Alzheimer's disease

INTRODUCTION — Alzheimer's disease (AD) is a form of dementia, a group of disorders characterized by a decrease in the overall level of cognitive (mental) functioning, especially memory. In addition to memory deficits, people with Alzheimer's disease may have behavioral disturbances and experience generalized physical and mental decline. This combination eventually prevents a person from functioning independently in day-to-day life.

Alzheimer's disease accounts for 60 to 80 percent of all cases of dementia among the elderly. About four million Americans have Alzheimer's disease now, and close to three million Americans are caring for relatives or friends who have it. There is striking variety in presentation and severity of symptoms and signs, often leading to underrecognition. Currently available medical treatments can be of help in controlling the mental and behavioral symptoms of the disease but leave much to be desired in many cases. Meanwhile, ongoing research has made major advances in understanding the underlying causes of this kind of dementia. This research holds great promise for developing treatments to slow down and hopefully delay the onset or even prevent Alzheimer's disease.

CAUSES — Scientists have not yet been able to determine exactly why and how Alzheimer's disease develops. Researchers have determined that the brains of patients with AD develop deposits of a protein called beta amyloid (these deposits are also known as plaques), and that people also develop disorganized masses of protein fibers within the brain cells known as neurofibrillary tangles.

In addition, Alzheimer's disease is associated with the death of nerve cells (neurons) in important parts of the brain. Currently, these changes to the brain can only be seen during autopsy after a patient's death, but researchers are working to develop ways of imaging these brain changes in living patients.

RISK FACTORS — A risk factor is not necessarily the cause of a particular condition, but merely something that helps predict it. Some risk factors can indeed cause a particular illness. As an example, we know that smoking can cause lung cancer. The relationship between other risk factors and specific diseases is more complicated, and in many cases scientists do not know if there is any causal relationship involved or not. They just know that people who have a particular risk factor are for some reason also more likely to get a particular disease.

Age — The biggest risk factor for Alzheimer's disease is age: the older you are, the more likely you are to develop Alzheimer's disease. As an example, one large study found that among people ages 65 to 69, less than 1 percent of people develop AD per year [1]. For people ages 70 to 74, the incidence was 1 percent, and for people ages 75 to 79, 2 percent. The number affected by Alzheimer's is more than 3 percent among people ages 80 to 84, and to more than 8 percent among those 85 and over.

Family history — Having a close family member with Alzheimer's disease increases the chances of developing it yourself. People with a first-degree relative, such as a parent or sibling, with Alzheimer's disease have a 10 to 30 percent chance of developing the disorder. The risk is probably higher if the family member developed Alzheimer's disease at a younger age and lower if the family member did not get Alzheimer's disease until late in life [2].

Scientists have discovered a particular gene increases a person's risk of developing Alzheimer's. But even among individuals with this gene, only about one-half develop Alzheimer's by age 90, suggesting that other factors are also involved [3]. It is possible to test for this gene in family members of patients with Alzheimer's disease, but this test is currently recommended only for people involved in a research study.

SYMPTOMS

Normal changes versus Alzheimer's — Many people worry that memory problems are caused by early Alzheimer's disease. Normal age-related changes usually cause minor difficulties in short term memory and a slowed ability to learn and process information. These changes are usually mild and do not worsen over time, nor should they interfere with a person's day-to-day functioning.

Early changes — The earliest symptoms of Alzheimer's disease are gradual and often subtle. Many patients and their families first notice difficulty remembering recent events or information. Other changes can include one or more of the following: Confusion Difficulties with language (eg, not being able to find the right words for things) Difficulty with concentration and reasoning Problems with complex tasks like paying bills or balancing a checkbook Problems with orientation or spatial ability (eg, getting lost in a familiar place)

Later changes — As Alzheimer's disease progresses, a person's ability to think clearly continues to decline, and personality and behavioral symptoms are more likely to appear. These can include: Increased anger, hostility, and/or suspicion Aggression and physical violence Hallucinations Delusions Wandering Increased number of physical accidents

The number of symptoms and speed with which symptoms progress can vary widely from one person to the next. In some people, severe dementia occurs within five years of the diagnosis; for others, the process can take more than 10 years. Most people with Alzheimer's disease do not die from the disease itself, but instead die from a secondary illness such as pneumonia, urinary tract infection, or complications of a fall.

