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Background to Alzheimer's Disease

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Alzheimer’s disease is a progressive brain disorder that causes a gradual and irreversible loss of higher brain functions, including memory, language skills, and perception of time and space,
Transcript:
Alzheimer’s disease is a progressive brain disorder that causes a gradual and irreversible loss of higher brain functions, including memory, language skills, and perception of time and space, and, eventually, loss of the ability to care for oneself. The disease was first identified in 1906 by the German psychiatrist Alois Alzheimer. He thought it was a relatively rare disorder, but today we recognize Alzheimer’s as the most common cause of the loss of mental function in people over the age of 65. As many as 4 million to 6 million people in the United States have the disorder. Among individuals around the age of 65, 5 percent to 10 percent have Alzheimer’s, and this proportion increases to about 10 percent to 15 percent among those in their 70s and to 30 percent to 40 percent among people 85 years of age or older. Given our aging population, it has been estimated that 14 million Americans will have Alzheimer’s disease by the middle of this century unless we find a cure or preventive measures. Alzheimer’s is a devastating disease. Those who suffer from it experience frustration, anger, and fear as the disorder begins to strip away their abilities and memories. Those who love and care for people with the disease experience the stress and pain of watching someone they love slowly slip away. Unfortunately, we still do not know what causes Alzheimer’s, nor do we know how to cure it. Symptoms of Alzheimer’s Disease Most cases of Alzheimer’s disease occur in people over 65 and are referred to as late-onset Alzheimer’s. Early-onset Alzheimer’s, which occurs in people who are in their 30s, 40s, or 50s, is much less common; only about 2 percent of Alzheimer’s cases are early-onset. The symptoms and manifestations of the two types are identical. Alzheimer’s disease evolves slowly, with occasional plateaus. Memory loss is usually one of the first noticeable symptoms, and can be quite mild. It often begins with difficulty recalling people’s names, telephone numbers, and the details of events or conversations during the day. Memories from the remote past and, for some people, previously learned facts tend to remain relatively intact at the beginning of the illness, but will fade later. A person in the beginning stages of the disease might discover that it is difficult to find the right word, or sense a decline in his or her reading comprehension and ability to write. Later the memory loss becomes more notable: a person may have difficulty remembering what day or month it is, or become unable to find his or her way around familiar surroundings. As Alzheimer’s disease progresses, depression becomes more frequent: 5 percent to 8 percent of people suffer serious depression with insomnia or anorexia. Muscular rigidity, slowed movements, shuffling gait, and stooped posture are also relatively frequent in people with Alzheimer’s disease. Delusions, psychotic behavior, agitation with aggressive behavior, and hallucinations may occur, but only in 20 percent of individuals. People in the final stages of the disease become completely unable to care for themselves and must be helped with all their basic needs. The average length of time between the appearance of the first symptoms of Alzheimer’s and death seems to range from 4 to 16 years. Women with the disease generally survive longer than men. Most Alzheimer’s patients die of complications such as pneumonia. Diagnosing Alzheimer’s Disease It is essential to note that memory loss does not necessarily presage Alzheimer’s disease. All of us forget things once in a while. Furthermore, some slowing of memory is a normal consequence of aging. If you experience memory loss, but not at a level that interferes with the activities of daily life, you probably do not have the disease. The vast majority of people past the age of 65 do not have Alzheimer’s disease. Furthermore, many conditions besides Alzheimer’s can cause memory loss and dementia, a term used to describe impairment of other mental functions, such as language or the ability to think abstractly, along with memory. These conditions include hypothyroidism, depression, adverse drug reactions, and nutritional deficiencies. Some of these problems can be treated or cured, so it is critical to obtain an early and accurate diagnosis of dementia. Only after doctors rule out other neurological or medical problems do they focus on the diagnosis of Alzheimer’s disease. Then they use neuropsychological testing, brain imaging, and other techniques, such as blood tests and neurological and physical examination and history, to place people on two levels of diagnostic certainty: * probable Alzheimer’s disease—the