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Alzheimer's |
Alzheimer's Disease Over the past few decades, Alzheimer's disease has emerged from obscurity. Once considered a rare disorder, it is now recognized as a major public health problem having a severe impact on millions of Americans and their families. Research on Alzheimer's disease has grown accordingly. The small group of pioneers who conducted research on the disease in the 1970's has expanded to thousands of scientists in laboratories, institutions, and communities all over the world. At the National Institutes of Health (NIH), several institutes conduct and sponsor studies on Alzheimer's disease, including the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, and the National Institute of Nursing Research. The lead agency for Alzheimer's research at NIH is the National Institute on Aging (NIA), which launched an Alzheimer's disease program in 1978. Since then the study of this disease has become one of NIA's major priorities. In the private sector, the Alzheimer's Association and other groups are working to combat this disease. They fund research, contribute to public policy decisions, inform and educate the public, and provide services to people with Alzheimer's disease and their families. Their support for research is critical in the effort to understand and defeat this disorder. Thanks to these many groups, the study of Alzheimer's disease is moving ahead rapidly. Based on the pace of research over the past two decades, many scientists now think that effective treatments are not far in the future. The purpose of this booklet is to describe what we have learned to date and where research is now headed in the search for answers about Alzheimer's disease. About
using this booklet Many people contributed to this booklet. The NIA extends special thanks to the managers and residents of Sunrise of Arlington for the photographs by Richard Nowitz; and to researchers in NIA's Laboratory of Neuroscience for the photographs by Kay Chernush. This booklet was written by Caroline McNeil, Public Information Office, NIA; designed by Beth Singer Design; and illustrated by Lydia Kibiuk. What
Is Alzheimer's Disease? This excerpt from the journal of a man with Alzheimer's disease offers a glimpse of what it's like to be one of the 4,000,000 people in the United States who have this progressive, degenerative brain disorder. Cary Henderson, a history professor in Virginia, was diagnosed with Alzheimer's disease at age 55. Alzheimer's disease is one of the most common causes of the loss of mental function known broadly as dementia. This type of dementia proceeds in stages, gradually destroying memory, reason, judgment, language, and eventually the ability to carry out even the simplest of tasks. "You just feel that you are half a person," Henderson says in his narrative, which was dictated on a tape recorder in the early stages of the disease. "And you so often feel that you are stupid for not remembering things or for not knowing things... Just the knowledge that I've goofed again or I said something wrong or I feel like I did something wrong or that I didn't know what I was saying or I forgot--all of these things are just so doggone common..." Such personal accounts inevitably make one ask, why? What causes this disease? Can't anything be done to stop it? To prevent it? Scientists ask essentially the same questions, and this booklet describes their search for answers. It provides a brief overview of dozens of paths that are bringing us closer to ways of managing, and eventually defeating, Alzheimer's disease. Basics These characteristic symptoms acquired a name in the early part of the 20th century when Alois Alzheimer, a German physician, described the signs of the disease in the brain. Alzheimer had a patient in her fifties who suffered from what seemed to be a mental illness. But when she died in 1906, an autopsy revealed dense deposits, now called neuritic plaques, outside and around the nerve cells in her brain. Inside the cells were twisted strands of fiber, or neurofibrillary tangles. Today, a definite diagnosis of Alzheimer's disease is still only possible when an autopsy reveals these hallmarks of the disease. Plaques and tangles remained mysterious substances until the 1980's, when neuroscientists--the scientists who study the brain--discovered the proteins that make up these telltale anomalies. As research progresses, it is turning up clues to how plaques and tangles develop and how they relate to other changes in the brain. In the meantime, much more about the disease has come to light. We now know that Alzheimer's begins in the entorhinal cortex and proceeds to the hippocampus, a waystation important in memory formation. It then gradually spreads to other regions, particularly the cerebral cortex. This is the outer area of the brain, which is involved in functions such as language and reason. In the regions attacked by Alzheimer's, the nerve cells or neurons degenerate, losing their connections or synapses with other neurons. Some neurons die. The
course of the disease As Alzheimer's disease spreads through the cerebral cortex, it begins to take away language. "Lately, I've had trouble with words (practically have to play charades)" says Letty Tennis, a North Carolina woman with Alzheimer's disease who also kept a journal. Tennis talks about how her judgment is changing and refers to the emotional outbursts that are common in this disease. "We had a great time shopping, but...I bought everything in sight....My poor dear husband didn't stop me very much unless it was too outrageous and then I'd get very angry. I bought a pair of boots--galoshes really...and I told George it's something I've always wanted so we bought them and when we got home I had no memory of buying them--they were awful and cost $40...I used to be the sensible one in the family." Disturbing behaviors, such as wandering and agitation, beset many people as the disease progresses. In its final stages Alzheimer's disease wipes out the ability to recognize even close family members or to communicate in any way. All sense of self seems to vanish, and the individual becomes completely dependent on others for care. Patients often live for years with this condition, dying eventually from pneumonia or other diseases. The duration of Alzheimer's disease from time of diagnosis to death can be 20 years or more. The average length is thought to be in the range of 4 to 8 years. Definitions
Progress Studies of Alzheimer's disease can be divided into three broad, interacting categories. The first is research on causes, the second is diagnosis, and the third is treatment, which includes caregiving. The following chapters give a brief overview of what is known about each topic. They highlight some key findings to date, the clues researchers are now pursuing, and the paths that are expected to lead to answers about Alzheimer's disease. Further
Reading Khachaturian ZS and Radebaugh TS. Alzheimer's Disease: Progress Toward Untangling the Mystery, Encyclopaedia Britannica: 1995 Medical and Health Annual, Chicago: Encyclopaedia Britannica, Inc., 222-228, 1994. Tennis L. "Alzheimer's Diary: I Have What!" The Caregiver: Newsletter of the Duke Family Support Program 12(1):6-13, 1992. Tennis L. "More From Letty's Diary," The Caregiver: Newsletter of the Duke Family Support Program 12(3):8-10, 1992. The Public Health Impact of Alzheimer's Disease How