DIAGNOSIS — There is no single medical or laboratory test that can determine if a person has Alzheimer's disease. Instead, a healthcare provider must make the diagnosis based upon information gathered from the patient and family, and upon the results of tests that measure mental functioning.

The provider will want to know about the patient's recent history: the nature of any mental changes or memory loss, behavioral changes, any medical conditions or illnesses, and any medications the patient has been taking. A complete physical check-up and blood work may be done at this time.

It is important to rule out other possible causes for a patient's mental difficulties. These can include medications or other medical conditions. As examples, both delirium and depression have symptoms similar to those of Alzheimer's disease and may occur in patients with dementia.

The provider will also need to rule out other forms of dementia before diagnosing Alzheimer's disease. These include vascular dementia (changes caused by blood vessel abnormalities), dementia caused by Parkinson's disease, dementia related to alcohol or medications, and other conditions.

To get a sense of how the patient is functioning mentally, the doctor will probably administer a brief test such as the Mini-Mental State Exam, or MMSE. This is the most widely used test to assess a person's ability to think and remember. It takes about seven minutes to complete and evaluates a range of mental functions, including being able to state today's day, month, and year to being able to remember a short list of words or write a full sentence spontaneously.

TREATMENT — Although scientists are learning more about Alzheimer's disease all the time, currently there is no cure. There are a number of medications that may help to control some of the symptoms of Alzheimer's disease. Research suggests that treatments to prevent and even cure the condition may be available in the not too distant future.

Safety issues — A major issue in managing individuals with Alzheimer's disease is safety. Because many patients do not realize that their mental functioning is impaired, they try to continue their day-to-day activities as usual. This can lead to physical danger, and caregivers must help to avoid situations that can threaten the safety of the patient or others.

Driving — Driving is often one of the first safety issues that arises. This is often difficult to face because driving represents independence for many people. Although people with Alzheimer's disease do not have more car accidents than others during the first year after diagnosis, the risk of crashes more than doubles after the first year. It is best to discuss the issue of driving early.

There may be significant resistance to stopping driving since the patient may not realize that he or she has impairments in mental functioning or reaction time. But all patients with Alzheimer's disease will eventually reach the point where driving is dangerous to themselves and others. The healthcare provider and family must work together to determine when a patient needs to stop driving.

Most states do not have specific regulations or restrictions on driving for patients with dementia, although some do provide roadside testing and other ways of evaluating an individual's ability to drive safely. Even if a person with newly diagnosed, mild Alzheimer's disease is still able to drive, the appropriateness of driving needs to be reassessed every six months, with the expectation that driving will eventually no longer be possible.

Cooking — Cooking is another area in which dementia can lead to serious safety concerns. Symptoms such as distractibility, forgetfulness, and difficulty in following directions can lead to burns, fires, or other injuries. Many providers recommend that patients be taught early how to use a microwave oven, which poses fewer dangers than stove-top cooking.

Wandering — As dementia progresses, some patients with Alzheimer's disease begin to wander. Because restlessness, distractibility, and memory problems are common, a person who wanders may easily become lost. Identification bracelets can help ensure that a lost wanderer gets home. The Alzheimer's Association provides a "safe return" program with ID tags and 24-hour assistance (www.alz.org/we_can_help_safe_return.asp).

Regular exercise may decrease the restlessness that may lead to wandering. For patients that continue to wander, alarm systems are available that alert caretakers when the wearer goes too far from home.

Falls — For all types of dementia, including Alzheimer's disease, falls eventually become a safety concern. As an example, one study in Sweden found that among people over age 75, those with cognitive impairment were twice as likely to suffer from hip fractures as those with no impairment [4]. Caregivers should assess the physical environment in the home to eliminate potential hazards such as loose electrical cords, slippery rugs, and so forth.

Aggressive behavior — One of the most difficult issues for caregivers and Alzheimer's patients is aggressive behavior. Fortunately, this behavior is not common. However, many family members are reluctant to report a patient's aggressive behavior. In some cases, the behavior becomes physically abusive as dementia progresses. In addition, some caregivers become so frustrated that they themselves begin to behave abusively.

Family members should discuss any concerns regarding aggressive behavior with a healthcare provider, and arrange for help if necessary. Medications are available to help control behavioral difficulties in patients with Alzheimer's and also to help with mental functioning (see "Treatment of behavioral symptoms" below).

Medications — Although there are no medications available that cure Alzheimer's disease, several drugs have been developed to help control symptoms of the disease. These include medications to manage memory and cognitive impairments as well as behavioral problems. In addition, research shows promise for developing treatments to modify the course of the disease and possibly delay or even prevent it.