person has no other illnesses that may contribute to the symptoms * possible Alzheimer’s disease—the person meets the criteria for other illnesses that may contribute to his or her mental problems, such as hypothyroidism or cerebrovascular disease We must reserve the designation of definite Alzheimer’s disease for cases confirmed by autopsy; we can be sure of the diagnosis only after examining brain tissue under a microscope after the person dies. Alzheimer’s Disease and the Brain An autopsy of a brain affected by Alzheimer’s reveals distinctive changes that we now recognize as hallmarks of the disease. A key step in the progression of the disorder appears to be the accumulation of a protein substance in the form of plaques, or clumps of fibers, in the brain’s gray matter. These plaques contain beta-amyloid peptide, a hard, waxy deposit that results from the breakdown of the protein amyloid. Beta-amyloid is also deposited in the walls of the blood vessels in and around the brain. Another characteristic of brains affected by Alzheimer’s disease is neurofibrillary tangles within neurons, composed of an abnormal form of the protein tau. There is also a substantial loss of neurons and of the synapses connecting them throughout the neocortex. Scientists believe that the plaques and tangles cause neurons to shrink and eventually die, first in the memory and language centers of the brain, and finally throughout the brain. Degeneration in the basal forebrain also profoundly reduces the supply of some brain chemicals, including the neurotransmitter acetylcholine, which is known to influence memory. We do not know what causes these alterations in the brain, but animal studies suggest that immunizing mice with a synthetic form of the amyloid protein can prevent the accumulation of amyloid plaques. This suggests that treatment directed at the amyloid protein might be an effective way to prevent the disease in individuals at risk or in the early stages of illness. But research teams are investigating many avenues of treatment, including drugs to block the generation of the amyloid protein, anti-inflammatory drugs, and antioxidants. What Affects the Risk for Alzheimer’s Disease? While we do not know what causes Alzheimer’s disease, we can point to a number of factors that determine an individual’s risk. Genetics appears to play a key role. First-degree relatives of people with Alzheimer’s have more than twice the chance of developing the disease than do individuals without a family history. Researchers have discovered that mutations in three genes—the amyloid precursor protein (APP) on chromosome 21, presenilin 1 (PS1) on chromosome 14, and presenilin 2 (PS2) on chromosome 1—result in rare autosomal-dominant and familial forms of Alzheimer’s disease beginning as early as the third decade of life. The autosomal dominance means that all living children of an affected parent have a 50 percent chance of developing the disease. Both men and women can pass on the mutations, and this form of the disease seldom skips a generation. Researchers have also associated a polymorphism on chromosome 19 with Alzheimer’s disease, but in a different way. Unlike genetic mutations, which usually dramatically change how a protein works, polymorphisms represent normal variations in our genes. Polymorphisms probably account for our subtle differences in eye color, hair color, and height and are seldom associated with disease. Nonetheless, the epsilon 4 polymorphism of the apolipoprotein E (ApoE) gene has been strongly and consistently associated with Alzheimer’s disease beginning at age 60 and older. It is not clear how ApoE-4 increases the risk of Alzheimer’s disease, but it is known that ApoE participates in amyloid accumulation. Genetic testing is usually not recommended for ApoE or the other markers, because even if these genes are found, the current incomplete knowledge of their role does not allow doctors to offer a reliable analysis of their significance for an individual. Several other factors also appear to influence Alzheimer’s disease. Adults with Down’s syndrome, a form of mental retardation, develop the plaques and tangles of Alzheimer’s disease by age 40, but not all develop dementia. For people who have blood relatives with Down’s syndrome, the risk of Alzheimer’s disease increases two or three times, suggesting a genetic link. A history of depression has also been associated with Alzheimer’s disease. Whether depression represents incipient disease or is an early symptom remains to be determined, but some studies have found a significant link between the two conditions even when the depression occurred ten years earlier. Although results are not consistent, there is also a suggestion that a head injury can increase a person’s risk of Alzheimer’s, perhaps by activating amyloid production. This effect may be especially strong among people who already have the ApoE-4 polymorphism. While popular reports periodically circulate about