One study estimates that a therapy that would delay the onset of Alzheimer's by only one year would save the United States $9 billion by 2007. The second approach, that of discovering a treatment for people who already have Alzheimer's, would alter the proportion of mild cases to those considered moderate or severe. The researchers conclude by stating: "None of our models predicts less than a threefold rise in the total number of persons with Alzheimer's disease between 2000 and 2050."

Types of Alzheimer's disease

As of 2002, some researchers think that Alzheimer's may be more accurately described as a group or family of diseases rather than a single disease. Moreover, more recent research is helping to differentiate Alzheimer's disease from other less common causes of dementia. In particular, some cases of dementia that were formerly thought to have been related to AD are now known to have been caused by Pick's disease or Lewy body dementia. Pick's disease is a rare type of dementia that affects certain areas of the brain and is characterized by a progressive loss of social skills, language, and memory. Lewy body dementia is a type of dementia in which the brain has characteristic Lewy bodies—areas of injury found on damaged nerve cells in certain parts of the brain.

Physicians now recognize three different forms of Alzheimer's disease.

EARLY-ONSET AD. Early-onset AD is a rare form of Alzheimer's found in fewer than 10% of AD patients. This group of patients, however, develops more of the brain abnormalities associated with AD than patients with the late-onset form. In addition, patients with early-onset Alzheimer's are more likely to develop myoclonus (a condition in which a muscle or group of muscles has sudden spasms or twitching).

LATE-ONSET AD. Late-onset AD is the most common form of the disease; its symptoms usually begin to appear after age 65. Late-onset Alzheimer's, which may or may not be affected by genetic variables, is also called sporadic Alzheimer's disease because it does not necessarily run in families.

FAMILIAL ALZHEIMER'S DISEASE (FAD). Familial Alzheimer's disease, or FAD, is a rare form that is entirely inherited. FAD accounts for fewer than 5% of all cases of AD. It has a very early onset, often in the patient's 40s, and there is a clear family history of the disease.

Stages

Health care professionals use the term "insidious" to describe Alzheimer's, which means that it is very gradual in onset. Many times people recognize the first symptoms of the disorder in a friend or family member only in hindsight. In addition, the present generation of people old enough to be at risk for Alzheimer's is the first generation in history to know what the diagnosis means; there are therefore very powerful emotional reasons for attributing the early signs of AD to normal aging, job stress , adjusting to retirement, and other less troubling factors. The insidious onset of Alzheimer's is a characteristic, however, that allows doctors to distinguish it from other causes of dementia, including vascular dementia .

EARLY-STAGE ALZHEIMER'S. Early-stage Alzheimer's may begin almost imperceptibly. The first symptoms usually include short-term memory loss, temporary episodes of spatial disorientation, groping for words while one is speaking, minor problems with arithmetic, and small errors of judgment. For example, the person may light a stove burner under a saucepan before noticing that he has forgotten to put the food or water in the pan first, or he may have difficulty balancing a checkbook as quickly as he used to. At this stage in the disease, however, the patient can usually keep up with most activities of daily life. Although some persons at this point can still operate a motor vehicle safely, it is advisable to consult a physician about possible impairment behind the wheel. Many patients with early-stage AD voluntarily give up their driver's licenses for their own safety and that of other drivers on the roads.

MIDDLE-STAGE ALZHEIMER'S. In the middle stage, which typically begins two to three years after onset, the person begins to lose awareness of his or her cognitive deficits. Memory lapses are more frequent and the person begins to have more severe problems with language. Unlike early-stage AD, the problems caused by loss of cognitive functioning are impossible to ignore. The middle stage of AD is the point at which the behavioral and psychiatric symptoms that are so stressful to caregivers often begin— the agitation, wandering, temper outbursts, depression, and disorientation. The patient is at high risk for falls and similar accidents. In addition, the patient becomes increasingly unable to understand simple instructions or to follow a conversation, and begins to lose his or her basic sense of personal identity.

END-STAGE ALZHEIMER'S. End-stage Alzheimer's is marked by the loss of the ability to walk and eventually even to sit up. Patients may be able to use a wheelchair for awhile but eventually become completely bedridden. They lose bladder and bowel control. When the disease begins to affect the patient's brain stem, the basic processes of digestion, respiration, and excretion shut down. Patients usually stop eating at this point and sleep most of the time. The hands and feet begin to feel cold, the breathing becomes shallow, and the patient is generally unresponsive to caregivers. Eventually the patient's breathing simply stops.

Causes and symptoms

Causes

Evidence has accumulated that Alzheimer's disease is multifactorial— that is, it is caused by a combination of several genetic and environmental factors.

GENETIC. Early-onset AD is caused by a defect in one of three genes known as APP, presenilin-1, and presenilin-2, found on human chromosomes 21, 14, and 1, respectively. Early-onset AD is also associated with Down syndrome, in that people with trisomy 21 (three forms of human chromosome 21 instead of a pair) often develop this form of Alzheimer's. The brains of people with Down syndrome age prematurely, so that those who develop early-onset AD are often only in their late 40s or early 50s when the symptoms of the disease first appear.

