Progress Report on Alzheimer's Disease, 1997 Contents Alzheimer's Disease Prevalence and Costs of Alzheimer's Disease Research Directions National Institute on Aging Structure and Function of the Brain Changes in the Brain in Alzheimer's Disease Amyloid Plaques Neurofibrillary Tangles Genetic Factors in Alzheimer's Disease Transgenic Mouse Model for Alzheimer's Disease Advances in Identifying Risk Factors for Alzheimer's Disease Presenilins Oxidative Damage and Alzheimer's Disease Cultural or Environmental Changes, Japanese Americans, and Alzheimer's Disease Brain Infarction and Alzheimer's Disease Advances in Diagnosing Alzheimer's Disease Diagnostic Criteria for Alzheimer's Disease New Guidelines for Early Recognition and Assessment of Alzheimer's Disease Symptoms Advances in Treating and Preventing Alzheimer's Disease Estrogen Replacement Therapy and Alzheimer's Disease Anti-Inflammatory Drugs and Alzheimer's Disease Use of Selegiline and Vitgamin E To Treat Alzheimer's Disease Alzheimer's Disease Cooperative Study Alzheimer's Disease Centers Consortium To Establish a Registry for Alzheimer's Disease Special Care Units Initiative Enhancing Family Caregiving Stress Reduction for Family Caregivers: Effects of Using Day Care Exploratory Centers on Demography of Aging: Alzheimer's Disease Research Conducted by Other NIH Institutes National Heart, Lung, and Blood Institute National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Neurological Disorders and Stroke National Institute on Deafness and Other Communication Disorders National Institute of Mental Health National Human Genome Research Institute National Center for Research Resources National Institute of Nursing Research Outlook Alzheimer's Disease Alzheimer's disease (AD) is a progressive brain disorder that occurs gradually and results in memory loss, unusual behavior, personality changes, and a decline in thinking abilities that cannot be reversed. These mental losses are related to the death of brain cells and the breakdown of the connections between them. The course of this disease varies from person to person, as does the rate of decline. On average, AD patients live from 4 to 8 years after they are diagnosed; however, the disease can continue for up to 20 years. AD advances by stages, from early, mild forgetfulness to severe dementia. Dementia is a specific case of loss of healthy mental function. In most people with AD, symptoms appear after age 60. First symptoms often include loss of recent memory, faulty judgment, and changes in personality. Often, people with AD think less clearly and forget the names of familiar people and common objects. Later in the disease, they may forget how to do simple tasks like washing their hands. Eventually, people with AD lose all reasoning abilities and come to depend on other people for their everyday care. Finally, the disease becomes so debilitating that patients are bedridden and likely to develop coexisting illnesses. Most commonly, people with AD die from pneumonia. The risk of developing AD increases with age, but AD and dementia symptoms are not a part of normal aging. AD and other dementing disorders in old age are caused by diseases. In the absence of a disease, the human brain often can function well into the tenth decade of life and beyond. Prevalence and Costs of Alzheimer's Disease AD is the most common cause of dementia among people age 65 and older. AD affects approximately 4 million Americans; slightly more than half of these people receive care at home, while the others are in many different health care institutions. Before long, ongoing population studies may give estimates of the number of people at different stages of the disease. The prevalence of AD and other dementias doubles every 5 years beyond age 65. Prevalence is the number of people in a population with a disease at a given time. In fact, some studies indicate that nearly half of all people age 85 and older have symptoms of AD. Life expectancy has increased dramatically since the turn of the century. About 33 million people--13 percent of the total population of the United States--are age 65 and older. According to the Bureau of the Census, this percentage will climb to 20 percent by the year 2025. In addition, the proportion of very old people (those aged 85 and older)--who often are most in need of care--will increase considerably. In most industrialized countries, the 85 and older age group is the fastest growing segment of the population over age 65. Now 3.5 million, the number of American aged 85 and older will total nearly 9 million by the year 2030. A great many spouses, relatives, and friends take care of people with AD. These caregivers are the backbone of the Nation's informal system of long-term care for AD patients; their numbers also can be expected to grow significantly as the population ages. During years of caregiving, families experience emotional, physical, and financial stresses. They watch their loved ones become more and more forgetful, frustrated, and confused. Many caregivers--most of them women--juggle child care and jobs with caring at home for relatives with AD who cannot function on their own. As the disease runs its course and the abilities of people with AD steadily decline, family members face painful decisions about the long-term care of their loved ones. AD puts a heavy economic burden on society as well. A recent study estimated that the cost of caring for one AD patient with severe cognitive impairments at home or in a nursing home, excluding indirect losses in productivity or wages, is more than $47,000 a year. For a disease that can span from 2 to 20 years, the overall cost of AD to families and to society is staggering. The annual economic toll of AD in the United State in terms of health care expenses and lost wages of both patients and their caregivers is estimated at $80 to $100 billion. AD is a major health problem and expense for the United States. Until researchers find a way to cure or prevent AD, a large and growing number of people, especially those who live to be very old (85+), will be at risk for AD. Providing and financing the care of this growing older population will increase the strain on our already burdened health care system. Research Directions AD research is divided into three broad, overlapping areas: causes/risk factors, diagnosis, and treatment/caregiving. Research into the basic biology of the aging nervous system is critical to understanding what goes wrong in the brain of a person with AD. Understanding how nerve cells lose their ability to communicate with each other and the reasons why some nerve cells die is at the heart of scientific efforts to discover what causes AD. Many researchers are working to slow AD's progression, delay its onset, or eventually, prevent it altogether. In looking for better ways to diagnose AD, investigators strive to identify diagnostic markers (indicators) of dementias, develop and improve ways to test patients, determine causes and assess risk factors, and improve case-finding and sampling methods for population studies. Scientists also seek better ways to treat AD, improve a patient's ability to function, and support caregivers of people with AD. National Institute on Aging The National Institute on Aging (NIA) is part of the Federal Government's National Institutes of Health (NIH). The NIA has primary responsibility for research aimed at finding ways to prevent, treat, and cure AD. One of NIA's main goals is to enhance the quality of life of older people by expanding knowledge about the aging brain and nervous system. NIA's AD research has important implications for public policy. Changes in the way the brain works are associated with many age-related losses that lead to institutional care. Changes in the brain that significantly affect the senses, movement, and the ability to think influence the quality of life of older people. For people with AD, decline in these abilities limits independence, affects self-image, and influences the attitudes of others. Ultimately, these attitudes determine the nature and quality of health care services AD patients receive. AD research can identify early treatments that may change the disease's course or reduce its severity. Although no cure exists yet for AD, there is reason to be optimistic. Many researchers are working hard to find what causes this devastating illness and how to treat it effectively. This report highlights recent progress in AD research conducted or supported by the NIA and other components of the NIH, including the following: National Heart, Lung, and Blood Institute National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Neurological Disorders and Stroke National Institute on Deafness and Other Communication Disorders National Institute of Mental Health National Human Genome Research Institute National Center for Research Resources National Institute of Nursing Research Other smaller AD research projects not summarized in this report are supported by the National Cancer Institute, National Eye Institute, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Child Health and Human Development, National Institute of Dental Research, National Institute of Environmental Health Sciences, and Fogarty International Center. Structure and Function of the Brain The brain does many things to ensure our survival. It integrates, regulates, initiates, and controls functions in the whole body, with the help of motor and sensory nerves outside of the brain and spinal cord. The brain governs thinking, personality, mood, and the senses. We can speak, move, and remember because of complex chemical processes that take place in our brains. The brain also regulates body functions that happen without our knowledge or direction, such as digestion of food. The human brain is made up of billions of nerve cells, called neurons, that share information with one another through a large array of biological and chemical signals. Even more numerous (between 10 and 50 times the number of neurons) are glial cells, which surround, support, and nourish neurons. Each neuron has a cell body, an axon, and many dendrites. The nucleus, which contains deoxyribonucleic acid (DNA), controls the cell's activities. The axon, which extends from the cell body, sends messages from axons of other nerve cells or from specialized sense organs. Axons and dendrites collectively are called neurites. Neurons communicate with each other and with sense organs by producing and releasing chemicals. An electrical charge (nerve impulse) builds up within the sending neuron as it receives messages from surrounding cells. The charge travels down the nerve cell until it reaches the end of the axon. Here, the nerve impulse triggers the release of neurotransmitters. These chemicals carry messages from the axons across synapses (gaps between nerve cells) to the dendrites or the cell bodies of other neurons. Scientists estimate that the typical neuron has up to 15,000 synapses. Neurotransmitters carrying messages bind to specific receptor sites on the receiving end of dendrites of adjacent nerve cells. Receptors are proteins (molecules that determine the physical and chemical traits of cells and organisms) that recognize and bind to chemical messengers from other cells. When the above receptors are activated, they open channels into the receiving nerve cell's interior or start other processes that determine what the receiving nerve cell will do. Some neurotransmitters inhibit nerve cell function; that is, they make a neuron less likely to act. Other neurotransmitters stimulate nerve cells; they prime the receiving cell to become active or send a message. In this way, signals travel back and forth across the brain in a fraction of a second. Millions of signals flash through the brain all the time. Groups of neurons in the brain have specific jobs. For example, the brain's cerebral cortex is a large collection of neurons all over the surface of the brain. Some of these nerve cells are involved in thinking, learning, remembering, and planning. The survival of nerve cells in the brain depends on the healthy functioning of three dynamic mechanisms all working in harmony. These mechanisms control nerve cell activities related to communicating information, using energy, and repairing cells and tissues. The first mechanism, communication between nerve cells, is described in the preceding paragraphs. The loss or absence of any one of