Alzheimer's disease

Definition

Alzheimer's disease (AD) is the most common form of dementia, a neurologic disease characterized by a progressive 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.

In 2001, four million Americans have been diagnosed with AD. That number is expected to grow to as many as 14 million by the middle of the twenty-first century as the baby-boomer population ages. These numbers may be seriously underestimated due to new research that suggests mild cognitive impairment may be early stages of AD.

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 10% of all people over the age of 65 and nearly half of those over 85. Slightly more women than men are affected with AD, since women tend to live longer and occupy a larger proportion of the most affected age groups.

The costs for caring for loved ones with AD is considerable, and has been estimated at approximately $174,000 per person over the course of the disease. More than 70% of people with AD are cared for at home at an estimated annual cost of $196 billion. These costs are not supplemented by outside sources. If patients are cared for by paid home caregivers or are placed in nursing homes, the total annual out-of-pocket costs by families or third party payees account for $83 billion and $32 billion respectively.

Causes and symptoms

Causes

The cause of Alzheimer's disease is 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 responsible for learning, reasoning, and memory. Autopsies of people with AD indicate 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 (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 responsible for the mental changes of AD, presumably by interfering with the normal communication between neurons in the brain. Drugs approved by the Food and Drug Administration (FDA) 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. 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. However, studies in 2001 do not show estrogen as a protection against the development of AD.

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 is showing some benefit.

Several genes have been implicated in AD, including the gene for amyloid precursor protein (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, 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, 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.

Promising research in 2001 has discovered a protein, apoptosis-inducing factor, that kills cells by disrupting the genetic material at their cores. This discovery could lead to drugs that could turn off this protein that triggers apoptosis or biologically regulated cell death, which is important in fetal development but is also implicated in stroke, heart disease, and AD. It is thought that this protein runs out of control and shuts off otherwise healthy cells.

There are several risk factors that seem to 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 sooner.

Many environmental factors have been suspected of contributing to AD, but population studies generally have not borne these out. A study in early 2001, however, showed a specific link between aluminum in drinking water and the incidence of AD. Other suspected risk factors were other pollutants in drinking water, aluminum in any form, and mercury in dental fillings. To date, none of these other factors has been shown to cause AD or to increase its likelihood.

Lifestyle factors, moreover, may prove to be better indicators of risk. Lack of stimulation, mentally and physically, between the ages of 20 and 60 seems linked to the incidence of AD. Studies have not shown, though, that a sedentary lifestyle early in life causes AD or whether it is a marker for the incidence of the disease.

Another study of African Americans and their Nigerian counterparts shows AD appearing more often in the American population than the African one. Researchers suggest that environmental or cultural factors may play a role in the formation of AD. Here, physical activity or diet may play a part.

Symptoms

The symptoms of Alzheimer's disease begin gradually, usually with memory lapses. Occasional memory lapses are 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 progresses to more profound or disturbing losses such as forgetting how to even drive a car. Being 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 end of the sentence.

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, known as sunsetting. In some cases, people with AD repeat the same ideas, movements, words, or thoughts, a behavior known as perseveration. There may be delusional thinking or even hallucinations. 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, as in word-find problems or inappropriate word substitutions

disorientation about 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 the symptoms may have another cause. Approximately 20% of those originally suspected of having AD actually have some other disorder; about half of these cases are treatable.

Diagnosis

Diagnosis of Alzheimer's disease is complex and may require visits to several different specialists over several months before a determination can be made. With new diagnostic tools and criteria, it is possible to make a provisional diagnosis that is about 90% accurate. A positive confirmation of these findings can be made only through autopsy.

Early diagnosis is essential in helping the patient and the family make decisions about treatment, long-term care, and financial matters. Finding out that a loved one's behavior is based on a degenerative mental disease can help a family avoid unnecessary anger and feelings of impotence when dealing with the progression of the disease.

There are two diagnoses the clinical team can make for a patient. They are probable AD or possible AD. Probable AD is determined when physicians and psychiatrists rule out all other disorders that might produce similar symptoms. A diagnosis of possible AD is made when AD is considered the primary reason for the symptoms but is complicated with the presence of another disorder that might confuse the general progression of the disease.

Diagnosis for AD begins with the elimination of other physical and psychological causes for the patient's behavior. This is done through a multi-step process that tests for other disorders and measures the amount of deficit the patient is experiencing.

Patient history

A detailed medical history should be taken, noting a list of the patient's medicines (prescription and over the counter), vitamins, and herbs. Since there are many pharmaceuticals that can cause the same mental changes as AD, a careful review of the patient's medication, alcohol, and herbal use is important. If the patient's symptoms are related to any of these, most likely the condition can be reversed through adjustments in the patient's medications or herbal use. Any illicit drugs should also be reported.

Next, the physician should take a detailed report of any changes in the patient's mental functioning and memory. This will determine the mode of onset of symptoms, the progression of the deficits, and the impact of the impairment on daily functioning.

Physical exam and lab tests

AD-like symptoms can also be provoked by other medical conditions, including tumors, infection, thyroid malfunctioning, and dementia caused by mild strokes (multi-infarct dementia). These possibilities must be ruled out through blood screens, urine tests, electroencephalographs (EEGs), and a variety of imaging techniques.

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.