Many People One problem in getting accurate figures lies in the lack of a single definition of either dementia or Alzheimer's disease. Different surveys use different criteria for determining whether a person falls into one category or another. This is one reason their findings can be different. Another problem is that in all populations studied, a large proportion of people are unable or unwilling to participate in surveys of dementia. Although there is still no agreement on the exact percentage of people with Alzheimer's disease or other dementia, all studies do project one picture clearly--the exponential rise of this disease with age. After age 65, the percentage of affected people approximately doubles with every decade of life, regardless of how a survey defines dementia or Alzheimer's disease. It is also clear that as America's older population grows, the number of people with Alzheimer's will rise. If current population trends continue and no cure is found, the actual number of people with the disease could double every 20 years. ...And How Much It Costs. Alzheimer's disease has been estimated to cost the nation $80 to $90 billion a year. This figure includes both direct financial outlays, such as for nursing care, as well as indirect costs, such as lost productivity on the part of patients and the family members who care for them. Caring for a patient with Alzheimer's disease costs more than $47,000 a year whether the person lives at home or in a nursing home, according to a recent study in northern California. This study found that the families of Alzheimer's disease patients living at home spent about $12,000 annually, per family, for formal services, such as physician care and home health aides. But when the researchers added the estimated cost of unpaid, informal care provided by family members, the total annual cost was $47,049--comparable to the cost of nursing home care. Sources Rice D, Fox PJ, Max W, et al. The Economic Burden of Alzheimer's Disease Care, Health Affairs, 12(2):164-176, 1993. The Search for Causes Somewhere in this complex signaling system lies the cause of Alzheimer's disease. In the past two decades, neuroscientists have combed through it in search of defects that might explain what goes wrong in this disease. One of their earliest findings came from studies of neurotransmitters, the chemicals that relay messages between neurons. Neurotransmitters In the mid 1970's, scientists discovered that levels of a neurotransmitter called acetylcholine fell sharply in people with Alzheimer's disease. The discovery was intriguing for several reasons. Acetylcholine is a critical neurotransmitter in the process of forming memories. Moreover, it is the neurotransmitter used commonly by neurons in the hippocampus and cerebral cortex--regions devastated by Alzheimer's disease. Since that early discovery, which was one of the first to link Alzheimer's disease with biochemical changes in the brain, acetylcholine has been the focus of hundreds of studies. Scientists have found that its levels fall somewhat in normal aging but drop by about 90 percent in people with Alzheimer's disease. They have turned up evidence linking this decline to memory impairment. And they have looked for ways to boost its levels as a possible treatment for Alzheimer's disease. Other neurotransmitters have also been implicated in Alzheimer's disease. For example, serotonin, somatostatin, and noradrenaline levels are lower than normal in some Alzheimer's patients, and deficits in these substances may contribute to sensory disturbances, aggressive behavior, and neuron death. Most neurotransmitter research, however, continues to focus on acetylcholine because of its steep decline in Alzheimer's disease and its close ties to memory formation and reasoning. On
the Other Side of the Synapse First, these molecules have chemical bonds with molecules of fat, called phospholipids, that lie next to them in the membrane. Several studies have detected phospholipid abnormalities in neurons affected by Alzheimer's disease. These abnormalities might change the behavior of neighboring receptors and garble the message as it passes from neuron to neuron. Second, researchers have uncovered several types of receptors for acetylcholine and are now exploring their different effects on message transmission. It may be that the shapes and actions of the receptors themselves, independent of their neighboring phospholipids, play a role in Alzheimer's. But the receptor is just the starting point of the cell's communications system. When a neurotransmitter binds to a receptor, it triggers a cascade of biochemical interactions that relay the message to the neuron's nucleus, where it activates certain genes, or to the end of the axon, where it passes to other cells. This messaging system involves a number of proteins, and abnormalities in these proteins or dysfunction at the relay points could block or garble the message. So could other events and processes in the cell, such as problems with the system that turns food into energy (metabolism) or the mechanisms that keep calcium levels in balance. Drug therapies aimed at these various postsynaptic events are now being explored, although most are still in the very earliest phases of testing. Two of them, vitamin E and deprenyl, are currently in clinical trials (studies of people). The
Proteins Scientists also know something about how beta amyloid is formed. Its parent protein, APP, protrudes through the neuron membrane, part inside and part outside the cell. There only for a moment, it is continually replaced by new APP molecules manufactured in the cell. While it is embedded in the membrane, enzymes called proteases snip or cleave it in two, creating the beta amyloid fragment. What happens to the beta amyloid segment once it separates from APP is less clear. A number of studies have centered on how beta amyloid is processed, searching for abnormalities that could explain what goes wrong. Others are seeking clues in the environment surrounding the protein. For instance, certain other substances in the neighborhood of beta amyloid protein may normally bind to it and thus keep it in solution. But in Alzheimer's disease, according to one theory, something causes the beta amyloid to drop out of solution and form the insoluble plaques. Other areas of research center on how beta amyloid affects neurons--if at all. In one laboratory study, hippocampal neurons died when beta amyloid was added to the cell culture, suggesting that the protein is toxic to neurons. Another recent study suggests that beta amyloid breaks into fragments, releasing free radicals that attack neurons. The precise mechanism by which beta amyloid might cause neuron death is still a mystery, but one recent finding suggests that beta amyloid forms tiny channels in neuron membranes. These channels may allow uncontrolled amounts of calcium into the neuron, an event that can be lethal in any cell. Other recent studies suggest that beta amyloid disrupts potassium channels, which could also affect calcium levels. Still another study links beta amyloid to reduced choline concentrations in neurons; since neurons need choline to synthesize acetylcholine, this finding suggests a link between beta amyloid and the death of cholinergic neurons. Tau: Another set of clues centers on a protein called tau, the major component of neurofibrillary tangles. Neurofibrillary tangles resisted analysis until the late 1980's, when researchers discovered they were associated with neurons' internal structures, called microtubules. In healthy neurons, microtubules are formed like train rails, long parallel tracks with crosspieces, that carry nutrients from the body of the cells down to the ends of axons. In cells affected by Alzheimer's, this structure has collapsed. Tau normally forms the crosspieces between microtubules, but in Alzheimer's it twists into paired helical filaments, like two threads wound around each other. These are the basic constituents of neurofibrillary tangles. Genes
