Alzheimer's Disease

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 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 21st 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, and so there is a higher proportion of women in the most affected age groups.

The costs for 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 AD patients 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 unknown. Some strong leads have been found through recent research, however, and these have also 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 short-term memory of the person fails, and the ability to perform familiar tasks decreases. Later AD affects the cerebral cortex, particularly the areas responsible for language and reasoning; this language skills are lost and the ability to make judgments is changed. Personality changes occur, which may include emotional outbursts, wandering, and agitation. The severity of these changes increases with the progression of the disease. 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, is 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. As of 2000, three drugs for the treatment of AD symptoms have been approved by the United States 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.

What triggers the formation of plaques and tangles and the development of AD are 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 is also described in terms of age at onset, with early on-set AD occurring in people younger than 65, and late-onset occurring in those 65 and older. Early on-set AD comprises about 5-10 of AD cases and affects people aged 30 to 60. Some cases of early on-set AD are inherited and are common in some families. Early-onset AD often progresses faster than the more common late-on-set type.

All FAD, which are relatively uncommon, that have been identified so far are the early on-set type. As many as 50% of the 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 may also be important in the synaptic connections between brain cells.

There is no evidence that the mutated genes that cause early on-set FAD also cause late on-set AD, but genetics does appear 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 does develop. 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 can also 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 also 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) 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, which 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. 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 are still 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. Blood cholesterol levels may also 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 are also 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, results from one study indicated that rural residence in childhood, along with fewer than six years of schooling, was associated with increased AD risk. However, the low educational attainment that was identified as a risk factor might be a marker or surrogate for other deleterious socioeconomic or environmental influences in childhood, thus illustrating the difficulties in interpreting epidemiological findings, due to the complexity of the issues and the large number of variables involved.

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 patients 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, a behavior known as perseveration. 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 ten 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 definitively diagnosed 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 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), 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 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.

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.

Diseased tissue from the brain of an Alzheimer's patient showing senile plaques within the brain's gray matter. (Photograph by Cecil Fox, Photo Researchers, Inc. Reproduced by permission.)

Treatment

Alzheimer's disease is presently incurable, so therefore the mainstay of 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 are often 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 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 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 2000, only three 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.

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. However, estrogen does not appear to have a beneficial effect on women who already have AD.

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, and naproxen, although not acetaminophen. Inflammation of the brain is a distinctive characteristic of AD, but whether it is a cause or an effect of the disease is not yet known.

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. 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 increasing 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 patients 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 AD patients 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 will usually need to spend increasing amounts of time for 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 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.

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 is often 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. John's 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

There is currently no sure way to prevent Alzheimer's disease, although some of the drug treatments discussed above may eventually be proven to reduce the risk of developing the disease. The most likely current candidates are estrogen, NSAIDs, vitamin E, and ginkgo biloba, although this list may grow or shrink with further research.

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 are also 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.