Cognitive functioning evaluation

Several types of oral and written tests are used in AD diagnosis and disease progression, including tests of mental status, language ability, functional ability, memory, and concentration. In the early stages of the disease, the results of these tests are usually normal. It should be noted that the widely-used Mini-Mental State Examination (MMSE) may not be accurate for highly educated or poorly educated individuals, or cultural minorities.

Neuropsychiatric evaluation

A detailed cognitive evaluation can be done by a psychologist or psychiatrist. These tests of memory and mental functioning provide a quantitative measure of the patient's deficits.

One of the most important parts of the diagnostic process is the evaluation of depression and delirium, since 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.

Imaging studies

Several imaging techniques can assess brain function and pathology, thus eliminating these as causes of the patient's symptoms. Most frequently used imaging scans are magnetic resonance imaging (MRI) or computed tomography (CT) scans, which detect structural changes in the brain. Brain function can be assessed through MRI, positron emission tomography (PET), and single-photon emission CT (SPECT). These tests help rule out stroke, subdural hematoma, and brain tumor as possible causes for the patient's symptoms.

Treatment

Alzheimer's disease is currently incurable, though a number of pharmaceuticals and home care strategies can mange the disease. The mainstay of AD treatment continues to be good nursing care, providing both physical and emotional support, as the patient gradually is able to do less independently and whose behavior becomes more erratic. Modifications of the home to increase safety are often necessary. Creative strategies to help the patient stay as independent as possible are also indicated. The caregiver also needs support to minimize anger, despair, and burnout.

Drugs

Donepezil hydrochloride (Aricept), rivastigmine (Exelon), and galantamine (Reminyl) have been approved for use in AD treatment. These drugs increase the levels of the neurotransmitter acetylcholine in the brain, thereby increasing the communication ability of the remaining neurons. They do this by inhibiting the enzymes, acetylcholinesterase and butylcholinesterase, which normally break down acetylcholine and butylcholine released by neurons. These drugs modestly increase attention span, concentration, mental acuity, and information processing. Tacrine (Cognex), the first drug used, is no longer used due to the risk of liver toxicity. All cholinesterase inhibitors have mild gastric side effects such as nausea and vomiting.

The antioxidant, vitamin E, is also thought to delay AD onset because it prevents neuron damage caused by free radicals. Vitamin E therapy, in combination with cholinesterase inhibitors, has become a practice standard in the treatment of AD.

Drugs that have been found ineffective are Selegiline (used in the treatment of Parkinson's disease), prednisone, and the anti-inflammatory NSAID diclofenac. Estrogen, once thought to be the keystone in treatment and prevention of AD in women, was found to be ineffective in mitigating symptoms in 2001. There is still some discussion about estrogen's ability to delay the onset of AD.

Depression may be treated with selective serotonin reuptake inhibitors (SSRIs) such as citalopram and sertraline. Physicians may also prescribe typical antipsychotics for agitation, aggression, or hallucinations, such as olanzapine, quetiapine, or risperidone. It should be noted that AD patients have more side effects from most medications, especially psychoactive drugs, and care should be taken in their selection.

Alternative treatment

Several substances are currently being tested for their ability to slow the progress of Alzheimer's disease. Among them are gingko extract, derived from the leaves of the Gingko biloba tree, and huperzine A, from the moss Huperzia serrata. Gingko extract has antioxidant, anti-inflammatory, and neuroprotective effects. It has been used for many years in China and is widely prescribed in Europe for treatment of circulatory problems. It has been shown to modestly improve cognitive function. Huperzine A is a natural cholinesterase inhibitor. It is reported to produce greater improvement than the synthetic cholinesterase inhibitors and has few side effects. Since neither herbal is regulated, they may have inconsistent levels of their active ingredients per dosage.

Nursing care and safety

The person with Alzheimer's disease will gradually lose the ability to dress, groom, feed, bathe, or use the toilet without help; in the late stages of the disease, the individual 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 the patient unattended for even a few minutes, which would make even the home a potentially dangerous place. In addition, some patients may exhibit inappropriate sexual behaviors.

Nursing care required for AD patients is simple enough to learn. The difficulty for many caregivers comes in the constant but unpredictable nature of the demands put on them. Additionally, the personality changes presented in 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 gentle, spending increasing amounts of time in dream-like states.

A loss of grooming skills 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 begin to assume more and more grooming duties for the patient as the disease progresses.

Ensuring proper nutrition for the AD patient may require using a colored plate to focus the patient's attention on the food. Finger foods may be preferable to those foods requiring utensils. Later, the caregiver may need to feed the patient. As movement and swallowing become difficult, a feeding tube may be placed into the stomach through the abdominal wall, which will require special attention.

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.

Safety will become of prime importance. 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 far from home while disoriented. In the home, grab bars in the bathroom, bed rails on the bed, and clutter-free 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 out of reach. The hot water heater temperature should 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.

A calm, structured environment with simple orientation aids such as calendars and clocks may reduce anxiety and increase safety. Labeling cabinets and drawers may keep the patient's attention focused. Scheduling meals, bathing, and other activities at regular times and places will provide emotional security and routine, since unfamiliar places and activities can be disorienting for the patient. Sleep disturbances may be minimized by keeping the patient engaged in activities during the day, offering structure and providing physical activities.

Care for the caregiver

Family members or others caring for a person with AD have a 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 an AD patient. Support groups are an important way to deal with the stress of caregiving. 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 an AD patient. 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.