dietary (for example, zinc) and other environmental factors (such as aluminum), none of these suspects have yielded anything definitive under investigation. People’s educational achievement appears to have a profound influence on their likelihood of developing Alzheimer’s disease. Those who are illiterate or who have had little formal education are at higher risk for developing the disease. In one study of nuns, the women’s linguistic ability at age 20 predicted their level of cognitive impairment and Alzheimer’s disease at age 70. This has led some theorists to propose that having more education helps people develop a “cognitive reserve” that works against the effects of Alzheimer’s disease. Other researchers suggest that genetic or environmental factors play a role in both educational achievement and the disease. On the other hand, some factors seem to lessen the risk of Alzheimer’s disease. The use of estrogen replacement therapy by women after menopause has been associated with a decreased risk of Alzheimer’s disease. For women who took estrogen, the age at which they developed Alzheimer’s disease was significantly later, and their relative risk was significantly lower than it was for other women, even after researchers adjusted for differences in education, ethnic group, age, and ApoE-4. A study is now in progress to assess the effectiveness of estrogen replacement in delaying or preventing Alzheimer’s disease. People who develop Alzheimer’s disease tend to use anti-inflammatory agents like aspirin and acetaminophen less often than their peers. Because chronic inflammation has been associated with amyloid deposition, anti-inflammatory agents could play an important role in slowing or inhibiting the disease. Several large studies are now in progress to test whether or not these drugs can prevent Alzheimer’s disease. Cigarette smoking was once purported to protect people from Alzheimer’s disease, but studies have not borne out that idea. In fact, there is a clear link between smoking and dementia associated with strokes. Drug Treatments for Alzheimer’s Disease Since there is no cure for Alzheimer’s, current treatment focuses on lessening its symptoms. Some researchers consider the loss of acetylcholine to be the reason for declining memory, so they have adopted the strategy of enhancing the brain’s acetylcholine production. A class of drugs called cholinesterase inhibitors has a modest but positive effect on the memory-loss symptoms of the disease. A handful of medications have been approved for treating Alzheimer’s disease itself. Physicians may begin prescribing these drugs at any time after a person is diagnosed because they are modestly effective at delaying problems in both mild and moderate stages of disease. Whether people develop a tolerance to their effects after long-term use is unknown. Because higher doses of these drugs have both the greatest benefits and the most adverse effects, physicians usually begin with a small dose and increase it gradually while they and their patients watch for adverse reactions. Treatment can be continued indefinitely, but doctors often recommend discontinuing the drugs because their effects have declined or because the person with Alzheimer’s is no longer so able to tolerate their adverse effects. Individuals with Alzheimer’s disease and their families should be alert to the possibility of deterioration after drug treatment is stopped. Tacrine (tetrahydroaminoacridine), sold as Cognex, was the first drug approved in the United States specifically for treating Alzheimer’s disease. People must take it four times daily, and eating at the same time decreases the amount the body absorbs. Studies have found that this drug helps people improve their performance on tests of memory, but there is little to no change in overall function. Tacrine can cause a number of side effects, including nausea and vomiting in 28 percent of patients, so few people use it now. Donepezil (Aricept) was approved for Alzheimer’s disease in 1996. Compared with tacrine, it has minimal side effects (nausea and vomiting in 15 percent of people, insomnia in up to 14 percent) and a longer life in the bloodstream, allowing people to take it only once a day. As with tacrine, the efficacy of donepezil is modest, but its relative convenience has caused it to be widely used. Rivastigmine (Exelon) is similar to tacrine and donepezil in efficacy. It lasts up to ten hours. Because of its side effects, however, people must start taking this drug at a low dose and slowly build up the amount. At high doses, about 35 percent of people suffer nausea; other dose-related adverse effects include vomiting, diarrhea, and anorexia. Nearly 20 percent of people taking high doses of rivastigmine experience weight loss. Galantamine (Reminyl) will soon be available in the United States. Two studies suggest benefits in the same range as the preceding similar drugs, and its side effects are similar to those of donepezil. Although