Genetic research has turned up evidence of a link between Alzheimer's disease and genes on three chromosomes--14, 19, and 21. The apoE4 gene on chromosome 19 has been linked to late-onset Alzheimer's disease, which is the most common form of the disease. The
AplE4 and Alzheimer's disease In the same laboratory, another group of researchers were looking for proteins that bind to beta amyloid. They were disappointed at first. One version of a protein called apolipoproteinE (apoE) did bind quickly and tightly to beta amyloid, but apolipoproteinE was well known as a carrier of cholesterol in blood. No one suspected that it could have anything to do with Alzheimer's disease. But by coincidence, or so it seemed, the gene apoE, which produces the protein, was also on chromosome 19. Moreover, it was on the same region of chromosome 19 as the Alzheimer's gene for which they had been searching. The two groups of scientists decided to see if the apoE gene and the still missing Alzheimer's gene could be one and the same, and what they found made headlines: The apoE gene was identical to the gene they had been seeking. ApoE, it turned out, is much more common among Alzheimer's patients than among the general population. More precisely, one version of apoE is more common among Alzheimer's patients. Like some other genes, the one that produces apoE comes in several forms or alleles. The apoE gene has three different forms--apoE2, apoE3, and apoE4. ApoE3 is the most common in the general population. But apoE4 occurs in approximately 40 percent of all late-onset Alzheimer's patients. Moreover, it is not limited to people whose families have a history of Alzheimer's. Patients with no known family history of the disease, cases of so-called sporadic Alzheimer's disease, are also more likely to have an apoE4 gene. Since that finding, dozens of studies around the world have confirmed that the apoE4 allele increases the risk of developing Alzheimer's disease. People who inherit two apoE4 genes (one from the mother and one from the father) are at least eight times more likely to develop Alzheimer's disease than those who have two of the more common E3 version. The least common allele, E2, seems to lower the risk even more. People with one E2 and one E3 gene have only one-fourth the risk of developing Alzheimer's as people with two E3 genes. What does the apoE4 gene do? On one level, all genes function by transcribing their codes into proteins, so when we ask what a gene does, we are really asking what its protein product does. Many laboratories are now exploring what the apoE4 product does, and they have several clues. Some of these clues point to beta amyloid. While the apoE4 protein binds rapidly and tightly to beta amyloid, the apoE3 protein does not. Normally beta amyloid is soluble, but when the apoE4 protein latches on to it, the amyloid becomes insoluble. This may mean that it is more likely to be deposited in plaques. Studies of brain tissue suggest that apoE4 increases deposits of beta amyloid and that it directly regulates the APP protein from which beta amyloid is formed. Other clues, however, point to tau as the pivotal protein. As the crosspiece in the microtubule, tau's function seems to be to stabilize the microtubule structure. One hypothesis suggests that the apoE4 protein allows this structure to come undone in some way, leading to the neurofibrillary tangles. While still controversial and far from proven, the hypotheses surrounding apoE4 are driving new research. One next step is to see how tau and beta amyloid react with apolipoprotein in its several forms in living cells. Other experiments will attempt to determine the actions and role of the protein. Once these are clear, it should be easier to see how they might be affected by drugs. For instance, if apoE2 does turn out to be beneficial, then substances that mimic its effects might be designed to help prevent or slow the progress of Alzheimer's disease. The theories surrounding apoE4 are not confined to the proteins. One finding that intrigues neuroscientists is that Alzheimer's patients with the apoE4 gene have neurons with shorter dendrites--the branchlike extensions that receive messages from other neurons. Researchers speculate that the dendrites have been pruned back by some unknown agent, limiting the neuron's ability to communicate with other neurons. Although this pruning can also occur in people without the apoE4 allele, it happens 20 or 30 years earlier in people with apoE4. Will the genetic information available now ever be used in screening for Alzheimer's disease? Probably not. One of the puzzles surrounding apoE4 is why some people with the gene do not develop Alzheimer's disease and why, conversely, many people develop the disease even though they do not have the gene. ApoE4, in other words, is not a consistent marker for Alzheimer's. This is one reason that few people advocate widespread screening for apoE4. Screening would miss a large percentage of those who will develop Alzheimer's and falsely identify others as future Alzheimer's patients. Some scientists suggest, however, that testing for the gene may someday help in the diagnosis of Alzheimer's. Genes
in early-onset Alzheimer's disease Alzheimer's strikes early and fairly often in these and other families around the world--often enough to be singled out as a separate form of the disease and given a label: early-onset familial Alzheimer's disease or FAD. Combing through the DNA of these early-onset families, researchers have found a mutation in one gene on chromosome 21 that is common to a few of the families. And they have linked a much larger proportion of early-onset families to a recently-identified gene on chromosome 14. The gene on chromosome 21 occurs less often in people with FAD than the chromosome 14 gene, which codes for a membrane protein whose function is not yet known. The chromosome 21 gene carries the code for a mutated form of the amyloid precursor protein, APP, the parent protein for beta amyloid. The discovery of this gene supports the theory that beta amyloid plays a role in Alzheimer's disease, although the mutation occurs in only about 5 percent of early-onset families. The chromosome 21 gene intrigues Alzheimer's researchers also because it is the gene involved in Down syndrome. People with Down syndrome have an extra version of chromosome 21 and, as they grow older, usually develop plaques and tangles like those found in Alzheimer's disease. Few researchers think that the search for Alzheimer's genes is over. The Volga Germans, for one thing, have neither the chromosome 14 nor the chromosome 21 abnormality. Most investigators are convinced that there are several genes involved in Alzheimer's disease and, moreover, that other conditions must also be present for the disease to develop. One of these