Treatment of the memory disturbance — There are four drugs currently available for treating memory disturbances in Alzheimer's disease. All work by decreasing the release of a chemical called cholinesterase, allowing more of a chemical called acetylcholine to be active in the nervous system. People with Alzheimer's disease have declining levels of acetylcholine in the brain. Donepezil (Aricept®) is taken once a day, usually 5 mg per day for four weeks and then increased to 10 mg per day. Clinical studies have shown that donepezil can slow memory loss in some patients with mild to moderate Alzheimer's disease [5]. Side effects, including diarrhea, nausea, and vomiting, should be monitored. Rivastigmine (Exelon®) is a cholinesterase inhibitor that helps some patients with mild to moderate disease. This drug has side effects similar to those produced by donepezil, and appears to be similarly effective. It is usually started at a dose of 1.5 mg twice per day and gradually increased to 6 mg twice per day. Galantamine (Reminyl®) is used in patients with mild to moderate Alzheimer's disease to slow the loss of mental abilities and the decline in a patient's ability to perform normal daily activities.. Memantine (Namenda®) is a unique medication that works differently than cholinesterase inhibitors. It may function to protect the brain from further damage caused by AD. It has shown promise in treating persons with moderate to severe AD. Dizziness is the most common side effect, and aggression and hallucinations may worsen in some patients. It is sometimes used along with a cholinesterase inhibitor.

Typically, one of these drugs will be tried for a period of about eight weeks while the patient is monitored for side effects and response. If there is no improvement, the drug is usually stopped (with the exception of memantine, which may be continued due to the possible protective benefits). Sometimes a patient will decline after the drug is stopped; if this happens, the drug may be started again. The drugs can be taken for as long as needed in people who benefit from their use.

It is important to have realistic expectations about the potential benefits of these drugs. As mentioned, none of them cures the disease, and over time most people will continue to have a decline in function. When these drugs are effective, the hope is that this decline will be sufficiently slowed so that patients and their families will have an improved quality of life for a longer period.

Treatment of behavioral symptoms — The behavioral symptoms of Alzheimer's disease are often more troubling than the cognitive symptoms. Even in mild cases, agitation, anxiety, and irritability can occur and generally worsen as the disease advances.

Before a patient is treated for these behavioral problems, the provider must be sure that the problem is not caused by another illness or medications. If AD is determined to be the sole cause, a combination of medication and behavioral therapy may be helpful.

Problems such as wandering, hoarding or hiding objects, withdrawal, and socially inappropriate behavior often improve more with behavioral therapy than medications. Other problems, such as agitation, aggression, delusions, and hallucinations may be more responsive to medications. Because these latter behaviors are often the reason for putting an Alzheimer's patient into a nursing home, most providers try to control these problems as soon as they appear.

Delusions are common in patients with dementia, occurring in up to 30 percent of those with advanced disease. Paranoid delusions are particularly distressing to both the patients and the caregivers: these often include beliefs that someone has invaded the house, that family members have been replaced by impostors, that spouses have been unfaithful, or that personal possessions have been stolen. If these delusions are troublesome, antipsychotic medications can be prescribed to help control them.

In choosing a medication, the side effects must be considered. Some medications can worsen mental processes and cause sedation, while others may cause unacceptable side effects such as muscle tremors, tics, rigidity, etc.

The choice of medications for troublesome delusions and hallucinations is complex. Providers typically begin these drugs at the lowest effective dose to minimize side effects. Depression — Depression is a problem that sometimes occurs in people with dementia. Depression is not always present throughout the course of dementia. It can be difficult to diagnose because other behavioral changes occur that have similar symptoms. (See "Patient information: Depression in adults").

If depression is suspected in a person with Alzheimer's disease, the first step may be to try an antidepressant medication. A group of medications known as selective serotonin reuptake inhibitors, or SSRIs, are usually preferred. SSRIs include fluoxetine (Prozac®), sertraline (Zoloft®), paroxetine (Paxil®), citalopram (Celexa®), and escitalopram (Lexapro®). These medications are often helpful, but may be needed lifelong.

Other antidepressants, such as venlafaxine, duloxetine mirtazapine, and bupropion may also be effective, but have not been well studied in people with Alzheimer's disease.