Genetic research indicates that late-onset Alzheimer's disease is a polygenic disorder; that is, its development is influenced by more than one gene. It has been known since 1993 that a specific form of a gene for apolipoprotein E (apoE4) on human chromosome 19 is a genetic risk factor for late-onset AD. People who have the apoE4 gene from one parent have a 50% chance of developing AD; a 90% chance if they inherited the gene from both parents. They are also likely to develop AD earlier in life. One of the remaining puzzles about this particular gene, however, is that it is not a consistent marker for AD. In other words, some people who have the apoE4 gene do not develop Alzheimer's, and some who do not have the gene do develop the disorder. In 1998 another gene on chromosome 12 that controls the production of bleomycin hydrolase (BH, an enzyme involved in the body's processing of amyloid precursor protein) was identified as a second genetic risk factor that acts independently of the APOE gene. In December 2000, three separate research studies reported that a gene on chromosome 10 that may affect the processing of a particular protein is also involved in the development of late-onset AD.

Familial Alzheimer's disease appears to be related to abnormal genes on human chromosomes 21 and 14.

NEUROBIOLOGICAL. Investigators since Alois Alzheimer's time have studied the abnormalities found at autopsy in the brains of patients with AD. One abnormality is plaques, or clumps, of a starchy protein called beta amyloid. Beta amyloid is formed when a substance called amyloid precursor protein, or APP, fails to be metabolized properly in the body. APP is a substance found in many parts of the body, but its precise function is not yet known. Following the formation of beta amyloid, pieces of it then stick to one another and gradually build up into plaques. The other abnormal finding is neurofibrillary tangles, which are twisted threads formed from parts of the dying nerve cell called the tau protein, which was discovered in 1986. If the tau protein is damaged by the addition of molecules of phosphorus, a process called hyperphosphorylation, it forms filaments that twist around each other to form the neurofibrillary tangles. As the plaques and tangles accumulate in the brain, they cause the nerve cells to wither and eventually die. As the nerve cells die, the affected parts of the brain start to shrink in size. It is not known as of 2002, however, whether the plaques and tangles are causes of AD or results of it. The relationship between the plaques and the tangles is another question that has not yet been answered. Although the plaques usually appear in brain tissue before the tangles, it is not clear that they cause the tangles. There are other brain disorders, such as Pick's disease, in which tangles appear in the brain cells without plaques.

Another nervous system abnormality in AD is the lowered level of neurotransmitters produced by the cells in the brain. Neurotransmitters are chemicals that carry nerve impulses across the small gaps (synapses) between nerve cells. The neurotransmitters whose production is affected by Alzheimer's include serotonin, norepinephrine, and acetylcholine. Many of the behavioral and psychiatric problems associated with AD are thought to result from the inadequate supply of these neurotransmitters.

ENVIRONMENTAL. Researchers have been studying the possibility that certain chemicals or other toxins in the environment may have a role in causing or triggering AD. The environmental factors that have been considered include aluminum, zinc, toxins in contaminated food, and viruses. Although there is little evidence as of 2002 that AD is caused by a virus or other infectious agent, the possibility cannot be completely excluded.

Other hypotheses about the causes of Alzheimer's include damage caused by oxidation, estrogen deficiency, and inflammation. All of these possibilities are presently under investigation.

RISK FACTORS. A number of factors have been identified that increase a person's risk of developing Alzheimer's:

• Age. The risk of developing AD rises after age 65, and rises sharply after age 75. While 1% of the population has AD at age 65, almost 50% of those over 85 have it.
• Sex. Women are more likely to develop AD than men. As of 2002, however, it is not known whether women are more susceptible to the disorder, or more likely to develop it because they live longer than men, on average.
• Family history of AD.
• Having Down syndrome.
• History of head injury.
• Substances in the environment. Higher-than-average amounts of aluminum have been found in the brains of patients with Alzheimer's. Some researchers in the late 1990s thought that exposure to aluminum might be a risk factor for the disorder. It now appears that the levels of aluminum in the brains of patients are a result rather than a cause of AD.
• Low occupational attainment and education level. Studies have found a clear correlation between employment in jobs that are not mentally challenging and an increased risk of AD. In addition, taking less rather than more challenging jobs as one grows older is associated with a higher risk of AD.
• High systolic blood pressure.
• High blood cholesterol levels. When both high systolic blood pressure and high cholesterol are present, the risk of developing AD increases by a factor of 3.5.
• Mild cognitive impairment (MCI). Mild cognitive impairment is a transitional decline in cognitive functioning that precedes the onset of AD. MCI is characterized primarily by memory loss while other cognitive functions remain intact. People with MCI are at higher risk for AD than people who do not develop the condition; 12% of people with mild cognitive impairment develop Alzheimer's disease each year, compared with 1–2% per year of people without MCI. After four years, 40% of people diagnosed with mild cognitive impairment have clear symptoms of Alzheimer's disease.

Symptoms

The symptoms of Alzheimer's can be grouped into three categories: cognitive deficits, or losses of brain function related to memory and learning; behavioral and psychiatric symptoms of dementia, or BPSD; and problems with activities of daily life, or ADLs.

COGNITIVE DEFICITS. There are four major symptoms of loss of cognitive capacities in Alzheimer's:

• Amnesia . Amnesia refers to memory impairment; however, loss of short-term memory also means that the patient loses his or her sense of time as well.
• Aphasia. Aphasia refers to loss of language function. The person may not remember the names of objects and may use words like "thing" or "it" instead; they may echo what other people say or repeat a word or phrase over and over. On occasion the person may lose the ability to speak except for curse words.
• Apraxia. Apraxia is the loss of the ability to perform voluntary movements in the absence of paralysis. A person with apraxia, for example, may have trouble putting on a hospital gown or brushing his or her teeth.
• Agnosia. Agnosia comes from a Latin word that means "to not know", and refers to inability to recognize familiar places and people. Patients with agnosia may even fail to recognize their own face in a mirror.