several chemical messengers or receptors disrupts cell-to-cell communication and interferes with normal brain function. In the second mechanism, metabolism, cells and molecules break down chemicals and nutrients into energy. Efficient metabolism in nerve cells requires adequate blood circulation to supply the cells with important nutrients, such as oxygen and glucose (a sugar). Glucose is the only source of energy available to the brain under normal circumstances. Depriving the brain of oxygen or glucose causes nerve cells to die within minutes. The third mechanism repairs injured nerve cells. Unlike most other body cells, neurons live a long time. Brain neurons are built to last more than 100 years. In the adult, when neurons die (due to disease or injury), they are not replaced. To prevent their own death, living neurons constantly must maintain and remodel themselves. If cell cleanup and repair slow down or stop for any reason, the nerve cell cannot function properly. It is not clear when and why some neurons start to die and some synapses stop working. Research shows that the damage seen in AD involves changes in all three mechanisms: nerve cell communication, metabolism, and repair. Changes in the Brain in Alzheimer's Disease In AD, communication between some nerve cells breaks down. The destruction from AD ultimately causes these nerve cells to stop functioning, lose connections with other nerve cells, and die. Death of many neurons in key parts of the brain harms memory, thinking, and behavior. AD destroys neurons in parts of the brain controlling memory, especially the hippocampus (a structure deep in the brain that helps code memories). As nerve cells in the hippocampus stop functioning properly, short-term memory fails, and often, the person's ability to do familiar tasks begins to decline. AD also attacks the cerebral cortex. The greatest damage occurs in areas of the cerebral cortex responsible for functions such as language and reasoning. Here, AD begins to take away language skills and change a person's judgment. Personality changes also occur; emotional outbursts and disturbing behavior, such as wandering and agitation, appear and can happen more and more often as the disease runs its course. Two abnormal structures are found in the AD brain: amyloid plaques and neurofibrillary tangles. Plaques are dense deposits of an amyloid protein, other associated proteins, and non-nerve cells that gradually accumulate (build up) outside and around neurons. Amyloid is a generic name for protein fragments that aggregate (collect or mass together) in a specific way to form insoluble deposits. The fragments can arise from different processes. Neurofibrillary tangles are insoluble twisted fibers that build up inside neurons. Much progress has been made in determining the makeup of amyloid plaques and neurofibrillary tangles and in proposing mechanisms that could account for their buildup in AD. Amyloid Plaques In AD, plaques develop in areas of the brain used for memory. These plaques consist of beta-amyloid intermingled with neurites from neurons and with non-nerve cells. These non-nerve cells include glial cells and microglia (cells that surround and digest damaged cells or foreign substances). In plaques, beta-amyloid is a protein fragment snipped from a larger protein--called amyloid precursor protein (APP)--during metabolism. Researchers do not know yet whether amyloid plaques cause AD or result from it. APP is a member of a large family of proteins that are associated with cell membranes. The cell membrane encloses the cell and acts as a barrier that selects which substances can go in and out of the cell. During metabolism, APP becomes embedded in the membrane of the nerve cell, partly inside and partly outside of the cell, like a needle poking partway through a piece of fabric. While APP is embedded in the cell membrane, proteases cleave APP apart. Proteases are enzymes (substances that speed up or cause chemical reactions in the body) that snip proteins into smaller pieces. Beta-amyloid is produced only when the cleavage happens at the wrong place in APP. After beta-amyloid is formed, scientists do not yet know exactly how it moves through or around nerve cells. In the final stages of its journey, it joins with other beta-amyloid filaments and fragments of dead and dying neurites to form the dense, insoluble plaques that are a hallmark for identifying AD in brain tissue. Researchers believe that beta-amyloid sets off the AD process and/or is an early byproduct in the slow, many-step process that ultimately leads to nerve cell damage and death in the brain. Many studies have centered on how beta-amyloid is processed and how enzymes break down APP. Investigators are looking for clues in beta-amyloid's environment. For example, normally, substances may bind to beta-amyloid and keep it in solution. But in AD, according to one theory, something causes beta-amyloid fragments to aggregate together, just as fluid proteins in eggs become hard after being cooked. Beta-amyloid aggregates gradually build up to form dense, insoluble plaques that the body cannot dispose of or recycle. Other areas of research focus on how beta-amyloid affects neurons. In one laboratory study, neurons from the hippocampal area of the brain died when aggregated beta-amyloid was added to the cell culture, suggesting that the protein fragment is deadly to neurons. Results of a recent study suggest that beta-amyloid causes the release of free radicals, which then attack neurons. (For more information about free radicals, see Oxidative Damage and Alzheimer's Disease.) Similar laboratory studies conducted by researchers at NIA's Gerontology Research Center (GRC) in Baltimore, Maryland, are looking at the effects of beta-amyloid on nerve cells from the cerebral cortex. So far, they have found that the cells try to defend themselves against attack from beta-amyloid by making cell stress proteins and other proteins that help prevent cell death. These scientists continue to study why these defense mechanisms fail to fully protect the cells. Still, the way that beta-amyloid may cause nerve cells to die remains a mystery. Some studies indicate that beta-amyloid disrupts potassium channels, which in turn can affect calcium levels inside the cell. Potassium (an element or electrolyte) helps control the normal activity of nerves and muscles. Among other things, potassium channels (tunnel-like structures in cell membranes) help balance the amount of calcium that the cell takes in and removes. Calcium (another element or electrolyte) helps cells do many things, such as carry nerve signals. The correct amount of electrolytes, such as potassium and calcium, also helps the body use energy. However, too much calcium inside the cell leads to cell death. A recent finding suggests that beta-amyloid itself is able to form small channels in the nerve cell membrane. These channels may allow too much calcium to enter a nerve cell, killing the cell. (For more information about these channels, see National Institute of Diabetes and Digestive and Kidney Diseases research.) Yet another study links beta-amyloid to lower choline levels in nerve cells. Since choline is a basic part of acetylcholine (a neurotransmitter), this finding suggests a link between beta-amyloid and decreases in acetylcholine levels found in the brains of people with AD. Following a different line of reasoning, NIA researchers at the GRC in Baltimore suggest that APP may help repair injured brain cells. Scientists do not yet know how APP acts, but these researchers think that it may help keep brain tissue healthy and boost brain repair activities. According to these NIA investigators, someday, a form of APP may be used as a therapy to help reverse or even prevent further destruction due to AD. More research is needed to determine the exact mechanism of selective nerve cell damage in the AD brain and the roles that beta-amyloid and APP play in this process. Neurofibrillary Tangles Neurofibrillary tangles are abnormal collections of twisted threads found inside nerve cells. The chief component of tangles is one form of the protein, tau. In the central nervous system, tau proteins are best known for their ability to bind and help stabilize microtubules (the cell's internal support structure or skeleton). In healthy neurons, microtubules form structures like train tracks, which guide nutrients and molecules from the bodies of the cells down to the ends of the axons. In cells affected by AD, these structures collapse. Tau normally forms the "railroad ties" or connector pieces of the microtubule train tracks. However, in AD tau is changed chemically, and this altered tau can no longer hold the railroad ties together, causing the microtubule train tracks to fall apart. this collapse of the transport system first may result in malfunctions in communication between nerve cells and later may lead to neuron death. In AD, chemically altered tau twists into paired helical filaments (two threads wound around each other). These filaments are the major substance found in neurofibrillary tangles. Genetic Factors in Alzheimer's Disease Every healthy person has 46 chromosomes in 23 pairs. Usually, people receive one chromosome in each pair from each parent. Chromosomes are rod-like structures in the cell nucleus. In each chromosome, DNA forms two long, intertwined, thread-like strands that carry inherited information in the form of genes. Genes are basic units of heredity that can direct almost every aspect of the construction, operation, and repair of living organisms. Each gene is a set of chemical instructions that tells a cell how to make one of the many unique proteins in the body. Every human cell has from 50,000 to 100,000 genes arranged on the chromosomes like beads on a string. Genes are made up of four chemicals (bases) arranged in various patterns along the strands of DNA. In each gene, the bases are lined up in a different order, and each sequence of bases directs the production of a different protein. Even slight changes in a gene's DNA code can make a faulty protein, and a faulty protein can lead to cell malfunction and possibly disease. Two types of AD exist: familial Alzheimer's disease (FAD), which is found in families where AD follows a certain inheritance pattern; and sporadic (seemingly random) AD, where no obvious inheritance pattern is seen. Because of differences in age at onset, AD is further described as either early-onset (younger than 65 years old) or late-onset (65 years and older). Early-onset AD is rare and generally affects people aged 30 to 60. Early-onset AD progresses faster than the more common, late-onset forms of AD. Almost all FAD known so far is early-onset, and many cases involve defects in three genes located on three different chromosomes (chromosomes 1, 14, and 21). Until recently, AD genetic research was dominated by the discovery that an unidentified defective gene on a particular region of chromosome 21 was the cause of AD in a few early-onset families. This finding was followed by the identification of gene mutations in the APP gene on chromosome 21 as the cause of AD in these families. (In affected people, the gene on chromosome 21 carries the code for an abnormal form of APP.) This emphasis shifted in 1992, when researchers at the University of Washington Alzheimer's Disease Center (ADC) in Seattle--supported by the NIA and the National Institute of Neurological Disorders and Stroke (NINDS)--discovered a link between other FAD cases and genes in a particular region of chromosome 14. They subsequently identified the defective gene and named it presenilin 1. More recently, these same scientists also found a link between FAD in families descended from a group of Germans living in the Volga Valley of the former Soviet Union (called the Volga Germans) and a gene in a particular region of chromosome 1. These families have a higher than average occurrence of AD and show no link to AD through genes on either chromosome 21 or 14. These investigators and others funded by the NIA and the NINDS at the Massachusetts ADC in Boston and in Toronto, Canada, identified the defective gene on chromosome 1 and called it presenilin 2. In these inherited forms of the disease, inheriting the mutation almost always results in the person getting AD. Only a very small fraction of early-onset FAD is caused by mutations in the presenilin 2 gene. Together, these mutations (presenilins 