conditions may be a problem with the way in which neurons turn sugar, or glucose, into energy, a process known as glucose metabolism. Metabolism PET works on a simple principle. Brain activity, whether one is looking at a picture, working out a problem in calculus, or simply observing the surroundings, requires energy. Neurons produce energy through metabolism, a chain of biochemical reactions that uses large amounts of glucose and oxygen. PET can track the flow of glucose and oxygen molecules in the bloodstream to the parts of the brain producing energy, thus revealing which areas are active. A patient having a PET scan rests on a long low platform as the scanner tracks the flow of glucose or oxygen. The data the scanner collects are fed into a computer program which translates it into multicolor images: red and orange for areas of high activity, yellow for medium, blue and black for little or none. By deciphering these patterns, Alzheimer's researchers can chart the progress of the disease. Glucose metabolism declines dramatically as neurons degenerate and die. Scientists are also using PET to learn how changes in brain activity match up with changes in skills, such as the ability to do arithmetic or to remember names of objects. No one knows whether the decline in glucose metabolism causes neurons to degenerate or whether neuron degeneration causes metabolism to decline. In the effort to find out, scientists have examined glucose molecules at every step of the way from bloodstream to neuron. The route is complex. It begins as glucose-laden blood flows through the capillaries, the tiny blood vessels that carry the blood past neurons. Specialized molecules capture glucose molecules from blood and shuttle them into the neurons. These transporter molecules come in several forms. One recent study found that levels of two of them, GLUT1 and GLUT3, were low in the cerebral cortex of people with Alzheimer's disease. These reductions could be one reason glucose metabolism drops in Alzheimer's. Another key element in this scenario could be the condition of the capillaries. The transport system could break down because of thickening of the capillary walls, deposits of minerals, cholesterol, and amyloid, or some injury to these microvessels. Once inside the cell, glucose molecules are delivered to inner structures, called mitochondria, where they are turned into energy through metabolism. This process involves various enzymes and other proteins, as well as glucose and oxygen. An alteration in any of the ingredients could have a profound effect on the end result, so investigating these enzymes is another important area in Alzheimer's research. Studies have found, for instance, that the enzyme cytochrome oxidase, important in glucose metabolism, is produced at lower levels in cells affected by Alzheimer's. Since its decline matches the declines in glucose metabolism, it may play a role in the disease. While the glitch in glucose metabolism has yet to be pinpointed, its results are known to be devastating. Neurons depend wholly on glucose for their sustenance and when glucose metabolism falters, they suffer in various ways. For example, they cannot manufacture as much acetylcholine as normal cells, which may be one reason this neurotransmitter declines in Alzheimer's. In addition, neurons having a problem with metabolism react abnormally to another neurotransmitter, called glutamate. When these neurons are stimulated by glutamate--even normal amounts of glutamate--their regular mechanisms go awry and they are flooded by calcium, with deadly consequences. The Calcium Hypothesis Too much calcium can kill a cell, and some neuroscientists suspect that in the end, a rise in calcium levels may be precisely what is killing neurons in Alzheimer's disease. According to one hypothesis, an abnormally high concentration of calcium inside a neuron is the final step in cell death. Several different series or cascades of biochemical events could lead up to this last, fatal step. What events might these be? One possibility is that an increase in calcium channels could allow an excess of calcium into the cell. Another possibility is that a defect develops in the structures that store calcium inside the cell or those that pump it out of the cell. Still another hypothesis suggests that calcium levels rise because of an "energy crisis" in the neuron. In this scenario, chronically high levels of the neurotransmitter glutamate disrupt energy metabolism, leading to an influx of calcium. Glutamate is an excitatory neurotransmitter; it triggers action in a neuron, stimulating the flow of calcium into the cell. If it is produced in higher-than-normal levels, it can overexcite a neuron, driving in too much calcium. Moreover, glutamate can be dangerous to a neuron even at normal levels if glucose levels are low. Thus a problem with glucose metabolism could allow glutamate to overexcite the cell, allowing an influx of calcium. Another hypothesis, involving the hormones called glucocorticoids, ties in with this theory. Glucocorticoids normally enhance the manufacture of glucose and reduce inflammation in the body. They came to the attention of Alzheimer's researchers when studies in older animals showed that long exposure to glucocorticoids contributed to neuron death and dysfunction in the hippocampus. Now several laboratories are exploring mechanisms by which glucocorticoids might lead to neuron death through their effect on glucose metabolism. Environmental Suspects Aluminum Aluminum does turn up in higher amounts than normal in some autopsy studies of Alzheimer's patients, but not in all. Further doubt about the importance of aluminum stems from the possibility that the aluminum found in some studies did not all come from the brain tissues being studied. Instead, some could have come from the special substances used in the laboratory to study brain tissue. Aluminum is a common element in the Earth's crust and is found in small amounts in numerous household products and in many foods. As a result, there have been fears that aluminum in the diet or absorbed in other ways could be a factor in Alzheimer's. One study found that people who used antiperspirants and antacids containing aluminum had a higher risk of developing Alzheimer's. Others have also reported an association between aluminum exposure and Alzheimer's disease. On the other hand, various studies have found that groups of people exposed to high levels of aluminum do not have an increased risk. Moreover, aluminum in cooking utensils does not get into food and the aluminum that does occur naturally in some foods, such as potatoes, is not absorbed well by the body. On the whole, scientists can say only that it is still uncertain whether exposure to aluminum plays a role in Alzheimer's disease. Zinc On the other hand, a recent study suggests that too much zinc might be the problem. In this laboratory experiment, zinc caused soluble beta amyloid from cerebrospinal fluid to form clumps similar to the plaques of Alzheimer's disease. Current experiments with zinc are pursuing this lead in laboratory tests that more closely mimic conditions in the brain. Food
borne poisons In Canada, an outbreak of a neurological disorder similar to Alzheimer's occurred among people who had eaten mussels contaminated with demoic acid. This chemical, like the legume amino acids, is a glutamate stimulator. While these toxins may not be a common cause of dementia, they could eventually shed some light on the mechanisms that lead to neuron degeneration. The