NEUROPSYCHIATRIC SYMPTOMS. Symptoms associated with BPSD include:

• Depression. Depression associated with AD is thought to result from the lowered production of the neurotransmitter serotonin. Depression in AD can be treated with medication, usually with one of the selective serotonin reuptake inhibitors, or SSRIs.
• Delusions . A delusion is a false belief that a person maintains even when presented with contrary evidence. For example, patients with AD may say that a person is stealing their things when they cannot remember where they have put them. Suspicions of other people caused by delusions can sometimes be treated with medication.
• Wandering. This behavior may result from becoming disoriented and getting lost, but sometimes people with AD wander for no apparent reason. The Alzheimer's Association in Chicago has a Safe Return Hotline (listed under "Resources," below) that can be contacted for information about registering a patient with AD. If the registered patient should wander from home, the Safe Return Hotline can help identify him or her and return them to their family or nursing home.
• Hallucinations . Like delusions, hallucinations in AD patients are thought to be related to the deterioration of the patient's brain tissue. In a hallucination, the patient has a sensory experience that is real to him or her but not to other people. Hallucinations can affect any of the senses, but most are either visual or auditory. For example, a patient with AD may say that he or she sees little Martians in the corner of the room, or that he or she hears the voice of a long-dead parent calling to them. Hallucinations are sometimes caused by medications that the patient may be taking.
• Aggression. Aggression refers to hitting, shoving, pushing, or threatening behavior.
• Agitation. Agitation refers to emotionally excited behavior (screaming, shouting, cursing, pacing, fidgeting, etc.) that is disruptive or unsafe. Agitation may result from the changes in the patient's brain tissue, or it may be a symptom of depression associated with Alzheimer's disease.

For most of the twentieth century, studies of Alzheimer's patients focused on the cognitive symptoms of the disorder. It was not until the 1980s and 1990s that researchers began to look more closely at the behavioral and psychiatric symptoms of AD. Such methods of standardized assessment of these symptoms as the neuropsychiatric inventory are very recent developments.

PROBLEMS WITH ACTIVITIES OF DAILY LIVING (ADLS). Needing help with ADLs, or personal care activities that are part of everyday living, is among the earliest symptoms of Alzheimer's. The functions that are often affected include:

• eating, including simple cooking and washing dishes
• bathing, showering, or shaving
• grooming and dressing in clothing appropriate to the weather and activity
• toileting
• other aspects of personal hygiene (brushing teeth or cleaning dentures, washing hair, etc.)
• shopping for groceries and other necessary items

Health care professionals usually assess the ADLs of a patient diagnosed with Alzheimer's in order to determine what type of care is needed.

Demographics

Some demographic statistics in the developed countries have already been cited in the context of risk factors for AD and public health concerns related to the disorder.

Relatively little is known about the demographics of AD and other forms of dementia in the developing countries. Alzheimer's Disease International, which is based in London, supports a group of researchers called the 10/66 Dementia Research Group. The 10/66 group is trying to correct the global imbalance of AD research; as of 2001, fewer than 10% of all population-based research studies of AD and related forms of dementia has been directed toward the 66% of people with these disorders who live outside the developed countries. Of the estimated 18 million people in the world with dementia, 12 million live in China, India, Latin America, and other developing nations.

Diagnosis

As of 2002, the diagnosis of AD is essentially a process of exclusion. The only definitive diagnosis of Alzheimer's is made post mortem (after death), by performing an autopsy and examining the patient's brain tissue. There are no present tests that can be done on a living person to make the diagnosis of AD more than probable.

Diagnostic evaluation of AD

At present, the diagnostic process includes the following components:

• Clinical interview. In the absence of laboratory tests or imaging studies that can provide definite diagnoses, the physician must rely on his or her clinical judgment. In evaluating the patient, the doctor will assess signs of cognitive impairment other than short-term memory loss. In most cases, the doctor will ask a family member or close friend of the patient about the suddenness of symptom onset and the length of time that the patient seems to have been impaired.
• Physical examination. The patient will be given a complete physical and have blood and urine samples taken to rule out vitamin deficiencies, head trauma, tertiary syphilis, thyroid disorders, and other possible causes of dementia. The doctor will also review all the medications that the patient is taking (including alternative remedies) in order to exclude reversible dementia caused by drug interactions.
• Neurological examination. In early AD, the neurological findings are usually normal. If the patient appears to have had a stroke , he or she will be referred for a more thorough assessment by a neurologist.
• Tests of cognitive function. The patient will be given the mini-mental status examination (MMSE) and such other tests of cognitive function as the clock test or verbal fluency tests. The MMSE is a screening test and should not be used by itself to make the diagnosis of AD. In addition, the MMSE is not very sensitive in detecting cognitive impairment in people who previously functioned at a high level and were well educated. It is possible for a well-educated person to score a perfect 30 on the MMSE and still suffer cognitive impairment. The clock test is a test in which patients are asked to draw a clock face. Sometimes, patients will also be asked to include a specific time on the clock, such as 3:20. Patients with Alzheimer's often draw the face of the clock with numbers out of order, or all of the hour markers in a portion of the clock face instead of evenly spaced around the face, and often have difficulty adding the clock hands.
• Neuropsychiatric evaluation. A neuropsychiatric examination may be given to determine the pattern of the patient's cognitive impairment and probe his or her level of functioning more deeply. The patient may be asked to write a sample check, to describe how they answer the phone, to interpret sample traffic signs, and to look at a shopping list and pick out the items on the list from a display.
• Diagnostic imaging. Imaging studies are useful in detecting such causes of dementia as a previously undiagnosed brain tumor or abnormal brain structure. Scans can show doctors that certain areas of the brain have lost tissue (as happens in AD), and can strengthen a physician's suspicion of a patient's AD diagnosis, but scans cannot diagnose AD on their own. Scans are used more to rule out other possible diagnoses and to confirm a suspected diagnosis. CT (computed tomography ) scans are commonly performed, as well as MRI (magnetic resonance imaging ) scans in patients who are having problems with gait or balance. PET (positron emission tomography ) and SPECT (single photon emission computed tomography ) scans can be used to evaluate patterns of glucose (sugar) metabolism in the brain and to differentiate the patterns that are characteristic of Alzheimer's from those associated with vascular dementia and Pick's disease. PET scans are more precise than SPECT scans, but their cost is prohibitive.