1 and 2) account for approximately 50 percent of early-onset FAD. The other genes have yet to be identified. (For additional information about these "presenilin" genes, see Presenilins.) Pursuing another avenue, researchers at the NIA are looking at Down's syndrome because it shares some traits with AD. Down's syndrome is caused by a birth defect in which the person has three, rather than the normal two, copies of chromosome 21. Down's syndrome is associated with mental retardation and the development of AD pathology. Because the gene for APP has been mapped to chromosome 21, researchers believe that AD is related to the "overexpression" of APP. Some gene changes occur more often in AD patients than among people in general. In 1992, researchers at the Duke University ADC in Durham, North Carolina, found an increased risk for late-onset AD with inheritance of the apoE4 (apolipoprotein E4) allele on chromosome 19. An allele is one of two or more alternate forms of the same gene. This finding helped scientists explain variations in age at onset, based on whether people had zero, one, or two copies of apoE4. Every person has two apoE genes, one inherited from each parent. AD researchers are interested in three common alleles of apoE: apoE2, apoE3, and apoE4. They are studying people who inherit different forms of this gene to learn more about risk factors for AD. A simple blood test can be used to determine which alleles a person has inherited. ApoE is a protein that sits on the surface of the cholesterol molecule and helps carry blood cholesterol throughout the body. ApoE is found in neurons of healthy brains, but also is associated with the plaques and neurofibrillary tangles found in AD brains. The relatively rare apoE2 may protect some people against the disease; it seems to be associated with a lower risk for AD and later age of onset. ApoE2 also appears to protect people with Down's syndrome from developing AD. ApoE3 is the most common version found in the general population; researchers believe it plays a neutral role in AD. AD scientists are most interested in apoE4 because it is linked to an increased risk of the disease. The apoE4 form in AD patients is not limited to those with a family history of AD. In addition, people who carry two copies of apoE4 are more likely to get AD than those with one copy of apoE4. How apoE4 increases a person's susceptibility to AD (likelihood of developing AD) is not yet known. ApoE4 may contribute to beta-amyloid buildup and APP regulation. ApoE4 also appears to lower the age of onset of AD, perhaps because apoE4 speeds up the AD process in some unknown way. Researchers believe that AD risk related to apoE4 may increase because the age of onset decreases. A flurry of activity has followed the apoE findings to discover the molecular mechanisms that underlie the effects of the different forms of apoE on the development of AD. Scientists are looking at how the different forms of apoE interact with both beta-amyloid and tau. Researchers also are studying how forms of apoE affect the way that cells remodel themselves and grow after being damaged. Whatever its role in AD, the mere inheritance of an apoE4 gene does not predict AD with certainty; that is, apoE4 is a risk factor gene. A person can have an apoE4 gene and not get the disease, and a person with AD may not have any apoE4 genes. As of now, no predictive test for AD exists. Even with the current knowledge about apoE, scientists cannot predict whether or when any person might develop AD, no more than a doctor can predict whether a person with high cholesterol will have a stroke. However, many researchers believe that inheriting an apoE4 gene, in association with lower memory performance in older people that gradually worsens with time, may be a predictor for who is going to develop AD. Genetic analysis someday could help scientists find people with probable AD to include in clinical trials of promising treatments. Because of the increased risk associated with apoE4, people with clinical signs of AD who have this allele may be among the first volunteers to be studied in clinical trials of experimental drugs. It may follow that having multiple risk-factor genes may increase a person's likelihood of developing AD. With each new finding, researchers gain more clues about basic mechanisms in AD and move closer to understanding the disease and designing treatments that slow its progression, delay its onset, or even prevent it. Transgenic Mouse Model for Alzheimer's Disease A team of researchers at the University of Minnesota in Rochester; Veterans Administration Medical Center in Sepulveda, California; Mayo Clinic in Jacksonville, Florida; and other institutions have developed a new mouse model for AD. The NIA, the NINDS, and the Alzheimer's Association supported this research. This research team has used the gene coding for APP to breed mice that make the mutated version of the APP protein in brain cells. The mice are double mutants of a human APP form in which two parts of the protein are changed. These changes mimic those in APP found in a large human family with early-onset FAD. This genetically-engineered (transgenic) mouse is the first to show cognitive signs of AD as well as protein-derived plaques like those found in the brain tissue of AD patients. Early in life, at 2 to 3 months of age, these transgenic mice appear normal. But later, at 9 to 10 months and older, the mice have problems doing several memory and spatial learning tasks that a group of healthy, similarly trained mice can do without difficulty. These deficits were correlated with a greater buildup of both amyloid and the mutant APP. In 1-year-old transgenic mice, plaques and amyloid deposits outside nerve cells were observed in the cerebral cortex. These deposits were not found in younger mice and controls. The oldest transgenic mice had between 5 and 14 times more beta-amyloid peptides (small protein fragments) associated with amyloid plaques than did younger, healthy mice. Thus, there was an association between the amounts of mutant APP and the onset of problems in learning and memory in the oldest transgenic mice. These mice give scientists the opportunity to study the relationship among certain mutations related to AD, abnormal behaviors, and changes in the brain, for example, the evolution and control of plaque development. This animal model will increase researchers' understanding of how AD progresses and ultimately make it possible for them to test promising therapies in mice showing some AD symptoms. For years, scientists have debated whether amyloid plaques cause AD or result from some process in the development of AD. The transgenic mouse model is the first animal model to show that amyloid is associated with deficits in learning and memory. However, researchers do not yet know whether the deficits are caused by, or merely correlate with, the buildup of amyloid. The mouse model can be used to study this question. Advances in Identifying Risk Factors for Alzheimer's Disease Researchers believe that AD is caused not by a single factor, but by a number of factors that interact differently in different people. Age remains the strongest risk factor identified for AD so far. In addition, having both apoE4 and a severe head injury that leads to even a brief loss of consciousness may increase a person's risk of developing AD later in life. In most cases, genetic risk factors alone, as previously noted for apoE4, are not enough to trigger AD. Other risk factors may combine with a person's genetic makeup to increase his or her chances of developing AD. Researchers looking at the frequency of AD and related dementias in people over age 65 seek to identify additional risk factors for AD and to show how and why AD develops. By studying various ethnic, racial, and social groups of people, scientists may discover new risk factors for AD. These risk factors, in turn, may suggest new theories about mechanisms involved in setting up and/or triggering the disease process. Last year, NIA-funded researchers made advances in many areas, including understanding the role of presenilin proteins 1 and 2 in AD, the possible relation between oxidative damage and AD, and how cultural or environmental changes may affect Japanese Americans' likelihood of developing AD. Findings from these and other investigations eventually may lead to new treatments and strategies for prevention. Presenilins In 1992, investigators supported by the NIA and the NINDS identified a defective gene (called presenilin 1) on chromosome 14 in people with AD in some inherited, early-onset AD families. Although researchers believe that presenilin 1 accounts for close to 50 percent of all cases of FAD (the most aggressive form), they do not know the function of this gene. Scientists at several ADCs have found almost 30 mutations of presenilin 1 in approximately 50 early-onset AD families. These defects are scattered across the protein encoded by the mutated gene. Some of these mutations may lead to AD earlier than others. Rather than cause protein products to stop working, mutations may produce altered, harmful protein products. Scientists do not know the normal function of presenilins or how mutations of these genes affect the onset of FAD. They also do not know whether presenilins play any role in the more common, sporadic or non-familial form of late-onset AD. Much evidence suggests that neurons are a major source of the beta-amyloid that forms plaques in AD. Thus, it is important to study how presenilins function in neurons. Researchers are looking at how presenilins 1 and 2 interact with APP processing, plaques, tangles, and beta-amyloid. A recent study showed that people with early-onset AD and presenilin 1 and 2 mutations have more of a longer form of beta-amyloid in their brains than do those with the sporadic form of AD. This finding suggests that mutations in the presenilins may drive the production of amyloid in AD. Oxidative Damage and Alzheimer's Disease One long-standing theory of aging suggests that the buildup of damage from oxidation in the body causes nerve cells to gradually decay. Scientists believe that free radicals produced through oxidative mechanisms play a role in several diseases, including cancer and AD. A free radical is a molecule with one unpaired (leftover) electron in its outer shell. Healthy metabolism can produce free radicals of oxygen with unpaired electrons. The body produces free radicals to help cells in certain ways, such as in fighting infections. However, having too many free radicals is bad for cells. Free radicals are highly reactive; they readily latch onto other molecules available nearby, such as part of the cell membrane or a piece of DNA. The resulting, newly combined molecule then can set off a chain reaction, releasing unwanted chemicals that can damage cells. Free radicals are suspected to play a role in the development of AD for several reasons. They attach to molecules of fat in nerve cell membranes and thus may upset the delicate membrane machinery that regulates substances that go into and out of a cell, for example, calcium. As mentioned before, too much calcium can kill cells. Further, oxidation due to free radicals may alter proteins; these new forms of proteins may be associated with the development of AD. Some of these oxidative changes are found in amyloid plaques in AD, where beta-amyloid causes the release of free radicals. Reactions like these also produce several free radicals of oxygen that may target the internal support structures of nerve cells. Scientists at Columbia University in New York City are studying a receptor on microglia (very small non-neuron cells found in the brain). They recently found that this receptor helps microglia bind to beta-amyloid. This binding leads to the release of reactive oxygen molecules and causes cells to become immobilized. Further studies are needed to understand the relation of oxidation to nerve cell damage in AD. In 1996, investigators also at Columbia University identified a protein that binds to synthetic beta-amyloid. This protein is identical to the central receptor for advanced glycation end products (AGEs), which are the results of certain molecular processes within the body. This receptor for AGE may define how beta-amyloid interacts with nerve cells and surrounding cells. Interactions between beta-amyloid and this receptor may contribute directly to nerve cell damage