search for a virus This line of research has yielded little in the way of hard evidence so far, although one study in the late 1980's did provide some data that have kept the possibility alive. A larger investigation is now under way. Alzheimer's
Risk Factors and the Search for Causes Epidemiologic studies also search for environmental causes of disease. For example, one current study is comparing a group of Alzheimer's patients in Nigeria to a group of African-Americans with Alzheimer's disease. If the prevalence is higher in one group than another, the scientists will then look for some factor in the environment that could explain the difference. So far, only two risk factors have been linked to Alzheimer's disease. Others are under investigation. Known risk factors
Possible risk factors
Sources: Khachaturian ZS and Radebaugh TS. Alzheimer's Disease: Progress Toward Untangling the Mystery, Encyclopaedia Britannica: 1995 Medical and Health Annual, Chicago: Encyclopaedia Britannica, Inc., 222-228, 1994. A Disease With Many Causes? There might, for example, be just two switches, such as a gene mutation and another event to trigger the gene. Or there might be several. According to this idea, called the AND gate theory, these events do not have to occur at the same time, but their effects would have to linger and eventually coincide to bring about Alzheimer's disease. Further Reading Pennis E. A Molecular Whodunit: New Twists in the Alzheimer's Mystery, Science News 145:8-11, 1993. Neurotransmitters
and Signaling Geula C and Mesulam M. Cholinergic Systems and Related Neuropathological Predilection Patterns in Alzheimer Disease. In Terry RD, Katzman R, and Bick KL eds. Alzheimer Disease, New York: Raven Press, 1994; pp 263-292. Horsburgh K and Saitoh T. Altered Signal Transduction in Alzheimer Disease. In Terry RD, Katzman R, and Bick KL eds. Alzheimer Disease, New York: Raven Press, 1994; pp 387-404. The
Proteins Lee VM, Balin BJ, Otvos L, and Trojanowski JQ. A68: A Major Subunit of Paired Helical Filaments and Derivatized Forms of Normal Tau, Science 251:675-678, 1991. Cotman CW and Pike CJ. Beta-Amyloid and Its Contributions to Neurodegeneration in Alzheimer Disease. In Terry RD, Katzman R, and Bick KL eds. Alzheimer Disease, New York: Raven Press, 1994; pp 305-316. Kosik K and Greenberg SM. Tau Protein and Alzheimer Disease. In Terry RD, Katzman R, and Bick KL eds. Alzheimer Disease, New York: Raven Press, 1994; pp 335-344. The Genes St. George-Hyslop PH. The Molecular Genetics of Alzheimer Disease. In Terry RD, Katzman R, and Bick KL eds. Alzheimer Disease, New York: Raven Press, 1994; pp 345-352. Metabolism Rapoport SI and Grady CL. Parametric In Vivo Brain Imaging During Activation to Examine Pathological Mechanisms of Functional Failure in Alzheimer Disease, International Journal of Neurosciences 70:39-56, 1993. Calcium Khachaturian ZS. The Role of Calcium Regulation in Brain Aging: Reexamination of a Hypothesis, Aging 1:17-34, 1989. Khachaturian ZS. Calcium Hypothesis of Alzheimer's Disease and Brain Aging, Annals of the New York Academy of Sciences 7471-7481, 1994. Environmental
Suspects Gatz M, Lowe B, Berg S, et al. Dementia: Not Just a Search for the Gene, The Gerontologist 34:251-255, 1994. Research on Diagnosis Bernice Judy had a range of medical tests that suggested she had Alzheimer's disease or a related disorder. The diagnosis, in her case, turned out to be Pick's disease, another brain disease that is similar in many ways to Alzheimer's. Ten years earlier Bernice Judy's illness would probably have been swept into a broad and ill-defined category labeled senile dementia. But with the recognition of Alzheimer's as a distinct and common disease, progress in diagnosing it has been rapid. Alzheimer's researchers are still some way from their ultimate aim--a reliable, valid, inexpensive, and early diagnostic marker--but they now have the tools to diagnose the disease with 85 to 90 percent accuracy. Despite the lack of a treatment for Alzheimer's, early diagnosis has advantages. Twenty percent of suspected Alzheimer's cases turn out to be something else, and it is often something that can be treated or even reversed. Tumors, strokes, severe depression, thyroid problems, medication side effects (or "drug intoxication"), nutritional disorders, and certain infectious diseases can all have effects that mimic those of Alzheimer's. Early diagnosis increases the chances of treating these conditions successfully. Even when the underlying cause of dementia turns out to be Alzheimer's, there are advantages to finding out sooner rather than later. One benefit is medical. The only drug now on the market to treat the cognitive decline in Alzheimer's disease, THA, is more likely to be effective in the early stages of the disease. The same may be true of other drugs now being developed. Other advantages to an early diagnosis are practical ones. The sooner the patient and family know, the more time there is to make future living arrangements, handle financial and legal matters, and establish a support network. Research on diagnosis falls into two categories. One major group of studies is looking for early biological markers--changes in blood chemistry or brain structures, for example. Another group is searching for telltale changes in mental abilities and personality--the so-called cognitive markers. Cognitive Markers More reliable cognitive markers are urgently needed. In the search for them, scientists are studying a phenomenon known as visual memory--the ability to remember and reproduce geometric patterns, for instance. People who develop Alzheimer's disease begin to lose immediate visual memory sooner than is expected in normal aging and long before other markers of dementia appear, according to some studies. Declines in verbal memory also may be an early marker. Followup studies are now looking for such markers in larger groups of people. They are also using brain imaging techniques, such as PET scans and MRI, to see if early cognitive markers can be linked to early biological changes in the brain. The familiar visual pattern of a clock forms the basis of one experimental method of diagnosing Alzheimer's. In this test, the patient draws the face of a clock, draws the hands to show certain times, and reads the time when someone else draws the hands. So far, findings suggest that the clock test may help differentiate Alzheimer's from the effects of normal aging and perhaps from other forms of dementia. Larger studies will follow up on this lead. Other researchers are searching for changes in personality that may herald the onset of Alzheimer's. In normal aging, personality does not change with age. In Alzheimer's, however, there is a hint that two facets of personality may change early in the disease; these are "conscientiousness," which declines and "vulnerability to stress," which increases. These findings are far from conclusive, but they do offer a lead. Researchers are following up by tracking personality changes in a larger group. Diagnosing Alzheimer's Disease: Current Tools Diagnostic Tools
Biological
Markers
