Neurofibrillary tangles

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 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, 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

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.

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

What triggers the formation of plaques and tangles is unknown, although 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, 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.

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. 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, called 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.

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. 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.

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"). 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 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 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 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. 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, since possessing even two copies does not ensure that a person will develop AD.

Treatment

Alzheimer's disease is currently incurable, and as of 1997 only two drugs--tacrine (Cognex) and donepezil hydrochloride (Aricept)-- have been approved by the FDA for its treatment. Several other drugs are being prescribed more often as their benefits are demonstrated in wider testing. Nonetheless, the mainstay of treatment for a person with AD continues to be 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.

Drugs

Tacrine (Cognex) and donepezil hydrochloride (Aricept), the two drugs approved so far, both increase the brain levels of the neurotransmitter acetylcholine, thereby increasing the communication ability of the remaining neurons. They do this by inhibiting the enzyme acetylcholinesterase, which normally breaks down acetylcholine after neurons release it. In this way, these drugs can modestly increase cognition and improve one's ability to perform normal activities of daily living.

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. Tacrine cost 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 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.

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, and naproxen, although not acetaminophen.

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.

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.

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.

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 late 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.

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.

Care for the caregiver

Family members or others caring for a person with AD have an extremely difficult and stressful job, which becomes harder still 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 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 insurance, special "reverse mortgages," viatical insurance, and other financial devices may be attractive 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. Gingko extract, derived from the leaves of the Gingko biloba tree, interferes with a circulatory protein called platelet activating factor. Gingko 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 gingko extract could improve their symptoms, though the study was criticized for certain flaws in its method. Gingko 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, 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 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, NSAIDs, vitamin E, and selegiline, although this list may grow or shrink with further research.

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.

Donepezil hydrochloride (Aricept)

A drug that increases the brain level of the neurotransmitter acetylcholine, which is given once a day to treat AD.

Ginko

An herb from the tree that some alternative practitioners recommend for the 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 and found in the brains of people with AD.

Tacrine (Cognex)

A drug that may help improve memory in people with mild to moderate cases of AD.

Further Reading

For Your Information

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.
• Larkin, Marilynn. When Someone You Love Has Alzheimer's: What you must know, what you can do, what you should expect... Dell, 1995.
• Mace, Nancy L., and Peter V. Rabins. The 36-Hour Day. The John Hopkins University Press, 1995.
• Powell, Lenore S. with Katie Courtice. Alzheimer's Disease: A Guide for Families. Addison-Wesley Publishing Company, 1993.

  Periodicals

• 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

Gale Encyclopedia of Medicine. Gale Research, 1999.