that leads to dementia. In another study, scientists at NIA's Laboratory of Biological Chemistry in Baltimore exposed nerve cell lines to the APP gene and the presenilin 2 gene, which each had mutations like those found in people with early-onset AD. These nerve cells were killed by the mutant products of the genes through programmed cell death. Nerve cells with extra mutated APP appeared to produce more free radicals. By adding anti-oxidants, such as vitamin E, that may intercept or latch onto free radicals before they have a chance to damage cells, researchers were able to prevent nerve cell damage related to beta-amyloid and caused by free radicals. These findings suggest that in AD, cell damage related to free radicals may cause nerve cells to die, and that anti-oxidants may help prevent nerve cell death. Anti-oxidants are found in common foods, especially those rich in vitamins A, C, and E. Cultural or Environmental Changes, Japanese Americans, and Alzheimer's Disease Looking at findings from the Honolulu-Asia Aging Study, NIA-supported researchers found that older Japanese American men have a higher rate of AD than their counterparts living in Japan. Analysts looked at data describing Japanese American men born between 1900 and 1919 who were living on Oahu, Hawaii, in 1965, when the study began. Based on data collected between 1991 and 1993 for 3,734 survivors, 9.3 percent had dementia (from all causes) and 5.4 percent had AD. The scientists compared these findings to those from studies of similar men living in Japan. In 1 such study, Japanese researchers recently found AD in 1.5 percent of 887 residents of Hisayama who were 65 years of age and older. Other Japanese studies also suggest lower rates of AD in the Japanese population. The same NIA study looked at the frequency of vascular dementia-mental decline caused by reduced blood flow to the brain and small strokes. Researchers found that 4.2 percent of the Oahu participants had vascular dementia, compared to 3.2 percent of the Hisayama residents. These comparisons suggest that AD is almost as common among older Japanese American men in Hawaii as it is in Americans of European ancestry, but it is less frequent in Japanese men living in Japan. Vascular dementia is only slightly less frequent among these Japanese Americans than among the Japanese. Researchers believe that environmental and lifestyle changes associated with migrating from Japan to Hawaii may have influenced the development of AD, while risk factors affecting the development of vascular dementia may have remained the same. Based on the results of the Oahu study, researchers will do more population studies to see if lifestyle changes after migration influence the occurrence of AD. Brain Infarction and Alzheimer's Disease NIA-funded researchers at the University of Kentucky's Sanders-Brown Research Center on Aging in Lexington studied the relationship between brain infarction and clinical signs of AD in a group of nuns. A brain infarction is an area of injury in brain tissue that occurs when the blood supply to that area is interrupted, or, less often, when a vein that carries blood away from the area is blocked in some way. Infarcts can be a sign of blood vessel disease and are thought to play a role in some strokes. Scientists studied 102 members of the School Sisters of Notre Dame religious order who took part in the Nun Study, a long-term study of aging and AD. While in this study, the nuns completed regularly scheduled cognitive tests. Clinical signs of AD include impairments in the following skills: memory, concentration, language, visuospatial ability, orientation to time and place, and social and daily function. Autopsies were performed when the nuns died. During autopsies, researchers identified infarcts, amyloid plaques, and neurofibrillary tangles in the brains of these nuns. Among 61 deceased participants who met the criteria for AD (had many amyloid plaques and neurofibrillary tangles in the brain), those with infarcts in particular brain regions previously had shown poorer cognitive function and more dementia than those without infarcts. Among 41 participants who did not meet the criteria for AD, brain infarcts were only weakly associated with previous poor cognitive function and dementia. These findings suggest that at least some brain infarcts do not themselves cause dementia, but may play an important role in increasing the severity of the clinical signs of AD. In addition, other signs of disease related to the brain's blood vessels or blood supply, such as atherosclerosis, may be involved in the development of AD. Atherosclerosis (often called "hardening of the arteries") is a common disorder of the arteries in which yellowish plaques of cholesterol, fat, and other remains are deposited in the walls of some arteries (blood vessels that carry blood with oxygen away from the heart to the rest of the body). Further research is needed to understand whether preventing these types of blood vessel diseases in the brain can help reduce the clinical signs of AD. Advances in Diagnosing Alzheimer's Disease AD is diagnosed conclusively only by an autopsy after death. Its telltale signs during life, such as dementia symptoms, also may be caused by other problems. To confirm AD, pathologists look for the presence of characteristic plaques and tangles in brain tissue during an autopsy. Through the work of many researchers, the diagnosis of AD in living people has become more and more accurate. In specialized research facilities, neurologists now can diagnose AD with up to 90 percent accuracy, as confirmed later at autopsy. The diagnosis includes taking a personal history from patients and their families, doing a physical exam and tests, and administering memory and psychological tests to patients. Nonetheless, important questions and knowledge gaps remain. Now, tests of mental status are needed that can pinpoint the gradual loss of cognitive ability in AD patients and identify people who are at a very early stage in the course of the disease. The search continues for reliable biological markers for diagnosing AD. The sooner an accurate diagnosis of AD is made, the greater the gain in managing symptoms, determining the natural history of AD, and defining subtypes of patients. An early, accurate diagnosis of AD is especially important to patients and their families because it helps them plan for the future and pursue care options, while the patient still can take part in decisions. The NIA supports research aimed at developing and testing reliable, valid diagnostic tools for AD and other dementias in older people. One possible advance in AD diagnosis was the discovery of apoE4 by NIA-funded researchers at the Duke University ADC in 1992. Before 1992, scientists studied people who were said to have probable or possible AD based on a clinical diagnosis alone. A later Duke University study asked whether obtaining a person's apoE4 status would increase diagnostic accuracy while the person still was alive. In this study, each study participant's clinical diagnosis was confirmed after death with an autopsy, and each participant's apoE status was determined. The findings show that every participant with at least one apoE4 allele and a clinical diagnosis of probable or possible AD was confirmed to have AD according to the autopsy criteria. These initial results need to be verified in a larger sample. Currently, all of the ADCs are taking part in a further cooperative study to determine if these preliminary results can be confirmed. Another promising new finding could contribute to the identification of patients at risk for AD. Collaborating scientists at the NIA, the National Cancer Institute, and the Howard University College of Medicine in Washington, District of Columbia, studied fibroblasts (cells from tissue that supports and joins collections of cells or parts of the body) and lymphocytes (one of two types of small white blood cells that play a role in fighting disease). They exposed the cells to fluorescent light and used agents to block the cells' natural tendency to repair strands of DNA. Cells from study participants with Down's syndrome or AD showed flaws in how the cells tried to repair the damage to DNA caused by fluorescent light. These results suggest that scientists might be able to use such techniques to develop a test that identifies people at higher and lower risk for losing cognitive skills due to AD. Further research is needed to confirm these initial findings. Other research by NIA scientists indicates that autopsied brain tissue from AD patients shows a marked decrease in messenger ribonucleic acid (RNA) and protein needed for enzymes involved in a body process related to metabolism, especially in neurons containing high levels of tangles. This decrease may be a marker for the loss in the ability of cells to communicate with each other in affected regions of the AD brain. Within a cell, messenger RNA is a substance that carries genetic information from DNA in the nucleus to the rest of the cell where proteins are made. When levels of messenger RNA and proteins needed for certain metabolic processes fall, nerve cells may be less able to communicate between themselves and tangles may develop within cells. Additional work will aim to distinguish whether the molecular changes are the cause or the result of decreased neuron activity, and whether it might be possible to reverse the changes, thus making the neurons more active again. In addition, many researchers are working to develop a better way to picture metabolism in the living brain using positron emission tomography (PET) scanning. NIA's Laboratory of Neurosciences (LNS) in Bethesda, Maryland, has begun to use certain fatty acids as one agent in imaging studies. Fatty acids may help scientists evaluate metabolic processes in the brain related to how the body breaks down and uses important energy-producing substances, including fatty acids and nitrogen. Some scientists believe that this type of metabolism in the brain is a better indicator of brain activity than just blood flow, which is routinely measured in PET scans. In continuing the search for ways to diagnose AD, other NIA researchers studying brain function in people with Down's syndrome have shown a gradual decline in cerebral blood flow that seems to mimic that in AD. The difference in metabolic activity in certain brain regions at rest versus stimulation may be an early indicator of disease. The failure of certain areas to show an increase in metabolic activity when the patient performs a memory task is a sign that the brain is not functioning properly. This finding could lead to an early diagnosis of AD in patients in high risk groups based on their family history or apoE4 status. Scientists at NIA's LNS have developed a passive test of memory that does not require patients to actively take part in a study. To complete standard memory tests, patients must be able to think, hear, see, speak, and write well enough to do memory tasks on demand. Most patients in the later stages of AD and dementia are unable to take part in research studies or to complete tests because they have lost so many of these abilities or they forget the instructions. LNS's researchers have developed tests to get around this major obstacle. Instead of using standard memory tests, they show a particular visual pattern of dots to AD patients. Viewing dots that are arranged in even or balanced patterns causes activity in the cerebral cortex of the brain that mimics what happens when a patient is asked to remember something. After repeated exposure to the even patterns, stimulation of the hippocampus can be seen, even in patients who are in the later stages of AD and cannot take part in standard learning and memory tests. This test may enable scientists to study patients with severe dementia and to look for ways to improve their cortical function. It may lead to a way for scientists to measure how treatments that might improve cognition affect pathways in the brain activated by passive stimulation. Ongoing work by NIA researchers has shown that at least part of the low performance of AD patients on memory tasks is due to their poor visual attention span. Being able to maintain visuospatial attention leads to better performance on memory tests. In 1996, scientists showed that one subgroup of possible AD patients with visual disturbances had lower metabolic activity mainly toward