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 the elderly; 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 the nerve cells in the brains of Alzheimer’s patients. 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, DC, 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 four million people in the United States had AD as of 2000, with 360,000–400,000 new cases identified every year. One person in ten over the age of 65 has AD, and nearly 50% of those over 85 have the disease. Unless a cure or preventive treatment is discovered, 14 million Americans will have Alzheimer’s by 2050. Very few people are wealthy enough to cover the cost of caring for an Alzheimer’s patient in the seven–10 years that typically extend between the beginning of the person’s dependency and death. The average lifetime cost of caring for one patient with AD is estimated at $174,000. The costs of laboratory tests, physicians’ visits, medications, nursing services, home care, and adult day care come to $114.4 billion per year in the United States alone. This sum is greater than the combined annual budgets of six Federal departments (Commerce, Education, Justice, Labor, Energy, and Interior).

The problem is expected to be complicated in future years by the fact that the so-called “baby boomer” generation is better nourished and better educated than the generation now at risk for AD. When the baby boomers are old enough to be at risk for late-onset Alzheimer’s, they are expected to live longer than the average Alzheimer’s patient does in 2002. Public health researchers who are making future projections about the impact of AD in the mid-twenty-first century point out that a treatment that would delay the onset of the disease would reduce the overall prevalence of AD. One study estimates that a therapy that would delay the onset of Alzheimer’s by only one year would save the United States $9 billion by 2007. The second approach, that of discovering a treatment for people who already have Alzheimer’s, would alter the proportion of mild cases to those considered moderate or severe. The researchers conclude by stating: “None of our models predicts less than a threefold rise in the total number of persons with Alzheimer’s disease between 2000 and 2050.”

Types of Alzheimer’s disease

As of 2002, some researchers think that Alzheimer’s may be more accurately described as a group or family of diseases rather than a single disease. Moreover, more recent research is helping to differentiate Alzheimer’s disease from other less common causes of dementia. In particular, some cases of dementia that were formerly thought to have been related to AD are now known to have been caused by Pick’s disease or Lewy body dementia. Pick’s disease is a rare type of dementia that affects certain areas of the brain and is characterized by a progressive loss of social skills, language, and memory. Lewy body dementia is a type of dementia in which the brain has characteristic Lewy bodies—areas of injury found on damaged nerve cells in certain parts of the brain.

Physicians now recognize three different forms of Alzheimer’s disease.

EARLY-ONSET AD. Early-onset AD is a rare form of Alzheimer’s found in fewer than 10% of AD patients. This group of patients, however, develops more of the brain abnormalities associated with AD than patients with the late-onset form. In addition, patients with early-onset Alzheimer’s are more likely to develop myoclonus (a condition in which a muscle or group of muscles has sudden spasms or twitching).

LATE-ONSET AD. Late-onset AD is the most common form of the disease; its symptoms usually begin to appear after age 65. Late-onset Alzheimer’s, which may or may not be affected by genetic variables, is also called sporadic Alzheimer’s disease because it does not necessarily run in families.

FAMILIAL ALZHEIMER’S DISEASE (FAD). Familial Alzheimer’s disease, or FAD, is a rare form that is entirely inherited. FAD accounts for fewer than 5% of all cases of AD. It has a very early onset, often in the patient’s 40s, and there is a clear family history of the disease.

Stages

Health care professionals use the term “insidious” to describe Alzheimer’s, 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 Alzheimer’s 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 Alzheimer’s 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 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 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, and presenilin-2, found on human chromosomes 21, 14, and 1, respectively. Early-onset AD is also associated with Down syndrome, in that people with trisomy 21 (three forms of human chromosome 21 instead of a pair) often develop this form of Alzheimer’s. The brains of people with Down syndrome age prematurely, so that those who develop early-onset AD are often only in their late 40s or early 50s when the symptoms of the disease first appear.

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 have the apoE4 gene from one parent have a 50% chance of developing AD; a 90% chance if they inherited the gene from both parents. They are also likely to develop AD earlier in life. 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 Alzheimer’s, and some who do not have the gene do develop the disorder. In 1998 another gene on chromosome 12 that controls the production of bleomycin hydrolase (BH, an enzyme involved in the body’s processing of amyloid precursor protein) was identified as a second genetic risk factor that acts independently of the APOE gene. In December 2000, three separate research studies reported that a gene on chromosome 10 that may affect the processing of a particular protein is also involved in the development of late-onset 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 starchy 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. APP is a substance found in many parts of the body, but its precise function is not yet known. Following the formation of beta amyloid, 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 formed from parts of the dying nerve cell called the tau protein, which was discovered in 1986. 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. 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 not known as of 2002, however, whether the plaques and tangles are causes of AD or results of it. The relationship between the plaques and the tangles is another question that has not yet been answered. Although the plaques usually appear in brain tissue before the tangles, it is not clear that they cause the tangles. There are other brain disorders, such as Pick’s disease, in which tangles appear in the brain cells without plaques.

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 whose production is 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, and viruses. Although there is little evidence as of 2002 that AD is caused by a virus or other infectious agent, the possibility cannot be completely excluded.

Other hypotheses about the causes of Alzheimer’s include damage caused by oxidation, estrogen deficiency, and inflammation. All of these possibilities are presently under investigation.

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. As of 2002, 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 Alzheimer’s. 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. People 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.

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 Alzheimer’s 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 provide 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.

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 Alzheimer’s 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 thiamin. Botanical supplements that have been said to improve cognitive function include Huperzine A, a Chinese tea, and an extract made from Gingko biloba, a tree that is native to China and is said to be the world’s oldest living deciduous tree. 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 Alzheimer’s, to improve mood, and to enhance their 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 as of 2002. 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 Alzheimer’s, ranging from development of a vaccine to prevent the formation of beta amyloid plaques to finding a drug that would stop the conversion of APP to beta amyloid. As of 2002, the vaccine, which was originally developed and tested on mice, does not appear to have any serious side effects in humans. It is presently being tested in Phase II trials on human subjects.