there has been some indication that antioxidants can protect against memory loss, none has been shown to prevent Alzheimer’s disease. People with Alzheimer’s disease given vitamin E (2000 IU per day) lived longer than those taking a placebo, but showed no improvement in their mental function. Ginkgo biloba, an extract from the leaves of a subtropical tree, was found to provide a small benefit on cognitive testing in people with Alzheimer’s disease, but the large number of dropouts in that trial has raised concerns about the validity of the results. Other Treatments Many people with Alzheimer’s suffer from a variety of symptoms beyond memory loss, and many of these symptoms can be treated. As noted above, depression is common and can make the mental losses appear worse than they are. People with Alzheimer’s disease can take almost all of the approved antidepressant drugs; studies have shown them to have comparable results, so the choice of one over another should depend on an individual’s response. Some tricyclic antidepressant drugs, such as amitriptyline, can result in confusion or orthostatic hypotension (low blood pressure on standing up) in 10 percent to 15 percent of people. Selective serotonin reuptake inhibitors (SSRIs) are better tolerated but can cause insomnia, anorexia, or, in men, ejaculatory failure in up to 5 percent. Delusions and psychotic behavior increase as Alzheimer’s disease progresses; once people display these symptoms, about 20 percent have them persistently. Symptoms disappear or diminish in 18 percent of people treated with neuroleptics such as haloperidol (Haldol) and atypical antipsychotic agents such as risperidone. Haloperidol may cause tardive dyskinesia (involuntary facial movements), persisting even after the drug is withdrawn. Parkinsonism, with shuffling gait and stooped posture, and drowsiness are rare side effects of all these medications. People with Alzheimer’s-related psychosis may also become aggressive and agitated, posing a threat not only to themselves but to those around them. Many different drugs have been tried for this problem, with little consistent benefit. Antidepressants, beta-adrenergic antagonists, lithium, benzodiazepines, and anticonvulsant drugs all show inconsistent results but are worth trying because they can help some individuals. In addition to sedating the person, many of these drugs worsen cognitive function; they have also been associated with falls and fractures. Treatment for sleep disturbances ranges from antipsychotic drugs to antidepressants and sedatives, all of which have adverse effects, so physicians try to use these medications for short periods only. Reducing daytime naps, restricting one’s time in bed, and exposure to bright light during waking hours may also be helpful. The Late Stages of Alzheimer’s Disease In the last stages of illness, people with Alzheimer’s disease are often unable to care for their most basic needs. Many individuals need round-the-clock care and are placed in nursing homes. People at this stage of illness may require tube feedings to maintain nutrition and decrease the risk of aspiration or choking. Skin care to prevent bedsores is important, as is bowel care. Because people at this stage of the disease are regularly incontinent, they may need frequent checks and adult diapers. Maintaining the dignity of the individual is still important: dressing, bathing, feeding, and grooming a person with Alzheimer’s each day is essential even though that person may appear unaware of his or her surroundings. When making end-of-life decisions, it is desirable to follow an individual’s wishes, but that may not be possible if the person has not made appropriate legal decisions. Some people make out documents authorizing certain life-support measures and not others, called Advance Directives, before they succumb to dementia. For people who have not put these choices in writing, the decision is usually up to the next of kin or legal guardian. Disagreements within the family can cause a great deal of difficulty, particularly when a rapid medical decision is required. Counseling can be of help. Although we have made significant progress in understanding some of the factors leading to Alzheimer’s disease, it is likely that the disease will continue to be a major health problem for a long time. Our gains in the ability to diagnose the disease and improvements in its treatment offer hope. Over the next decade treatments based on the known pathogenesis of the disease will become available. Grounded in the remarkable scientific achievements in the past decade, scientists remain hopeful that a cure or preventive treatments will emerge.
Keywords:
Alzheimer’s, Alzheimers, alz, stastics, disease, degeneration, tau, amyloid, treatments, apo, brain, memory
Creative Commons License This work by Cold Spring Harbor Laboratory is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.

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