the back of the brain, in regions associated with vision. The common form of AD has low metabolic activity in other areas of the brain. Autopsy confirmation of the clinical diagnosis in these patients will show whether they had a form of AD or a different disease. In addition, investigators at NIA's Laboratory of Personality and Cognition at the Gerontology Research Center in Baltimore are evaluating other tests as early indicators of AD. They found that an exam called the Trail-Making Test can tell the difference between normal and abnormal changes in cognition with age. This test may help identify patients with early AD who might be candidates for treatment. However, before this test can be used outside of a research setting, further studies are needed to confirm these findings. Diagnostic Criteria for Alzheimer's Disease Criteria for diagnosing AD at autopsy were developed in 1983. Now, researchers are trying to refine diagnostic methods using new knowledge about the locations of plaques and tangles in the brain. An international panel of 17 neuroscientists-the National Institute on Aging and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease-met in November of 1996 to revise the guidelines for diagnosing AD at autopsy. The Working Group examined recent research concerning changes in plaques and tangles, synapses, dendrites, and molecular events that may lead to the formation of plaques and tangles. They discussed how these findings eventually might improve AD diagnosis. Earlier guidelines called for evaluating plaque density as a diagnostic marker for AD. The Working Group called for definitions of low, moderate, and high probability of AD based on the numbers of neuritic plaques as well as neurofibrillary tangles in brain tissue after death. The Working Group recommended that pathologists record the number of amyloid plaques and neurofibrillary tangles that they find during an autopsy, along with other signs of damage, such as Lewy bodies and vascular lesions, that are likely to cause loss of mental function. (In Lewy body dementia, round, abnormal structures called Lewy bodies develop in cells within the midbrain and cerebral cortex, and significant plaques and tangles are absent.) New Guidelines for Early Recognition and Assessment of Alzheimer's Disease The Agency for Health Care Policy and Research (AHCPR), part of the Federal Government's Public Health Service, brought together a panel of experts from the private sector to develop a Clinical Practice Guideline (AHCPR Guideline 19) for identifying AD and related dementias. The NIA provided some staff as leaders for the panel. The panel focused on identifying early dementia in people showing certain symptoms that signal the need for further assessment. The panel's primary goal was to increase the early recognition and assessment of a potential dementing illness to: eliminate concern when it is not warranted, identify and address treatable conditions, and diagnose non-reversible conditions early enough so patients and their families might plan for the future. The panel also sought to improve the early detection of AD and related dementias in people showing certain signs and behaviors; educate health professionals, patients, and their families about symptoms that suggest the need for an initial assessment for a dementing disorder; and identify areas for further research on early recognition of dementia. In 1996, the AHCPR reported the following major findings of the panel: certain triggers should prompt a doctor to perform an initial assessment for dementia, rather than attribute apparent signs of mental decline to aging an initial clinical assessment should combine information from a focused history and physical exam, an evaluation of mental and functional status, reliable informant reports, as well as assessments for delirium and depression the Functional Activities Questionnaire is useful in the initial assessment for functional impairment the Mini-Mental State Examination, the Blessed Information-Memory-Concentration Test, the Blessed Orientation-Memory-Concentration Test, and the Short Test of Mental Status are effective mental status tests that discriminate early-stage dementia equally well doctors should assess and consider factors such as sensory impairment and physical disability in selecting mental and functional status tests, and other confounding factors such as older age, educational level, and cultural influence in interpreting test results In people who have possible risk factors for AD (e.g., family history and Down's syndrome) but do not show obvious symptoms, the panel recommends that the doctor's judgment and knowledge of the patient's current condition, history, and social situation should guide the decision to initiate an assessment for dementia. In summary, AHCPR Guideline 19 outlines methods for assessing people for dementia and interpreting results; the role of neuropsychological testing; the importance of followup; key points about AD for health care providers and patients; and symptoms that might indicate dementia. Advances in Treating and Preventing Alzheimer's Disease Immediate goals in treating and managing the dementia symptoms of AD are to slow, reduce, and/or reverse its mental and behavioral signs. The eventual goal is to stop the disease process altogether. Scientists are pursuing many leads to accomplish these goals, but the current focus is on the patient's symptoms and unusual behaviors. Researchers, including those supported by the NIA, have begun to test the effectiveness of drugs on the mental and behavioral aspects of AD. Several clinical trials are testing a variety of compounds. Scientists are looking for treatments that work on many patients, stay effective for a long time, ease a broad range of symptoms, improve patients' activities of daily living and cognitive function, and have no serious side effects. Treatments also are needed for managing unusual behaviors, such as verbal and physical aggression, agitation, wandering, depression, sleep disturbances, and delusions that occur in AD. Preliminary studies suggest that these types of behaviors greatly influence families' decisions to move loved ones to care outside the home. Improving these behaviors could delay or even prevent placement in long-term care facilities, maintain patients' dignity, reduce caregiver stress, and lower overall costs to families and to society. In 1996, the Food and Drug Administration (FDA) approved donepezil hydrochloride (Aricept) to help treat some mild to moderate symptoms of AD. Aricept (also known as E2020) is the second drug approved by the FDA to treat AD. The first drug, tacrine (Cognex), has been marketed since 1993. Both Aricept and Cognex slow the breakdown of acetylcholine, a key neurotransmitter in cognitive functioning. However, neither drug stops nor reverses the progression of AD. Occasional side effects of Aricept include diarrhea and nausea. The drug also can cause an irregular heartbeat, especially in patients with heart conditions. Fainting spells have been reported in some patients. However, Aricept seems not to affect liver enzymes, an effect that prevented many patients from taking Cognex. Most researchers agree that neither Aricept nor Cognex works for all, or even most, patients so that the drugs' effects and duration of usefulness are limited. In studies on animals, scientists at the NIA have preliminary evidence suggesting that a new drug, phenserine (a cholinesterase inhibitor), may be useful in treating AD patients. In animal models of cognitive decline, phenserine was significantly more effective in enhancing performance and learning in a maze test than drugs currently marketed to treat AD. Phenserine is undergoing toxicology testing (studies to find safe doses and any potentially problematic side effects). Similarly, NIA scientists recently found that a drug called arecoline seems to improve cognitive function and the process whereby chemical messages are sent across synapses in animals. Researchers now are studying the effects of arecoline in people. Still other NIA investigators have found that physostigmine helps improve working memory in healthy people by shortening the amount of time needed to react to study tasks and enhancing activity in a certain part of the brain. Physostigmine is a drug that also blocks the breakdown of acetylcholine and improves the way that acetylcholine sends messages at synapses. Scientists now are studying this drug in AD patients. These drugs (Aricept, Cognex, and physostigmine) only temporarily halt or reverse cognitive losses from AD, and do not prevent AD from continuing to kill the nerve cells that normally produce acetylcholine. Therefore, researchers are looking for other drugs to slow or prevent AD and to help vital acetylcholine-producing cells survive longer. The search for more effective ways to treat and prevent AD includes studying the use of estrogen, anti-inflammatory drugs, and other compounds in AD patients; determining which groups of people develop AD; and conducting several initiatives related to caregiving. Estrogen Replacement Therapy and Alzheimer's Disease In looking for factors associated with earlier or later onset of AD, the NIA and the National Center for Research Resources funded researchers at Columbia University. These investigators found that estrogen replacement therapy (ERT) was associated with a reduced incidence of AD in a group of older women. Incidence is the rate at which new cases of a disease occur. Study volunteers, initially free of AD, were taking part in a long-term study of aging and health. This 5-year investigation was unique because all of the women were examined and interviewed about their estrogen use before they developed AD symptoms; and it was the first AD study group with similar numbers of older women of African American, European, and Hispanic American ancestry. Previous studies depended on the review of death certificates and patients' and/or caregivers' memories of using estrogen. Researchers compared the self-reported history of estrogen use, medical history, apoE4 status, ethnic group, age, and education of 1,124 women. In this study, only 9 of the 156 women age 70 and older who had used estrogen for from 2 months to 49 years developed AD. Among 968 participants who never had used estrogen, 158 developed AD during the study. The estimated annual incidence rate for AD among women in the study who took estrogen was 2.7 percent, compared to 8.4 percent among those who did not take estrogen. These results suggest that estrogen use during and after menopause may significantly lower the risk of AD and delay the onset of AD symptoms. The duration of estrogen use also seemed important in reducing risk. Women with a history of long-term use (more than 10 years) had the lowest risk. But, even women who took estrogen for a short time and then stopped also benefitted. From this study, researchers conclude, for example, that a woman who takes estrogen for 10 years at and after menopause may reduce her risk of developing AD by 30 to 40 percent, compared to other women her age. Scientists at Johns Hopkins University in Baltimore reported similar results related to estrogen use among women in the Baltimore Longitudinal Study of Aging (BLSA). A long-term NIA study, the BLSA includes a physical and mental assessment of 2,283 men and women who were healthy at the start of the study. In a retrospective study (looking at what occurred in the past) of one group of BLSA women, a history of ERT was associated with a reduction in AD risk by about half, also suggesting that estrogen helps protect women from AD. This beneficial effect is added to the lower incidence of heart disease and osteoporosis (a disorder in which normal bone tissue is lost) for women who take estrogen after menopause. Estrogen is a hormone, a body chemical that starts or runs the activity of an organ or a group of cells. Some scientists believe that estrogen's role is in helping brain cells survive, which in turn delays the onset of AD. Other researchers think that estrogen aids the metabolism of APP, preventing it from forming beta-amyloid fibers. Still others propose that estrogen may work as an anti-oxidant to protect nerve cells. Additional laboratory research is needed to learn exactly how estrogen may protect women from AD. In turn, this research will help scientists develop new treatments for the disease. While these findings are