Ethical considerations

With regard to genetic factors, tests are now available for the apoE4 gene implicated in late-onset Alzheimer's, but the American College of Medical Genetics and the American Neurological Association do not recommend these tests as of 2002. One reason is that the test results are not conclusive— about 20% of people who eventually develop AD do not carry this gene. Another important reason is the ethical implications of testing for a disease that presently has no cure, in terms of the psychological consequences for patients and their families, and the possible loss of health insurance for people found to be carrying the gene. These considerations may change, however, if researchers discover better treatments for primary dementia, more effective preventive methods, or more reliable genetic markers for AD.

Treatments

At present the mainstay of Alzheimer's treatment is medication, both to slow symptom progression and to manage the behavioral and psychiatric symptoms of AD.

Medications to slow symptom progression

The medications most commonly given to delay the progression of symptoms in Alzheimer's are a group of drugs called cholinesterase inhibitors. These drugs were approved by the FDA over a decade ago. They work by slowing down the body's destruction of the neurotransmitter acetylcholine.

The cholinesterase inhibitors include:

• Tacrine (Cognex). This drug is the oldest cholinesterase inhibitor in use. It is used less often than newer agents because it must be taken four times a day and may cause liver damage.
• Donepezil (Aricept). This drug is the one used most commonly as of 2002 to treat AD. It has fewer side effects than tacrine and can be given in one daily dose.
• Rivastigmine (Exelon). This drug is taken twice daily.
• Galantamine (Reminyl). This is the newest cholinesterase inhibitor, approved in late 2001. It acts on an additional acetylcholine receptor.

None of these medications provide more than modest benefits to patients with AD: they slow the progression of symptoms for about six months to a year in one-third to one-half of patients with AD. In addition, the cholinesterase inhibitors have side effects, most commonly nausea, vomiting, diarrhea, muscle cramps, and sleep disturbances.

Medications for BPSD

Medications are also prescribed to manage the behavioral and psychiatric symptoms of AD, which are often quite stressful for caregivers if the patient is being cared for at home. These medications are usually prescribed for specific symptoms:

• Delusions: Antipsychotic drugs, usually haloperidol (Haldol) or risperidone (Risperdal).
• Agitation: Short-term anti-anxiety drugs, usually lorazepam (Ativan) or buspirone (BuSpar).
• Depression: One of the selective serotonin reuptake inhibitors (SSRIs), at half the dosage for a young adult.
• Pain: Acetaminophen or a very low dose of codeine.

In general, older patients require lower dosages than those given to younger adults. Patients with AD are also more susceptible to the side effects of medications. For these reasons, physicians often recommend making changes in the patient's environment to reduce the behavioral symptoms before trying medications.

Alternative and complementary treatments

Some complementary therapies have been shown to benefit patients with Alzheimer's.

NATUROPATHY. A naturopathic approach to Alzheimer's includes supplementing antioxidant vitamins (vitamins A, E, and C) in the patient's diet, along with adding carotenoids, small amounts of selenium and zinc, and thiamin. Botanical supplements that have been said to improve cognitive function include Huperzine A, a Chinese tea, and an extract made from Gingko biloba, a tree that is native to China and is said to be the world's oldest living deciduous tree. GBE, or gingko biloba extract, is the most frequently used herbal medicine in Europe. It is available in Germany by prescription and in an over-the-counter form; and has been approved by the German Commission E for dementia-related memory loss. Gingko extract is thought to work in a manner similar to the cholinesterase inhibitors. At present the National Center for Complementary and Alternative Medicine (NCCAM) is conducting studies of gingko extract as a treatment for Alzheimer's.

MUSIC THERAPY. Music therapy has been found to calm agitated patients with Alzheimer's, to improve mood, and to enhance their long-term memory. Old familiar songs are particularly effective in improving recall. In other studies, music therapy has been shown to reduce sensations of chronic pain in patients with AD.

Prognosis

There is no cure for Alzheimer's disease as of 2002. The prognosis is progressive loss of mental and bodily functions leading to death within seven to ten years. Some patients, however, die within three years of diagnosis and others may survive for as long as fifteen.

Prevention

Researchers are considering several different strategies to prevent Alzheimer's, ranging from development of a vaccine to prevent the formation of beta amyloid plaques to finding a drug that would stop the conversion of APP to beta amyloid. As of 2002, the vaccine, which was originally developed and tested on mice, does not appear to have any serious side effects in humans. It is presently being tested in Phase II trials on human subjects.