Although tricyclic antidepressants have been studied for years and in low doses generally have a good safety profile, they are no longer recommended as first line agents in the treatment of people with dementia who have with depression because they may cause increased side effects. It is not necessary to stop a tricyclic antidepressant if it is working well.

Other treatments, such as behavioral therapy may also be recommended for depression. Behavioral therapy involves changing the environment that produces the depression (eg, encouraging exercise, socialization). Behavioral changes are believed to lead to changes in thoughts and emotions. Anxiety and aggression — These problems can be caused by a number of factors, including: Confusion or misunderstanding Frightening or paranoid delusions Depression Sleep disorders Medical conditions such as difficulty urinating or severe constipation

The best treatment for these symptoms depends upon what triggers them. As an example, a person who becomes aggressive during periods of confusion might best be treated through behavioral therapy, while someone who becomes aggressive during delusions might require medication.

Studies of older antipsychotic medications (haloperidol, thioridazine, thiothixene, chlorpromazine, trifluoperazine and acetophenazine) concluded that there was no clear evidence of benefit for these agents in patients with dementia [6]. One review concluded that haloperidol may help control aggression, but not other neuropsychiatric manifestations of dementia [7].

A newer class of medications known as atypical neuroleptics (aripiprazole, olanzapine, quetiapine, and risperidone) have been the medications of choice for treating hallucinations in patients with dementia. However, use of these medications for the treatment of behavioral problems in elderly patients with dementia is associated with an increased risk of death [8].

Nonetheless, the benefit of atypical neuroleptics often still outweigh their risks when treatment of hallucinations and delusions is necessary. Because there are no other medications that are effective, some experts continue to use them cautiously, after informing the patient and family about the potential risks. Sleep problems — Patients with sleep disorders may benefit from both medication and behavior changes: for example, limiting daytime naps, increasing physical activity, avoiding evening consumption of caffeine and alcohol, as well as a sleeping medication. However, sleeping pills also will worsen confusion.

Medications typically used to ease agitation and sleeping difficulties include the antidepressant trazodone (Desyrel) and the mood stabilizer carbamazepine (Epitol, Tegretol). Benzodiazepines such as alprazolam (Xanax) and diazepam (Valium) are not generally recommended for people with Alzheimer's disease because of their side effects (sedation).

Treatments that may be effective — A number of therapies have been studied in patients with Alzheimer's disease, including some that may alter the course of the dementia, not just treat the symptoms.

Vitamin E and selegiline — Reports of the effectiveness of vitamin E (alpha-tocopherol) have appeared in the popular press and research findings suggest that vitamin E may slow the progression of Alzheimer's disease. Another substance believed to help slow the condition is the drug selegiline (Eldepryl). In a study that compared vitamin E, selegiline, and a combination of the two, the two treatments were equally effective, and no advantage was seen in the group that took both [9].

There were some problems with the methods of this study, making it difficult to know for sure if vitamin E is beneficial in preventing or slowing the progression of AD. Nevertheless, this trial was the first to show a benefit of any therapy for delaying the progression of Alzheimer's disease. Some clinicians recommend that people with Alzheimer's disease take 1000 IU of vitamin E twice daily; this has fewer side effects and is less expensive than selegiline.

There is growing concern regarding the increased risk of death related to use of vitamin E supplements. Vitamin E is appropriate only for patients with AD or at high risk of developing AD (ie, those who have more than one family member with AD) who lack significant heart disease. We do not recommend vitamin E for the routine prevention of AD or other types of dementia.

Estrogen — Estrogen has been studied as a treatment that might slow the course of Alzheimer's disease. However, the most recent and well-controlled studies have shown no beneficial effects [10-12].

Nonsteroidal antiinflammatory drugs — Research with nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, ibuprofen, naproxen, and indomethacin has been inconclusive. So far, there is no evidence that these drugs can help treat Alzheimer's disease. NSAIDs should not be used for the treatment or prevention of dementia.

Ginkgo biloba — The herbal supplement ginkgo biloba has also been studied in patients with Alzheimer's disease and shown some promise in reducing mental decline [13]. The use of ginkgo is appealing since it has few side effects. However, we do not recommend the use of ginkgo because there is little evidence that it is effective and because it's production is not regulated; it is considered to be a dietary supplement, which means that the dose and ingredients can vary from pill to pill and bottle to bottle.

FUTURE TREATMENT AND PREVENTION — A number of research projects are currently underway to study how Alzheimer's develops and progresses over time. This kind of research holds considerable promise for treatment of AD symptoms, changing the course of AD, and even preventing it.