encouraging, clinical trials are needed before doctors can recommend estrogen to women for delaying or preventing AD. Clinical trials will determine whether estrogen therapy can delay or prevent the onset of AD as well as the safety, dose, and duration of estrogen treatment needed to produce these effects. One such clinical trial, the Alzheimer's disease Cooperative Study (ADCS) trial of estrogen, is assessing the effect of ERT on the progression of AD in postmenopausal women who have the disease. Anti-Inflammatory Drugs and Alzheimer's Disease A growing body of evidence suggests a link between inflammation and some changes that occur in the brains of AD patients. However, scientists do not know yet whether inflammation is a cause or an effect of the disease. Researchers in NIA's 40-year BLSA believe they have found a link between anti-inflammatory drugs and a lowered risk of AD. Scientists surveyed 1,417 men and 648 women enrolled in the BLSA between 1955 and 1994 about their use of medications. A total of 110 participants eventually were diagnosed with AD. Those who regularly used non-steroidal anti-inflammatory drugs (NSAIDs) other than aspirin had a lower risk of developing AD than those who took acetaminophen (Tylenol) or no painkillers at all. For men and women in the BLSA study who took NSAIDs regularly for even as little as 2 years, researchers found a lower risk of AD by as much as 60 percent. NSAIDs include ibuprofen (Advil, Motrin), naproxen sodium (Aleve), indomethacin (Indocin), and many other painkillers. Tylenol has no anti-inflammatory properties. Aspirin users had a slightly decreased risk of AD, but this drop was not statistically significant in this particular study. Scientists advise against taking NSAIDs to prevent AD based on these results alone. The BLSA survey neither distinguished among the various NSAIDs nor compared specific doses. Further, it relied on the self-reports of those interviewed. Moreover, NSAIDs have potentially serious side effects, particularly stomach irritation and ulcers. Further research is needed to determine whether NSAIDs decrease a person's risk of developing AD and, if decreased risk is established, to develop anti-inflammatory drugs with less severe side effects. Another NIA-supported study suggests that older people who regularly take aspirin or other anti-inflammatory drugs may be at lower risk of age-related cognitive decline, including AD. Scientists studied changes in mental ability over 3 years among 7,671 older volunteers who are taking part in the Established Populations for Epidemiologic Studies of the Elderly. Twenty-one percent of the participants took NSAIDs regularly at the beginning of the study. After 3 years, participants who regularly used NSAIDs had significantly better cognitive function than those who had not taken NSAIDs. On average, the cognitive ability of a volunteer taking NSAIDs was equal to that of a person 3.5 years younger. Using NSAIDs was associated with a reduced risk of significant cognitive decline by about 20 percent. Mental decline was more likely to occur in female, older, and less-educated volunteers and in participants who had survived a previous stroke. Researchers previously had noted that AD is less common in arthritis patients. Now it appears that this finding may be associated with the high rate of NSAID use by arthritis patients. The way NSAIDs might reduce the risk of cognitive decline is unclear. However, some scientists think that NSAIDs may help prevent the inflammation found in the brains of people with AD. These findings do not confirm that taking NSAIDs can prevent cognitive decline. As with estrogen, the only way to prove a cause-and-effect relationship is through careful studies (clinical trials) in which older participants are assigned randomly to take NSAIDs or not and then reexamined several times over a long period. Until these studies are performed and the results carefully evaluated, taking NSAIDs to preserve cognitive function is not advised unless recommended by a doctor. Information gleaned from these and other studies (such as the ADCS's investigation of the steroidal anti-inflammatory drug, prednisone) brings scientists closer to being able to treat AD patients. Use of Selegiline and Vitamin E To Treat Alzheimer's Disease Oxidative changes are seen in the brains of AD patients. Studies of compounds that fight oxidation put researchers one step closer to understanding processes that damage cells and finding ways to treat and possibly prevent AD. The NIA-supported ADCS trial of selegiline (l-deprenyl or Eldepryl) and alpha-tocopherol (vitamin E) is one such study. Both selegiline and vitamin E act as anti-oxidants. Selegiline, which has been used to treat patients with Parkinson's disease, works by inhibiting an enzyme in the brain that impairs certain neurotransmitter systems. For 2 years, researchers studied 341 moderately impaired patients with probable AD who were recruited from 23 centers taking part in the ADCS. Participants were divided into four groups that received different treatments: selegiline, vitamin E, both selegiline and vitamin E, or a placebo (an inactive substance). Scientists compared the amount of time it took patients in each group to reach one of the following outcomes: death, institutionalization, loss of the ability to do basic activities of daily living (such as handling money, bathing, dressing, and eating), and severe dementia. They looked at the signs of AD that can worsen over time. The results suggest that compared to those who took a placebo, the estimated average time to reach any one of the four outcomes increased by 230 days for participants who took vitamin E, 215 days for those who took selegiline, and 145 days for those took both selegiline and vitamin E combined. Also compared to those who took a placebo, members of the treatment groups showed some improvements related to their level of independence and behavioral symptoms. No effect was found on cognitive measures. Overall, this study shows that treatment with selegiline or vitamin E reduced moderately impaired AD patients' risk of reaching one of the four primary outcomes, with an estimated average delay of 6.5 months. In addition, these findings support the idea that damage due to oxidation plays a role in AD. Scientists caution that further research is needed to confirm these preliminary findings. Researchers need to find out if these types of drugs actually can delay the development of symptoms much earlier in the course of the disease and learn how these drugs might affect patients at different stages of AD. They also need to study if the positive findings related to function occurred because the anti-oxidants improved other aspects of the patients' health, such as heart-related effects, rather than specifically fighting oxidation in the brain. Investigators further warn that selegiline may have potential side effects and interactions with other drugs. In addition, the dosage of vitamin E used in this study was much higher than that typically found in daily supplements. Vitamin E may be associated with an increased risk of bleeding in some people. AD patients and their families should consult their doctors to see whether these drugs or others approved by the FDA may be appropriate for a particular AD patient. Alzheimer's Disease Cooperative Study The ADCS was established in 1991 to build the organizational structure needed for many centers to cooperate in testing promising drugs in AD and to develop and improve tests for evaluating AD patients in clinical trials. The following six studies began in the first 5-year grant period (some were completed by June 1996 and others still are ongoing): safety and effectiveness of selegiline and vitamin E (results published); tests in English that measure treatment efficacy (results in press); tests in Spanish that measure treatment efficacy (results in analysis); use of haloperidol, trazodone, and behavioral management techniques in patients with disruptive agitated behavior (results in analysis); use of ERT in women with mild to moderate AD (still recruiting participants); and use of the anti-inflammatory drug prednisone (results in analysis). Five more proposed studies have been approved for the next 5-year grant period: development of improved measures of treatment efficacy; an anti-inflammatory study; AIT-082 (a molecule derived from hypoxanthine and procaine) in AD (in a Phase I study, which means the drug is being given to a small number of volunteers to determine toxic levels and safe doses); melatonin and sleep disorders in AD; and divalproex sodium (Depakote), an anti-seizure drug, as therapy for agitation and dementia in nursing home residents. Alzheimer's Disease Centers The NIA funds 27 ADCs across the United States. Each ADC supports four common functions: clinical practice, neuropathology, education and information transfer, and administration. The comprehensive ADCs also receive funding to perform specific research studies on AD. ADCs also perform other functions, such as neuroimaging. The primary goals of the ADC Program are to promote research, training and education, technology transfer, and multicenter and cooperative studies in the diagnosis and treatment of AD. Much of the success in AD research in this country since 1985 can be attributed to resources provided by the NIA to the ADCs. Recent advances include linking genes on chromosomes 1, 14, and 21 to FAD and identifying inherited risk factors related to apoE. In addition, researchers at the ADCs helped lay the groundwork for studying how proteins associated with amyloid plaques and neurofibrillary tangles are processed. Other programs funded by the NIA depend on research activities at the ADCs, including regular, investigator-initiated studies; the Consortium To Establish a Registry for Alzheimer's Disease (CERAD); and the ADCS. In addition to conducting research and pilot research projects, the ADCs contribute resources such as patient data, brain and other tissue samples, and molecular probes to other scientific programs. The ADCs also serve as a resource for many types of studies testing new AD treatments. In 1990, NIA began a program to link satellite diagnostic and treatment clinics to the ADCs. The satellite clinics offer diagnostic and treatment services to minority, rural, and other underserved people; and help increase diversity among research volunteers, so that answers to research questions apply to a wider group of people. This program makes it easier for diverse populations to take part in research studies and clinical drug trials through the parent ADC. Twenty-seven satellite clinics serve communities with broad ethnic and cultural diversity, including African Americans, Asian Americans, Hispanic Americans, and Native Americans. Eleven clinics serve rural areas, 12 serve urban areas, and 4 serve a combination of urban and rural areas. Consortium To Establish a Registry for Alzheimer's Disease In 1986, the NIA established CERAD to bring uniformity to clinical and pathological studies of AD patients by standardizing clinical, neuropsychological, neuroimaging, and neuropathological assessments. Members of the Consortium conduct followup, observation, and autopsies of patients; review data for consistency, accuracy, and completeness; and promote use of this unique data resource for publications by both CERAD and non-CERAD investigators. In fiscal year 1995, CERAD received funding from the NIA to maintain data on the current group of more than 1,200 AD patients and controls. Special Care Units Initiative Throughout 1996, researchers reported preliminary findings from the NIA-supported Special Care Unit (SCU) Initiative. SCUs are separate sections in nursing homes for residents with dementia. The idea behind SCUs is that people with dementia might benefit from specially designed programs or environments different from those provided in a traditional nursing home. The SCU Initiative is a study at several sites, including researchers at some ADCs, to evaluate the effectiveness and costs of special care for AD patients at nursing homes. Participating scientists already have contributed to what is known about nursing home care for people with dementia. Ten sites take part in this research consortium, funded for 5 years to: identify key elements of care specify appropriate outcomes evaluate the effects of key elements of care Study designs among the sites range from case