See also Dementia; Mini mental state examination (MMSE)

Resources

BOOKS

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th edition, text revised. Washington, DC: American Psychiatric Association, 2000.

Beers, Mark H., MD. "Behavior Disorders in Dementia." Chapter 41 in The Merck Manual of Geriatrics, edited by Mark H. Beers, MD, and Robert Berkow, MD. Whitehouse Station, NJ: Merck Research Laboratories, 2000.

Keck, David. Forgetting Whose We Are: Alzheimer's Disease and the Love of God. Nashville, TN: Abingdon Press, 1996.

Mace, Nancy L., and Peter V. Rabins. The 36-Hour Day. Revised and updated edition. New York: Warner Books, Inc., 2001; by arrangement with The Johns Hopkins University Press.

Marcantonio, Edward, MD. "Dementia." Chapter 40 in The Merck Manual of Geriatrics, edited by Mark H. Beers, MD, and Robert Berkow, MD. Whitehouse Station, NJ: Merck Research Laboratories, 2000.

Morris, Virginia. How to Care for Aging Parents. New York: Workman Publishing, 1996.

Pelletier, Kenneth R., MD. The Best Alternative Medicine. Part II. "CAM Therapies for Specific Conditions: Alzheimer's Disease." New York: Simon and Schuster, 2002.

Shenk, David. The Forgetting: Alzheimer's: Portrait of an Epidemic. New York: Doubleday, 2001.

PERIODICALS

Aisen, P. S., J. Schmeidler, G. M. Pasinetti. "Randomized Pilot Study of Nimesulide Treatment in Alzheimer's Disease." Neurology 58 (April 9, 2002): 1050-1054.

Bone, Kerry. "Gingko and Alzheimer's Disease." Townsend Letter for Doctors and Patients (January 2001): 27.

Desai, P. P., H. C. Hendrie, R. M. Evans, and others. "Genetic Variation in Apolipoprotein D Affects the Risk of Alzheimer's Disease in African Americans." American Journal of Human Genetics 69 (October 2001): 416.

Editorial Commentary. "Neuropsychiatric Phenomena in Alzheimer's Disease." Journal of Neurology, Neurosurgery and Psychiatry 71 (December 2001): 715.

"Head Injury Linked to Increased Risk of Alzheimer's Disease." FDA Consumer 35 (January-February 2001): 8.

Holmes, C., H. Smith, R. Ganderton, and others. "Psychosis and Aggression in Alzheimer's Disease: The Effect of Dopamine Receptor Gene Variation." Journal of Neurology, Neurosurgery and Psychiatry 71 (December 2001): 777-779.

in't Veld, Bas A., Annemieke Ruitenberg, Albert Hofman, and others. "Nonsteroidal Anti-inflammatory Drugs and the Risk of Alzheimer's Disease." New England Journal of Medicine 345 (November 22, 2001): 1515-1521.

Khosh, Farhang. "Naturopathic Approach to Alzheimer's Disease." Townsend Letter for Doctors and Patients (July 2001): 22-24.

Kim, S. Y., J. H. Karlawish, E. D. Caine. "Current State of Research on Decision-Making Competence of Cognitively Impaired Elderly Persons." American Journal of Geriartic Psychiatry 10 (March-April 2002): 151-165.

Kivipelto, M., and others. "Midlife Vascular Risk Factors and Alzheimer's Disease in Later Life: Longitudinal, Population-Based Study." British Medical Journal 322 (June 16, 2001): 1447-1451.

Langbart, C. "Diagnosing and Treating Alzheimer's Disease: A Practitioner's Overview." Journal of the American Academy of Nurse Practitioners 14 (March 2002): 103-109.

Luedecking-Zimmer, E., S. T. DeKosky, M. I. Kamboh. "Candidate Genes for Late-Onset Alzheimer's Disease on Chromosome 12." American Journal of Human Genetics 69 (October 2001): 518.

Moon, Mary Ann. "Mentally Demanding Work May Deter Alzheimer's Disease." Family Practice News 30 (September 1, 2000): 32.

O'Hara, R., and others. "Update on Alzheimer's Disease: Recent Findings and Treatments." Western Journal of Medicine 172 (February 2000); 115-120.

Olin, J. T., I. R. Katz, B. S. Meyers, and others. "Provisional Diagnostic Criteria for Depression of Alzheimer Disease: Rationale and Background." American Journal of Geriatric Psychiatry 10 (March-April 2002): 129-141.

Shah, Yogesh, Eric G. Tangelos, and Ronald C. Petersen. "Mild Cognitive Impairment: When Is It a Precursor to Alzheimer's Disease?" Geriatrics 55 (September 2000): 62-68.

Shigenobu, K., M. Ikeda, R. Fukuhara, and others. "Reducing the Burden of Caring for Alzheimer's Disease Through the Amelioration of 'Delusions of Theft' by Drug Therapy." International Journal of Geriatric Psychiatry 17 (March 2002): 211-217.

Silverman, Daniel H. S., Gary W. Small, Carol Y. Chang, and others. "Positron Emission Tomography in Evaluation of Dementia: Regional Brain Metabolism and Long-Term Outcome." Journal of the American Medical Association 286 (November 7, 2001): 2120.