Some research is aimed at discovering more about the amyloid-beta plaques that develop in the brains of Alzheimer's patients, and how to prevent or even remove them. The protein tangles that are characteristic of Alzheimer's are another target of research, with the first goal being to figure out whether these tangles actually contribute to the disease or are a result of it, perhaps caused by the amyloid-beta plaques.

Animal research has shown that vaccines made from the amyloid-beta proteins may be able to slow the progression of brain damage in Alzheimer's and possibly even reverse it [14-16]. This kind of research will not yield results for treating humans for years, but the findings so far are promising.

The best hope may be to discover risk factors for Alzheimer's disease. Simply delaying the age of onset could significantly reduce the burden of the illness for patients, families, and other caregivers.

LIFE WITH ALZHEIMER'S — Being diagnosed with Alzheimer's disease can be overwhelming for both patients and their loved ones. However, the diagnosis does not mean that life is over.

For patients — It is important for people with early Alzheimer's disease to care for their physical and mental health. This means getting regular checkups, taking medications if needed, eating a healthy diet, exercising regularly, getting enough sleep, and avoiding activities that may be risky.

It may be helpful to talk to a counselor or social worker to discuss feelings of frustration, anger, loneliness, or depression. All of these feelings are normal, and dealing with these feelings can help a person to feel more in control of their wellbeing. Support groups are also available for patients and families to discuss these issues with other people dealing with similar problems.

Another issue to consider is how to tell family and friends about the diagnosis of Alzheimer's disease. Explaining the disease can help others to understand what to expect and how they can help, now and in the future. This can be especially helpful for children and grandchildren, who may not be familiar with the condition.

Patients may live alone in the early stages of Alzheimer's, but often need help with tasks such as housekeeping, cooking, transportation, and paying bills. If possible, ask a friend or family member for help to develop plans to deal with these and other issues as the condition progresses. In addition, patients and their loved ones should discuss preferences regarding issues that are likely to become important as AD worsens, including health insurance, where the patient will live, and the financial resources to pay for care. A number of resources are available to assist in this type of planning. (See "Where to get more information" below).

For caregivers — Alzheimer's disease is a debilitating disease that can impose an enormous burden on patients and families or other caregivers. People with Alzheimer's disease become less able to care for themselves as the disease progresses. Some tips that may help caregivers create a positive environment include the following: Make a daily plan and prepare to be flexible if needed. Focus on the process, not the end result. Try to be patient when responding to repetitive questions, behaviors, or statements. This type of behavior is common, and often is the result of feeling insecure or nervous. Use memory aids such as writing out a list of daily activities, phone numbers, and instructions for usual tasks (ie, the telephone, microwave, etc). Establish calm nighttime routines to manage behavioral problems, which are often worst at night. Leave a night light on in the patient's bedroom. Avoid major changes to the home environment. Employ safety measures in the home, such as locks on medicine cabinets, keep furniture in the same place to prevent falls, remove electrical appliances from the bathroom, install grab bars in the bathroom, and set the water heater at or below 120ºF. Help the patient perform personal care as they are willing and able. It is not necessary to bathe every day, although a healthcare provider should be notified if the patient develops sores in the mouth or genitals related to hygiene problems (eg, urinary incontinence, ill-fitting dentures). Speak slowly, present only one idea at a time, and be patient when waiting for responses. Encourage physical activity and exercise. A daily walk can help prevent physical decline and improve behavioral problems [17]. Consider respite care. Respite care can provide a needed break for family and can strengthen the family's ability to provide care in the future. This is offered in many communities in the form of in-home care or adult day care. Caregiving can be an all-consuming experience. Be sure to take time for yourself, take care of your own medical problems, and arrange for breaks when you need them.

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Institute of Neurological Disorders and Stroke

(www.ninds.nih.gov)
National Institute of Mental Health

(www.nimh.nih.gov)
Administration on Aging (Department of Health and Human Services)

(www.aoa.dhhs.gov)
The American Geriatrics Society

(www.americangeriatrics.org)
Alzheimer's Association

(www.alz.org)
Alzheimer's Disease Education and Referral (ADEAR) Center (National Institute on Aging)

(www.nia.nih.gov/alzheimers)
Eldercare Locator (Administration on Aging)

(www.eldercare.gov)
Family Caregiver Alliance

(www.caregiver.org)



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