Rebecca Frey & Ruvanee Pietersz Vilhauer. The Gale Encyclopedia of Mental Health. Editor: Laurie J Fundukian & Jeffrey Wilson. Volume 1. Detroit: Gale, 2008.

Definition

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

Description

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

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

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

Types of Alzheimer’s Disease

There are two different types of Alzheimer’s disease.

Familial AD

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

Sporadic or Late-Onset AD

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

Stages

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

Early-stage Alzheimer’s

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

Middle-stage Alzheimer’s

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

End-stage Alzheimer’s

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

Causes and Symptoms

Causes

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

Genetic

Early-onset AD is caused by a defect in one of three genes known as APP, presenilin-1 (PS1), and presenilin-2 (PS2). The APP gene is found on chromosome 21. People with Down syndrome, who have three copies of chromosome 21, develop an Alzheimer’s type dementia if they live longer than 40 years of age. A family history of Down syndrome is associated with a greater risk of developing early-onset AD. Mutations of the APP gene are associated with an onset of AD between the ages of 55 and 60.

The PS1 gene is found on chromosome 14, and the PS2 gene is found on chromosome 1. Mutations in these genes are associated with an onset of AD between 30 and 50 years.

The APP, PS1 and PS2 gene mutations are very rare, and only account for about 5% of all cases of AD.

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

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

Neurobiological

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

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

Environmental

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

Risk Factors

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

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

Symptoms

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

Cognitive Deficits

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

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

Neuropsychiatric Symptoms

Symptoms associated with BPSD include:

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

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

Problems with Activities of Daily Living (ADLs)

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

• Eating, including simple cooking and washing dishes
• Bathing, showering, or shaving
• Grooming and dressing in clothing appropriate to the weather and activity
• Toileting
• Other aspects of personal hygiene (brushing teeth or cleaning dentures, washing hair, etc.)
• Shopping for groceries and other necessary items

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

Demographics

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

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

Diagnosis

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

Diagnostic Evaluation of AD

At present, the diagnostic process includes the following components:

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

Ethical Considerations

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

Treatments

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

Medications to Slow Symptom Progression

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

The cholinesterase inhibitors include:

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

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

Another medication that has recently been approved for AD is memantine (Namenda). Memantine is thought to regulate the activity of a neurotransmitter called glutamate. When used alone or together with donezapil, it appears to help AD patients to function better cognitively.

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

Medications for BPSD

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

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

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

Alternative and Complementary Treatments

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

Naturopathy

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

Music Therapy

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

Prognosis

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

Prevention

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