Over the past decade, small preliminary studies have raised hope--and headlines--for several different markers. So far none has stood up under closer scrutiny. Still under consideration is a marker that may show up during a simple eye test, according to one study. In this study, a drug commonly used in eye examinations to enlarge the pupils, called tropicamide, increased the pupil size of suspected Alzheimer's disease patients in the study more than in other older people. This study involved fewer than 20 patients. Again, the next step is larger studies. Imaging Their tools include PET, which traces blood flow and metabolism in the brain and SPECT (single photon emission computed tomography) which also measures blood flow. Another imaging technique, magnetic resonance imaging (MRI), lets researchers view the brain's structure in cross section. New techniques available to PET and SPECT researchers allow them to assess interactions among molecules in the brain, such as neurotransmitters and their receptors. Another new technique, magnetic resonance spectroscopy imaging or MRSI, lets neuroscientists observe certain substances throughout the brain, without using radioactive markers. All of the imaging techniques--PET, SPECT, MRI, and MRSI--are still primarily research tools. However, they hold the promise of leading to an early and cost-effective method for diagnosing Alzheimer's disease. Further Reading McKhann G, Drachman D, Folstein M, et al. Clinical Diagnosis of Alzheimer's Disease: Report of the NINCDS-ADRDA Work Group. In Alzheimer's Disease and Related Dementias: Legal Issues in ADRD Care and Treatment, Washington, DC: U.S. Department of Health and Human Services, Advisory Panel on Alzheimer's Disease, 1994. Cognitive Markers Siegler IC, Welsh KA, Dawson DV, et al. Ratings of Personality Change in Patients Being Evaluated for Memory Disorders, Alzheimer's Disease and Associated Disorders: An International Journal 5:240-250, 1991. Zonderman AB, Giambra LM, Kawas CH. Changes in Immediate Visual Memory Predict Cognitive Impairment, Archives of Clinical Neuropsychology (in press). Biological Markers Resnick SM, Zonderman AB, Golski S, et al. Memory Change as a Predictor of Regional Brain Structure and Function. In Kabota and Matsuo DS eds. Recent Advances in Aging Research: From the Molecule to the Human. Proceedings of the Fifth Joint Symposium of the Tokyo Metropolitan Institute of Gerontology and the National Institute on Aging, Tokyo:135-139, 1994. Investigating Treatments A second group of studies focuses on management of the disease. This area of research is looking for ways to treat the symptoms of Alzheimer's disease and slow its progress, either through drugs or behavioral approaches. Potential
Biomedical Treatments One member of the cholinergic system is acetylcholinesterase (often referred to simply as cholinesterase), the enzyme that breaks down acetylcholine after it crosses the synapse. Many of the experimental Alzheimer's drugs developed to date are cholinesterase inhibitors; that is, they are designed to suppress cholinesterase so that acetylcholine will not be broken down as quickly. One such cholinesterase inhibitor is THA or tetrahydroaminoacridine, the only drug approved so far by the Food and Drug Administration to slow the loss of cognitive ability in Alzheimer's disease. THA has helped some patients, but its impact on the disease in general has proved disappointing. However other cholinesterase inhibitors that may be more effective are under development. The discovery of acetylcholine deficits in Alzheimer's disease also raised hope that choline and lecithin, if added to the diet, could help in treating Alzheimer's disease. The body uses these nutrients to synthesize acetylcholine. Trials with the two substances have been disappointing so far, with choline supplements having no effect on cognitive function and lecithin only a slight effect in a few patients. Researchers are still interested in other substances that may enhance the availability of acetylcholine. Neurotrophic
factors Some older rats (about 2 years old) take longer to negotiate a maze or cannot seem to make memories of the correct turns at all. In a study in the mid-1980's, scientists took several rats with such memory impairment and gave them nerve growth factor or NGF. The rats' ability to negotiate the maze improved, coming close to the ability seen in older rats with no impairment. Because of this study and several similar ones, NGF intrigues neuroscientists as a possible treatment for Alzheimer's disease. How NGF works is not completely clear, but it is known to be one of several growth factors in the brain or, in neurobiologists' terms, neurotrophic factors. Growth factors elsewhere in the body promote and support cell division. Neurons cannot divide, but they can regenerate after injury and neurotrophic factors promote this regeneration. They also promote the growth of axons and dendrites, the neuron branches that form connections with other neurons. Other neurotrophic factors that may be implicated in Alzheimer's include brain derived neurotrophic factor and neurotrophin-3. Studies have turned up a number of clues that link NGF specifically to the cholinergic neurons (those that use acetylcholine as a neurotransmitter). In that early maze experiment, the rats whose memories had improved not only had higher NGF levels but also their cholinergic neurons had regenerated. In another study, NGF promoted the survival of cholinergic neurons after injury. Symptoms of Alzheimer's Disease Researchers, who need to have some standard way to measure the progression of symptoms, have devised several different scales. One, the Clinical Dementia Rating (CDR), delineates five stages in the disease, while another, the Global Dementia Scale (GDS), has seven stages. However most people who work with patients and families think of the disease in three phases: mild, moderate, and severe. These three stages can be viewed as follows, keeping in mind that the divisions are approximate, that they overlap, and that the appearance and progression of symptoms vary from one individual to the next. Mild Symptoms
Moderate Symptoms
Source: Getting
around the blood-brain barrier One way to circumvent the blood-brain barrier is through direct injections into the brain, but there is little evidence that such injections are effective. So researchers have been looking at other ways to deliver drugs to the brain. Animal experiments with the NGF gene show that it can be incorporated into skin cells and then implanted in brains, where it has prevented the loss and degeneration of cholinergic neurons. Other researchers are looking at ways to package NGF and other neurotrophic factors with substances that can cross the blood-brain barrier, in effect smuggling these potential treatments into the brain. Researchers are also investigating substances that interact with NGF. One of these is estrogen, the female reproductive hormone that falls sharply at menopause. Estrogen