Sloane, P. D., S. Zimmerman, C. Suchindran, and others. "The Public Health Impact of Alzheimer's Disease, 2000-2050: Potential Implication of Treatment Advances." Annual Review of Public Health 23 (2002): 213-231.

Walsh, D. M., I. Klyubin, J. V. Fadeeva, and others. "Naturally Secreted Oligomers of Amyloid Beta Protein Potently Inhibit Hippocampal Long-Term Potentiation in Vivo." Nature 416 (April 4, 2002): 535-539.

Wilcock, G. K., and others. "Efficacy and Safety of Galantamine in Patients with Mild to Moderate Alzheimer's Disease: Multicentre Randomised Controlled Trial." British Medical Journal 321 (December 9, 2000): 1445-1449.

ORGANIZATIONS

Alzheimer's Association. 919 North Michigan Avenue, Suite 1100, Chicago, IL 60611-1676. (800) 272-3900 or (312) 335-8700. Fax: (312) 335-1110. <www.alz.org>.

Alzheimer's Disease Education and Referral (ADEAR) Center. P. O. Box 8250, Silver Spring, MD 20907-8250. (800) 438-4380. <www.alzheimers.org>.

Alzheimer's Disease International. 45–46 Lower Marsh, London SE1 7RG, UK. (+44) 20-7620-3011. Fax: (+44) 20-7401-7351. <www.alz.co.uk>.

National Center for Complementary and Alternative Medicine (NCCAM) Clearinghouse. P.O. Box 7923, Gaithersburg, MD 20898. (888) 644-6226. TTY: (866) 464-3615. Fax: (866) 464-3616. <www.nccam.nih.gov>.

National Institute of Mental Health. 6001 Executive Boulevard, Room 8184, MSC 9663, Bethesda, MD 20892-9663. (301) 443-4513. <www.nimh.nih.gov>.

National Institute of Neurological Disorders and Stroke (NINDS). Building 31, Room 8A06, 9000 Rockville Pike, Bethesda, MD 20892. (301) 496-5751. <www.ninds.nih.gov>.

OTHER

Safe Return Hotline. (888) 572-8566. This hotline provides information about registering a patient with AD with the Alzheimer's Association as a means of identification in the event that he or she wanders away from home.

Rebecca J. Frey, Ph.D.

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 of daily living, and to reason and exercise judgment. Communication ability, mood, and personality may also be affected. Most people who have AD die within eight years of their diagnosis, although that 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 twenty-first century as the population as a whole ages. While a small number of people in

their 40s and 50s develop the disease (called early-onset 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, and has been estimated at approximately $174,000 per person over the course of the disease. Most people with AD are cared for at home; the cost of extended nursing home care adds substantially to this estimate.

Causes & symptoms

The cause or causes of AD are unknown. Some strong leads have been found through recent research, and these have also given some theoretical support to several new experimental treatments.

AD affects brain cells, mostly those in brain regions responsible for learning, reasoning, and memory. Autopsies of persons with AD show that these regions of the brain become clogged with two abnormal structures—neurofibrillary tangles and senile plaques. Neurofibrillary tangles are twisted masses of protein fibers inside nerve cells, or neurons. Senile plaques are composed of parts of neurons surrounding a group of brain proteins called beta-amyloid deposits. While it is not clear exactly how these structures cause problems, some researchers now believe that their formation is in fact responsible for the mental changes of AD, presumably by interfering with the normal communication between neurons in the brain.

What triggers the formation of plaques and tangles is unknown, although there are several possible candidates. Inflammation of the brain may play a role in their development, and use of nonsteroidal anti-inflammatory drugs (NSAIDs) seems to reduce the risk of developing AD. Restriction of blood flow may be part of the problem, perhaps accounting for the beneficial effects of estrogen that increases blood flow in the brain, among its other effects. 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.

Several genes have been implicated in AD, including the gene for amyloid precursor protein, or APP, responsible for producing amyloid. Mutations in this gene are linked to some cases of the relatively uncommon early-onset forms of AD. In 2001, scientists discovered a new rare mutation of the APP gene that might lead to new understanding on how the disease develops and new treatment possibilities. Other cases of early-onset AD are caused by mutations in the gene for another protein, called pre-senilin. AD eventually affects nearly everyone with Down syndrome, caused by an extra copy of chromosome 21. Other mutations on other chromosomes have been linked to other early-onset cases.

Potentially the most important genetic link was discovered in the early 1990s on chromosome 19. A gene on this chromosome, called apoE, codes for a protein involved in transporting lipids into neurons. ApoE occurs in at least three forms—apoE2, apoE3, and apoE4. Each person inherits one apoE from each parent, and therefore can either have one copy of two different forms, or two copies of one. Compared to those without ApoE4, 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. Despite this important link, not everyone with apoE4 develops AD, and people without it can still have the disease. Why apoE4 increases the chances of developing AD is not known.

There are several risk factors that increase a person's likelihood of developing AD. The most significant one is age; older people develop AD at much higher rates than younger ones. Another risk factor is having a family history of AD, Down syndrome, or Parkinson's disease . People who have had head trauma or hypothyroidism may manifest the symptoms of AD more quickly. No other medical conditions have been linked to an increased risk for AD.

Many environmental factors have been suspected of contributing to AD, but population studies have not borne out these links. Among these have been pollutants in drinking water, aluminum from commercial products, and 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 culprits, although no firm candidates have been identified.