studies to multi-State evaluations to a national assessment. Most of these collaborative investigations use large data sets to compare care and outcomes in SCUs with those in traditional nursing home care units. Researchers also seek to standardize a definition of units that provide special care. NIA-funded scientists compared national survey data on nursing homes for 1991 and 1995. Compared to 1,497 SCUs in 1991, there were more than 3,746 SCUs in 1995. Of these, 3,263 were units, wings, or clusters within units; and 483 were programs. In 1995, among the nation's 16,827 nursing facilities, more than 22 percent offered specialized care in some form for people with dementia and the total SCU capacity was 122,479 patients. The national study also showed several differences between residents in SCUs and those in traditional care. Compared with residents in traditional care, those in service-rich, specialized care settings are less likely to fall even though they are more likely to be up and about; less likely to be restrained, and when restrained, are restrained for fewer days; and more likely to be prescribed psychotropic medications (drugs that are designed to ease their negative behaviors). However, prescription use by the SCU goes down during the initial 6 month period of placement, suggesting a tailoring of medication to suit patients' changing needs. Moreover, residence in an SCU environment is associated with less agitated behavior, after controlling for gender and other baseline factors such as initial levels of agitation and cognitive impairment. The data also suggest that using strategies that match the needs of residents with dementia can have positive effects on behavior and emotional states of both patients and staff. Even within a broadly defined SCU, placement in an SCU environment lowers aggressive and agitated behaviors after 6 months. Not only are patients' aggressive behaviors decreased, but their positive behaviors and social interactions are increased. The final research year of the SCU Initiative, 1997, is devoted to comparing the data among the different nursing homes. Investigators hope to translate this research into practical guidelines for nursing home administrators and policy makers. Enhancing Family Caregiving In 1995, the NIH established a major initiative to develop and test new ways for families and friends to manage the daily activities and stresses of caregiving for people with AD. Called REACH--Resources for Enhancing Alzheimer's Caregiver Health--the studies are sponsored by the NIA and the National Institute of Nursing Research. This 5-year effort is a critical part of NIA's support for research on AD patients receiving care at home. Participating researchers are from the Center for Aging at the University of Alabama in Birmingham; Veterans Affairs Medical Center and the University of Tennessee at Memphis; the Center on Adult Development and Aging at the University of Miami, Florida; Veterans Affairs Palo Alto Health Care System and Stanford University, California; the Center for Collaborative Research at Thomas Jefferson University in Philadelphia, Pennsylvania; the Medical Information Systems Unit at the Boston University Medical Center, Massachusetts; and the University Center for Social and Urban Research at the University of Pittsburgh, Pennsylvania. They are studying the effects of educational support groups, behavioral skills training, family-based interventions, environmental redesign, and computer-based information services for African American, Caucasian, and Hispanic American families. The NIA has funded a Coordinating Center to develop and maintain a common database. Data from this initiative will enable researchers to study the feasibility and outcomes of different interventions at the participating sites. REACH is designed to stimulate research on home- and community-based interventions to help families provide care for loved ones with mild and moderate dementia. For example, NIA-supported researchers at the Center for Collaborative Research at Thomas Jefferson University are looking at the role of adjustments in the home environment (design changes and ways of managing tasks) in supporting family caregivers and enhancing their well-being. Both types of adjustments reflect adaptive strategies that caregivers may use to simplify the environment, make tasks easier, and increase patient safety. Stress Reduction for Family Caregivers: Effects of Using Day Care NIA-supported researchers at Pennsylvania State University in University Park and Kent State University in Kent, Ohio, studied the mental health benefits of adult day care use by 326 family caregivers of dementia patients. The participants were divided into a treatment group (122 people) and a control group (204 people). The treatment group used day care at least 2 days a week for 3 months. The control group used neither adult day care nor any other respite services during the study. During the time the treatment group of caregivers enrolled their loved ones in day care, researchers measured changes in caregivers' attitudes about their own primary stressors and well-being. Scientists compared the results of the treatment and control groups on rating scales that assess overload, worry and strain, caregiver role, lack of emotional control, distress, depression, well-being, anger, and positive feelings. Preliminary results suggest that 3 months of use of adult day care services by caregivers of dementia patients helped improve their well-being and greatly reduced stress within a relatively brief time. Using adult day care decreased participants' feelings of overload, depression, worry, and strain. Further study is needed to confirm this initial research. Exploratory Centers on Demography of Aging: Alzheimer's Disease The NIA supports research at nine collaborating Exploratory Centers on the Demography of Aging. Demography refers to the study of certain health factors--in this case, aging--in human populations. The goal of these centers is to provide innovative and public policy-relevant research on health, long-term care, and the economic aspects of aging. Each center brings experts from different backgrounds together to conduct research in several areas of interest. In the second year of this program, four new pilot projects are under way studying aspects of AD along with other demographic factors. As part of two of these, researchers at Duke University are studying the development of AD and the effects of different apoE gene statuses on AD. In other areas, the Duke University team is trying to forecast the life expectancy of older people and health service needs, studying how life expectancy can be extended, and measuring the rate of disease and disability in the U.S. population. Researchers in one of these studies are examining the costs and benefits of different medical treatments for older people. In another exploratory center study, scientists at the University of Chicago, Illinois, are investigating the well-being of spouses of institutionalized AD patients. University of Chicago researchers also are studying the economics of aging from a historical perspective, retirement prospects and minority issues for Hispanic Americans, and differences in family care and social supports between African Americans and Caucasians. Lastly, exploratory center researchers at the University of Pennsylvania are studying AD and life in nursing homes. These scientists are working to develop new measures of AD progression for use in projecting population and disability rates. They also are examining relationships between members of different generations, measuring death rates for African Americans from 1930 to the present, comparing English and Spanish versions of the Dementia Severity Measure, and looking for ways to encourage minority researchers. By collecting and analyzing data about health and economic trends in the older population, exploratory centers foster a better understanding of aging and its effects on both individuals and society. Research Conducted by Other Institutes National Heart, Lung, and Blood Institute How AD develops has attracted the attention of investigators from diverse disciplines funded by the National Heart, Lung, and Blood (NHLBI). When a protease(s) cuts APP apart, a peptide may form that is 1 of 2 lengths: a chain of 40 amino acids or 42 amino acids. Amino acids are organic compounds needed for forming proteins and pieces of proteins. The shorter beta-amyloid is very soluble and aggregates slowly. The longer beta-amyloid rapidly forms insoluble aggregates and appears to play a critical role in the initial buildup of plaque and in the onset of AD. Proteases generally are controlled by their inhibitors. One NHLBI grantee at the Scripps Research Institute in La Jolla, California, has been studying APP processing by certain proteases in platelets (disk-shaped blood cells that play a role in blood clotting) and large bone marrow cells. Since inhibitors control the activity of proteases, NHLBI researchers are trying to identify inhibitors of APP processing associated with platelets and bone marrow. So far, they have found one inhibitor related to platelets and one related to bone marrow. A disease of blood vessels in the brain, called cerebral amyloid angiopathy (CAA), is common in patients with AD. CAA appears to be associated with the buildup of beta-amyloid peptide within the network of blood vessels in the body. In hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) (bleeding in the brain with amyloid buildup), the pathology tends to be more severe, and patients develop frequently recurring bleeding within the brain when they are about 50 years of age. Amyloidosis is a generic term for a group of diverse diseases, all of which involve amyloid buildup in various organs and tissues to a degree that normal body function is altered. People with HCHWA-D have a mutation in their APP gene that is at a different place from those causing AD. As a result, the beta-amyloid peptide produced in these patients has an amino acid substitution within it. An NHLBI grantee at the State University of New York in Stony Brook reported this year that the longer, not the shorter, beta-amyloid peptide caused damaging responses (including cell decay) in laboratory cultures of muscle cells surrounding blood vessels in the human brain. Recent results show that the mutation in the shorter beta-amyloid peptide from HCHWA-D patients converts the normally harmless peptide to a highly destructive form. In fact, the shorter beta-amyloid peptide containing the mutation caused more damage to these muscle cells in laboratory cultures than the longer beta-amyloid peptide. These findings on the altered properties of the mutated peptide may help explain the severe damage found in blood vessels of the brain observed in this disorder. National Institute of Diabetes and Digestive and Kidney Diseases The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) conducts and supports research on molecular and biochemical mechanisms of cell signaling, including the roles of neurotransmitters and ion channels; and mechanisms involved in abnormal metabolic processes. This year, scientists at the NIDDK reported progress in understanding how beta-amyloid affects ion channels in cells. Investigators found that beta-amyloid, when added to artificial membranes, spontaneously formed pores (openings) or ion channels. To understand how these pores for amyloid are formed, researchers performed a molecular modeling study and developed three basic types of channel models. Two of these models showed how adding a certain substance to the channel pore complex can affect whether the channel reacts to atoms that have positive or negative charges. These models were then used to design experiments to test the binding of zinc, a metal ion that some scientists think may play a role in the formation of amyloid plaques in AD. Researchers found that addition of zinc to the pore complex had a strong effect on how the channel worked, essentially blocking pore activity. To determine whether beta-amyloid could form ion channels in natural membranes, investigators studied the buildup of beta-amyloid molecules in a nerve cell line. Once again, they found that exposing the membrane to beta-amyloid caused pores to form, and that addition of zinc blocked channel activity. These results support the idea that amyloid damages nerve cells by forming these