Replacement It was not the first time that neuroscientists had taken notice of this hormone. Earlier studies sought connections between estrogen and mental skills with mixed results. One study of 800 women found that taking estrogen after menopause had no effect on later mental functions. Another showed that estrogen did not seem to protect intellectual function in general, although it did enhance verbal memory. Nonetheless, the California study and others have provided enough evidence in favor of estrogen to spur much larger population studies of postmenopausal estrogen therapy and its possible preventive effect on Alzheimer's. A clinical trial of estrogen as a treatment in early-stage Alzheimer's disease is under way. In the meantime, biochemical studies have come up with a string of related findings. Researchers have found that the cholinergic neurons of the brain have numerous estrogen receptors, and they occur on the same neurons that have receptors for nerve growth factor; that estrogen in animals boosts levels of nerve growth factor; and that estrogen injected in rats' brains strongly affects neurons in the cerebral cortex and the hippocampus--regions affected by Alzheimer's disease. These pieces of evidence have given rise to the hypothesis that nerve growth factor and estrogen interact in some way to protect cholinergic neurons from degenerating. It is much too early, of course, to tell whether taking estrogen does reduce the risk of Alzheimer's disease. Like the other areas of treatment research, this one is still at a preliminary stage. And since estrogen replacement therapy following menopause is not recommended for all women, scientists have urged caution in interpreting the findings to date. Calcium
regulators Drugs called calcium channel blockers, already in wide use to treat high blood pressure and other problems, might fill this role, say some researchers. Calcium enters and exits neurons through several kinds of channels, so finding the right channel and channel blocker may be a complex task. Currently one drug company is testing a channel blocker in Alzheimer's patients and other calcium regulators are being considered for trials. Antioxidants A free radical is a molecule with an unpaired electron in its outer shell. Ordinarily an oxygen molecule, like other molecules, has an even number of electrons in orbit. But the normal process of turning food into energy--metabolism--produces oxygen radicals with an odd number of electrons. The oxygen radical is extremely reactive; it will latch readily onto another molecule--a part of the membrane or a unit of DNA, for instance. When this happens, it can set off a chain reaction, releasing chemicals that can be harmful to the cell. Scientists theorize that damage from oxygen radicals plays a role in aging as well as in diseases ranging from glaucoma to cancer. In Alzheimer's disease, free radicals are suspects for several reasons. They attack phospholipids, the molecules of fat in neuron membranes. Some researchers hypothesize that free radicals upset the delicate membrane machinery that regulates what goes into and out of a cell, such as calcium. Free radicals may also have a connection with beta amyloid. One study has found that in neuritic plaques, beta amyloid breaks easily into fragments, releasing free radicals. The body has certain lines of defense against oxygen free radicals. Enzymes like superoxide dismutase (SOD) and catalase can disarm the damaging oxygen molecules. And the vitamins in food known as antioxidents--vitamins C and E and beta-carotene, which is related to vitamin A--also counter free radicals. Several proposed treatments for Alzheimer's hinge on the theory that free-radical damage plays a key role in the disease and that antioxidents, therefore, should be able to slow down its progression. One clinical trial is testing vitamin E and deprenyl, a drug that inhibits oxidation, to see if they can make a difference. Another compound now in clinical trials, acetyl-L-carnitine, may also slow Alzheimer's by reducing the production of free radicals. This synthetic compound is very similar to a naturally occurring molecule that can help neurons carry out the process of metabolism. Acetyl-L-carnitine also may provide important constituents for the synthesis of acetylcholine. Anti-inflammatory
drugs Managing Symptoms These chapters are about daily routines and problems. "If all of the person's socks will go with all of his slacks, he doesn't have to decide which is right to wear with what... Many families have told us that a bath seat and a hand-held hose greatly reduce the bath time crisis." When the first edition of this book came out in 1981, it filled a great void. Information on the symptoms of the disease was sparse and guidance on managing them even sketchier. Throughout the 1980's, other publications appeared, filled with informal observations about symptoms and coping strategies. Toward the end of the decade, more and more formal research began to focus on this aspect of Alzheimer's disease. In contrast to the biological research described earlier, the low-tech, behavioral approach centers as much on family members and caregivers as on the patients themselves. The rationale is that if the people who care for Alzheimer's patients know how to cope with symptoms of the disease, they can reduce the degree of disability associated with it. Current studies are looking at two kinds of caregiving strategies: those that help the patient maintain independence in daily activities as long as possible and those that help prevent disturbing behaviors. Independence Maintaining independence has obvious advantages: The longer the patient can function independently, the better his or her quality of life and self esteem. Strategies that increase or maintain independence as long as possible also lower the level of stress for the spouse, child, or other caregiver. Researchers are experimenting with several methods to slow the loss of independence. Some are looking for ways to improve cognitive functions. For instance, one research team has used mental stimulation exercises for 1 hour each day in an attempt to improve cognitive abilities. So far, the Alzheimer's patients who do these exercises show improvement in comparison with a control group. Moreover, the caregivers in the group who did the exercises reported lower stress levels. Researchers are now testing mental exercises in-group settings outside the home. Other studies are testing ways to improve patients' functional abilities. This term encompasses the ability to carry out the so-called activities of daily living (ADLs), such as dressing and eating, as well as the more complex instrumental activities of daily living (IADLs). The latter include tasks like shopping and cooking. Some findings show promise. Techniques that have been successful in small studies of getting dressed include having the caregiver demonstrate what to do, so that the patient can mimic the action (the technical term is "modeling"). Another technique is laying out clothes in the order that they should be put on ("stimulus control"). Still another is "prompting." Verbal prompts are statements like, "Pick up the shirt. Put your arm in the sleeve." Physical prompts are when the caregiver uses touch to show the patient which arm to use. Researchers are now extending these strategies to other activities, such as bathing and feeding. One of the most intriguing results of such studies is the effect that the strategies have had on other aspects of Alzheimer's disease. Improved functioning seems to go along with a significant improvement in the behavioral problems that afflict Alzheimer's patients and families. Disturbing