The symptoms of AD begin gradually, usually with short-term memory loss. 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 patients have trouble sleeping and may suffer from confusion or agitation in the evening ("sunsetting"). In some cases, people with AD repeat the same ideas, movements, words, or thoughts, a behavior known as perseveration. Some patients may exhibit inappropriate sexual behaviors. In the final stages of the disease, people may have severe problems with eating, communicating, and controlling their bladder and bowel functions.

The Alzheimer's Association has developed a list of 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 dementing illnesses, 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 AD 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 definitively diagnosed until autopsy examination of the brain for senile 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 can also be provoked by other medical conditions, including tumors, infection, and dementia caused by mild strokes (multi-infarct dementia). These possibilities must be ruled out as well through appropriate blood and urine tests, brain magnetic resonance imaging (MRI) or computed tomography scans (CT), tests of the brain's electrical activity (electroencephalographs or EEGs), or other tests.

In 2001, researchers demonstrated that postitron emission tomography (PET) scans could help predict who might develop memory impairment. Although PET scanning is a relatively new and expensive technology, it is becoming more readily available. 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 are both common in the elderly, and the combination of the two can often be mistaken for AD. Depression can be treated with drugs, although some antidepressants can worsen dementia if it is present, further complicating both diagnosis and treatment.

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

Treatment

The mainstay of treatment for a person with AD continues to be the establishment of daily routines and good nursing care, providing both physical and emotional support for the patient. Modifications of the home to increase safety and security are often necessary. The caregiver also needs support. Regular medical care by a practitioner with a non-defeatist attitude toward AD is important so that illnesses can be diagnosed and treated properly.

People with AD are also often 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 for safety if necessary) promotes overall health. A calm, structured environment with simple tools that support orientation (like calendars and clocks) may reduce anxiety and increase safety.

Diet and supplements

DIET. The incidence of AD is lower in countries whose citizens have a diet that is lower in fats and calories. There have been a few reports that a diet rich with fish improves mental function in patients with AD or dementia. AD patients treated with essential fatty acids showed greater improvement in mood and mental function than patients on placebo. Because of its disease-preventing properties, red wine in moderation may be beneficial to AD patients.

VITAMIN E. Studies have shown that AD patients have lower blood levels of vitamin E than age matched control subjects. A large, two year study of moderately affected AD patients found that taking 2,000 IU of vitamin E daily significantly delayed disease progression as compared to patients taking placebo. This delay was equivalent to that seen with patients taking the drug selegiline. Vitamin E is also thought to delay AD onset. High levels of vitamin E put the patient at higher risk for bleeding disorders.

THIAMINE (VITAMIN B ₁). Several small studies to determine the effectiveness of thiamine (vitamin B₁) on AD have been carried out. Daily doses of 3 g for two to three months have improved mental function and AD assessment scores. Other studies have shown that thiamine had no effect on AD patients. Side effects include nausea and indigestion .

COBALAMIN (VITAMIN B ₁₂). Although results are conflicting, some studies have found that AD patients have lower levels of cobalamin (vitamin B ₁₂) than others. Some studies have shown that cobalamin supplementation improves memory and mental function in AD patients whereas other studies have found no effect.

ACETYL-L-CARNITINE. Acetyl-l-carnitine is similar in structure to the neurotransmitter acetyl-choline. Studies have shown that 2 g or 3 g of acetyl-l-carnitine daily slows the progression of AD, especially in patients who developed the disease before age 66. Patients who developed disease after 66 years of age worsened with treatment. Side effects include increased appetite, body odor , and rash.

DHEA. DHEA (dehydroepiandrosterone) is a steroid hormone. There may be a link between decreasing levels of DHEA in the elderly and development of AD. Studies on the effect, if any, of DHEA on AD are needed. Side effects include acne , hair growth, irritability, insomnia, headache , and menstrual irregularity.

MELATONIN. Melatonin is a hormone that helps to regulate mood and sleep cycles. The effect of melatonin treatment on AD is unknown but it may be beneficial in regulating sleep cycles. The usual dose is 3 mg taken one to two hours before bedtime. Side effects are drowsiness, confusion, headache, decreased sex drive, and decreased body temperature.

Herbals and Chinese medicine

GINKGO. Ginkgo, the extract from the Ginkgo biloba tree is the most commonly used herbal treatment for AD. Several studies have been performed to test the effectiveness of ginkgo for treating AD. The dose range studied were 120–160 mg daily divided into three doses. Although results have been mixed, the evidence suggests that ginkgo is an effective treatment for patients with mild to moderate AD. Side effects are not common but include headache, allergic skin reaction, and gastrointestinal disturbance. Ginkgo also decreases blood coagulation. Individuals with coagulation or platelet disorders should use extreme caution and consult a physician before using ginkgo.

PHYTOESTROGENS. Phytoestrogens may be beneficial in the treatment of AD based on the findings that women with AD who are on hormone replacement therapy have improved mental function and mood. Estrogens may prevent AD, therefore, phytoestrogens may have the same effect. Phytoestrogens are mainly found in soy products.

CLUBMOSS. Huperzine A is a compound isolated from clubmoss (Huperzia serrata ). Studies have shown that taking 0.1–0.4 mg daily improves mental function in AD patients. Side effects are nausea, muscle cramps, vomiting , and diarrhea .

Therapies

Music therapy has been shown to be effective in treating the depression, agitation, wandering, feelings of isolation, and memory loss associated with AD. AD patients have benefited from listening to favorite music or participating in musical activity. Participation in a music therapy group was more effective at improving memory and decreasing agitation than being part of a verbal (talking) group.