behaviors As Alzheimer's disease makes inroads into memory and mental skills, it also begins to alter emotions and behavior. An estimated 70 to 90 percent of Alzheimer's patients eventually develop behavioral symptoms. One of the most common is agitation, which Letty Tennis describes: "It's a feeling like no other--like your engine is racing 100 mph and you can't go anywhere.... I'm getting cross at people and I hate that. When my psychologist kept asking me questions--the same ones over and over, I got so impatient inside that I had a strange impulse to throw my purse on the floor or better yet to bite him and say NO MORE!" In addition to agitation, Alzheimer's patients often experience feelings of anger, frustration, and depression. The disease can also lead to wandering, pacing, and screaming. Behavioral symptoms may become worse in the evening, a phenomenon called sundowning, or during certain daily routines, especially bathing. These symptoms of the disease and their effects on the family are thought to be one of the most common reasons that Alzheimer's patients are institutionalized. Pharmaceuticals One area of special interest is the effect of antidepressants on cognitive function. Many antidepressants suppress activity in the neurons that use acetylcholine. These are the same neurons affected by Alzheimer's disease, so suppressed activity in these neurons might make the cognitive symptoms, such as loss of memory, even worse. Some studies show this may be true. On the other hand, there is evidence that reducing depression may improve functional ability in people with Alzheimer's disease. In one study, for example, those patients who were more depressed were less able to carry out the activities of daily living than patients who were less depressed. The effects of depression on functioning appeared to be over and above the effects of cognitive impairment. This finding interests researchers because it raises the possibility that treating depression may be one way to improve functional abilities. Behavior
management Other behavior management techniques have specific targets. Aggressiveness and agitation commonly afflict patients during bathing, for instance, so researchers are trying to pinpoint the precise circumstances or events that trigger the problem. They then will test methods of avoiding those triggers or alleviating the patient's distress in other ways. Wandering and pacing are also common among Alzheimer's patients. One hypothesis suggests that if pacing and wandering can be accommodated in some way, both patients and caregivers will benefit. To test this idea, one researcher has arranged for Alzheimer's patients in a nursing home to have access to an outdoor sheltered park for pacing. In addition, the researchers have had stimulating patterns painted on the floors. The study will compare the effects of this approach to the effects of drugs and physical restraints, the more traditional ways to manage pacing and wandering. Screaming, also common among Alzheimer's patients, may be affected by changes in the environment as well. Several researchers are testing the effects of music. One is experimenting with videotapes of the patient's relatives and direct social interaction, to see if they have an effect on screaming. Studies of behavior management techniques fall into two groups. Many are still small descriptive studies. That is, their aims are to establish a base of knowledge about the disturbing behaviors, such as how prevalent they are and what circumstances trigger them. Other studies are clinical trials of strategies that seem most promising. One current trial is comparing the effects of non-drug behavior management strategies to the effects of two different medications, haloperidol and trazodone, in treating disturbing behaviors. Caregiving "Your friends...will say we think of you, or we'll visit, but they never do, because they don't know how to act around Alzheimer's." "I must have looked at 30 different homes." These quotes, culled from support groups and personal conversations, express a few of the special problems that confront the wives, husbands, children, and other family members who take care of Alzheimer's patients. Formal research on caregiving, begun in the early 1980's, is still young. The early studies documented that caregiving has a severe impact on both the physical and mental health of the caregiver. Fatigue, insomnia, and other physical symptoms are frequent. Cardiovascular risk factors, such as high blood pressure, may be affected. Studies also have linked the high levels of stress in caregivers with depression, a sense of isolation, and strained relationships with other family members. Special Care Units for Alzheimer's Disease First appearing in the 1980's, SCUs have proliferated rapidly. About 9.6 percent of all U.S. nursing homes with 30 or more beds had SCUs by the end of 1990, according to the National Survey of Special Care Units in Nursing Homes. The number may continue to grow. A 1991/92 survey of Medicare/Medicaid nursing facilities found that between 13 and 14 percent of certified facilities had at least one SCU. Aside from their dramatic growth, little is known about SCUs as a group. What features do they offer? Which features, if any, make a difference to patients, families, or staff? Ten research teams are now studying SCUs in search of answers to questions like these. Early in these studies it became clear that SCUs vary widely. Some offer only one special feature, such as a sheltered area for pacing, perhaps, or staff training. Most have several special features, such as family counseling, support groups, and therapeutic activities for patients. Still unknown is whether or not these special features make a difference. To find out, investigators are studying both SCU patients and dementia patients in traditional care settings, comparing them in areas such as: mental function, frequency of disturbing behaviors, degree of family involvement with the patient, staff and family satisfaction with the SCU, and costs in relation to benefits. The studies, begun in 1991, will be completed in 1996. Who are family caregivers? Researchers are now studying the experiences of caregivers from various ethnic and racial groups to see if their approaches to caregiving differ. African-American caregivers, according to several studies, are less likely to see caregiving as a burden and more likely to share it with a large number of extended family members, when compared to white caregivers. Scientists are exploring these differences to see if they can pinpoint the coping strategies or other factors that affect how different racial and ethnic groups perceive caregiving. What can be done to reduce the burden? Emotional
support: To date, studies have generally shown a high level of satisfaction with support groups, although it is not clear whether they also help decrease caregivers' sense of burden. Individual counseling has alleviated specific problems such as depression. Services: Knowledge
and skills training The outcomes of many of these studies are positive, in that caregiver behavior and sometimes patient behavior is changed. In some cases, these studies have also demonstrated improvements in caregiver stress, anxiety, and depression. On the other hand, some of these studies show that decreased stress does not necessarily translate into a reduced sense of burden. A fourth category of interventions combines all three of these approaches. Studies of such comprehensive efforts suggest that the more components they have, the better the chance that they will meet the needs of caregivers. However, questions remain about the cost effectiveness of comprehensive interventions and about the relative benefits of their individual components Other
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