A wide variety of other therapies have been beneficial in the treatment of the psychologic symptoms of AD. These include:

• Light therapy in the evening to improve sleep cycle disturbances.
• Supportive therapy through touch, compliments, and displays of affection.
• Sensory stimulation through massage and aromatherapy.
• Socio-environmental therapies use activities fitted to previous interests, favorite foods, and pleasant surroundings.
• Cognitive therapy to reduce negative perceptions and learn coping strategies.
• Insight-oriented psychotherapy addresses the patient's awareness of his or her disease.
• Dance therapy.
• Validation therapy.
• Reminiscence therapy.
• Reality-oriented therapy.

Nursing care and safety

The nursing care required for a person with AD is easy to learn. Caregivers will usually need to spend increasing amounts of time grooming the patient as the disease progresses. The patient may require assisted feeding early on to make sure that he or she 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. 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.

In all cases, a person diagnosed with AD should not 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. 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.

Care for the caregiver

Family members or others caring for a person with AD have an extremely difficult and stressful job that becomes harder as the disease progresses. It is common for 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. 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 may also 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. Many families consider nursing home care when AD advances to the late-stage.

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.

Allopathic treatment

The only two drugs approved for AD, tacrine hydrochloride (Cognex) and donepezil hydrochloride (Aricept), increase the brain levels of the neurotransmitter acetylcholine, thereby increasing the communication ability of the remaining neurons. These drugs can modestly increase cognition and improve the ability to perform normal activities of daily living. The most significant side effect of tacrine is an increase in the liver enzyme alanine aminotransferase (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. Donepezil has two advantages over tacrine: fewer side effects and once daily dosing. Donepezil does not appear to affect liver enzymes and the frequency of abdominal side effects is lower.

Estrogen, the female sex hormone, is widely prescribed for post-menopausal women to prevent osteoporosis . Several preliminary studies have shown that women taking estrogen have lower rates of AD, and those who develop AD have a slower progression and less severe symptoms.

Preliminary studies have also suggested a reduced risk for developing AD in older people who regularly use nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen (Advil), and naproxen (Aleve), although not acetaminophen. A 2001 study reported that those subjects who used NSAIDs for at least two years were up to 80% less likely to develop Alzheimer's. Further study on the effects of NSAIDs on AD are underway.

Selegiline, a drug used in the treatment of Parkinson's disease, appears to slow the development of AD. Selegiline is thought to act as an antioxidant, preventing free radical damage. However, it also acts as a stimulant, making it difficult to determine whether the delay in onset of AD symptoms is due to protection from free radicals or to the general elevation of brain activity from the stimulant effect.

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.

Expected results

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 1-20 years.

Prevention

There is currently no sure way to prevent Alzheimer's disease, though some of the drug treatments discussed above may eventually be proven to reduce the risk of developing the disease. The most likely current candidates are estrogen, phytoestrogens, NSAIDs, vitamin E, and selegiline. In 2001, researchers found preliminary indications that onest of Alzheimer's might be tied to cholesterol levels. Although results must be confirmed by other scientists, lowering cholesterol in the diet might help prevent onset of the disease.

Resources

BOOKS

Bridges, Barbara J., Therapeutic Caregiving: A Practical Guide for Caregivers of Persons with Alzheimer's and Other Dementia Causing Diseases. BJB Publishing 16212 Bothell Way S.E., Suite F171 Mill Creek, Washington 98012-1219.

Carrier, Louise, and Henry Brodaty. "Mood and Behaviour Management." In Clinical Diagnosis and Management of Alzheimer's Disease. 2nd edition, edited by Serge Gauthier. London: Martin Dunitz, 1999.

Larkin, Marilynn. When Someone You Love Has Alzheimer's: What you must know, what you can do, what you should expect.. Dell, 1995.

Luskin, Frederic M., Ellen M. DiNucci, Kathryn A. Newell, and William L. Haskell. "Complementary/Alternative Therapies in Select Populations: Elderly Persons." In Complementary/Alternative Medicine: An Evidence Based Approach. Edited by John W. Spencer and Joseph J. Jacobs. St. Louis: Mosby, 1999

Mace, Nancy L., and Peter V. Rabins. The 36-Hour Day. The John Hopkins University Press, 1995.

PERIODICALS

Gottlieb, Scott R."NSAIDs Can Lower Risk of Alzheimer's." British Medical Journal 323 no. 7324 (December 1, 2001):1269.

Mitka M."PET and Memory Impairment." JAMA, Journal of the American Medical Association 286 no. 16 (October 24, 2001):1961.

Ott, Brian R., and Norma J. Owens. "Complementary and Alternative Medicines for Alzheimer's Disease." Journal of Geriatric Psychiatry and Neurology 11 (1998):163-173.

"Alzheimer Chemical Engineers Suggest Alzheimer Onset Tied to Cholesterol." Pain and Central Nervous System Week (December 24, 2001):3.

Stephenson Joan. "Alzheimer Treatment Target?" JAMA, Journal of the American Medical Association 286 no. 14 (October 10, 2001):1704.

"Wiser Now." Better Directions. PO Box 35 Spencerville, MD 20868.(800) 999-0795.

ORGANIZATIONS

Alzheimer's Association. 919 North Michigan Ave., 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.

OTHER

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

Belinda Rowland

Teresa G. Odle

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

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