channels. NIDDK-funded scientists also are interested in amyloidosis; the most common form of amyloidosis is AD. In this disease, the amyloid is a fragment of APP. Recent studies have shown that beta-amyloid exists as a soluble protein in many body fluids, linking AD more closely to other amyloidoses such as transthyretin (TTR) amyloidoses, where a fragment of the TTR protein forms the insoluble amyloid. These diseases, like AD, are late-onset diseases and affect a large number of families in the United States. Collaborating NIDDK-supported researchers at the Richard L. Roudebush Veterans Administration Medical Center at Indiana University/Purdue University of Indianapolis and Texas A&M University in College Station are studying the structure of normal and abnormal TTR proteins to understand the factors needed for protein processing that leads to amyloid formation. The goal of this research is to identify methods of interfering with the formation of amyloid fibrils and, thereby, preventing this abnormal buildup of protein fragments. In other studies, NIDDK-supported researchers at the University of California at San Francisco and the Joslin Diabetes Center in Boston, Massachusetts, which is affiliated with the Harvard Medical Center, are studying the role of islet amyloid polypeptide (IAPP) in non-insulin-dependent (type 2) diabetes, which also is an age-dependent disease. IAPP is the major component of amyloid deposits in islets (isolated clusters of cells or tissue) in the pancreas and is thought to play a role in the development of type 2 diabetes. Information gained studying TTR and IAPP proteins will contribute to the overall understanding of the mechanisms underlying amyloid and associated protein buildup. Increased understanding can lead to the design of treatments to: reduce the effects of tissue damage, increase the rate of recovery from tissue damage, and ultimately, prevent disease. National Institute of Neurological Disorders and Stroke The National Institute of Neurological Disorders and Stroke (NINDS) supports a broad array of studies directed toward understanding how AD develops. In studying the cause(s) of AD, NINDS-funded researchers are looking at the organization of the memory system in the cerebral cortex of mammals, the structure and function of neurons in this system, the pathology of these neurons including plaques and tangles, and genetic factors. They also seek to develop and use animal models of the disorder. The pace of discovery in AD research has been most impressive in genetic studies. Scientists supported by the NIA and the NINDS found two genes linked to FAD, presenilins 1 and 2. (For a more complete description of this research, see Presenilins.) The two genes produce similar proteins with unknown functions. In analyzing gene sequences, scientists recently have shown that proteins produced by these two genes have chemical structures that are similar to that of a protein involved in the signaling and development of cells in a species of worm. The powerful genetic techniques that can be applied in this species may help researchers understand the function of these proteins. Additional recent studies suggest that these proteins are made by neurons throughout the brain and that they play a role in the processing of other proteins such as APP. Until recently, there has been no good animal model for AD. The discovery of three defective genes that underlie inherited forms of AD has presented the opportunity to develop transgenic animal models. (For a more complete description of this research, see Transgenic Mouse Model for Alzheimer's Disease.) Newer imaging studies, particularly PET scans and magnetic resonance imaging (MRI), have made it possible for researchers to study the selective abnormalities in brain functioning in AD patients. These studies give scientists a research baseline for use in finding ways to develop diagnostic measures, define the metabolic defect involved, and evaluate the effects of treatments. The NINDS Laboratory of Adaptive Systems is determining whether a laboratory test they have developed may be a useful diagnostic test for AD. This test is not available outside the laboratory or research setting. It is based on drug-induced light signals that are missing in single skin or smell-receptor cells of AD patients but not healthy controls. The same test also may be useful for cells obtained from a simple blood sample. Beta-amyloid was found to produce the defects in the cells of healthy people. A simple laboratory diagnosis for AD would eliminate the cost of lengthy exams and procedures (e.g., computerized tomography (CT) scans, metabolic tests, etc.) as well as guide family members and clinicians for future decisions concerning patient care. Further biochemical studies will explore the relationship of the observed changes to the cause(s) of AD. NINDS's Experimental Therapeutics Branch has initiated a clinical trial of a new anti-dementia medication, CX 516 (Ampakine), for patients with mild to moderate dementia. Scientists are studying CX 516 for properties that improve thinking and memory. The identification of more genes for FAD should foster a better understanding of how FAD and sporadic AD develop, much as recent findings in familial breast cancer are leading to a better understanding of all breast cancer. National Institute on Deafness and Other Communication Disorders Investigators funded by the National Institute on Deafness and Other Communication Disorders (NIDCD) at the University of Pennsylvania in Philadelphia studied the understanding of subject-predicate sentences independent of their truth value by asking a group of AD patients to judge the coherence of statements such as "The tulip is tall" or "The tulip is jealous." The results suggest that these AD patients were significantly more impaired than healthy volunteers in judging the coherence of these simple sentences. Moreover, AD patients in the study were more successful at judging the coherence of statements that contained attributes with a narrow scope of reference compared to attributes with a broad scope of reference. These findings suggest that AD patients have impaired semantic (related to the meaning of words or language) memory and have trouble processing the network of semantic relations underlying word meaning in semantic memory. Superoxide dismutases are among a cell's major enzyme-related defenses against toxic reactive oxygen molecules and oxidative stress. Reactive oxygen molecules, which induce these enzymes to work, have been implicated in the nerve cell decline associated with AD. As some people with AD show early, severe deficits in their olfactory ability (related to the sense of smell), NIDCD-supported scientists at the University of Kentucky in Lexington studied the location and activity of two enzymes, manganese and copper-zinc superoxide dismutases, within certain nose cells. Participants were young, middle-aged, and older people without dementia, and people with AD. Tissues were obtained at autopsy from people ranging in age from 19 to 98 years old. These researchers studied how each enzyme reacted with cells from different regions of the nose. Manganese and copper-zinc superoxide dismutases showed a lot more disease-fighting activity in people with AD than in older participants without dementia. This finding suggests that oxidative stress may be responsible, at least in part, for the smelling deficits in AD patients. NIDCD-funded scientists at the University of Kentucky also are studying a calcium-binding protein, called S-35, in nose cells of people who ranged in age from 16 weeks of fetal development to 98 years of age, including some with AD. This protein binds calcium that is outside cells and helps prevent cell death related to cells having too much calcium. The disease-fighting activity of S-35 was observed in olfactory (smell) receptor neurons (ORNs) and olfactory nerve bundles that react with olfactory marker protein (OMP) and neuron-specific enolase (NSE), another enzyme. At all ages, the mean number of ORNs that reacted with OMP did not change significantly. However, the mean number of NSE-reactive and S-35-reactive ORNs declined markedly in postnatal infant, young, and old patients when compared with that of the fetuses. S-35-reactive ORNs decreased significantly in AD patients when compared with control patients. These results suggest that ORNs in humans express S-35, and that there is an age-related decrease in the expression of S-35. Furthermore, the marked decrease of S-35 expression in ORNs of AD patients suggests that cell excitability associated with calcium ions and the ability of cells to protect themselves from too many calcium ions decline in these patients. National Institute of Mental Health Research supported by the National Institute of Mental Health (NIMH) includes the etiology, pathogenesis, clinical course, and treatment of AD; the stresses caregivers face; and the services AD patients and their caregivers use. The NIMH Alzheimer's Disease Genetics Initiative has established a national resource of clinical information and DNA samples from people with AD and their family members. The NIMH funds research at three universities (Harvard Medical School/Massachusetts General Hospital in Boston, the University of Alabama at Birmingham, and Johns Hopkins University) to collect data and conduct genetic analyses. As of February 1997, the data set included clinical/diagnostic data and DNA samples from 1,161 people in 362 family lineages, including 804 subjects with AD. This data set includes 441 affected sibling pairs, and is the largest for late-onset AD thus far collected. Six research groups currently are conducting genetic analyses of samples provided by the Initiative. Descriptive information for the sample (including tables that are updated daily), instructions for gaining access, and a copy of the Distribution Agreement that must be signed by investigators requesting access, are available on the Internet at http://www-srb.nimh.nih.gov/gi.html. Analyses based on data collected through the NIMH Alzheimer Disease Genetics Initiative confirm the role of the apoE4 gene as a risk factor for AD. Among 679 people with AD in the sample, having 2 copies, but not 1 copy, of the apoE4 allele was associated with a lower age at onset. These results also show that apoE4 exerts its maximal effect on risk for AD in people in their sixties, although an effect also was observed at later ages. As with other studies of late-onset diseases, this finding suggests that genes other than the apoE4 gene also influence a person's risk for developing late-onset AD. Researchers also are looking at whether AD patients with the E4 allele are more likely to have a faster rate of decline. NIMH-funded researchers at Stanford University have found apoE4 to be a poor predictor of decline in AD, consistent with other recent reports. However, the E4 allele was found to be related to several measures of behavioral disturbance (discussed below). NIA- and NIMH-supported researchers at the Albert Einstein College of Medicine in New York City have been conducting neurochemical analyses of AD to find biochemical events that occur very early in the development of the disease. By producing monoclonal antibodies that recognize protein abnormalities, these scientists can explore different neuronal sites for abnormal changes that occur with AD. Antibodies are substances that play a role in protecting the body from disease by binding to foreign proteins. They are used in research to identify the location and amount of AD-related proteins. In particular, the order of changes that take place in these proteins is crucial for detecting the very early stages of AD. For example, it appears that tau is altered in the AD brain before paired helical filaments and neurofibrillary tangles develop. If confirmed, early detection of altered tau could be used as a marker in drug trials aimed at stopping or preventing AD. Through an NIMH Small Business Technology Transfer grant, researchers at Isolab, Inc., in Akron, Ohio, are developing a laboratory test based on cerebrospinal fluid (CSF) samples to determine the density of paired helical filaments of neurofibrillary tangles using antibody assays (tests). This diagnostic kit for monitoring CSF potentially will be developed to serve as one element of the physician's evaluation of dementia, and holds potential as a useful diagnostic tool. Researchers at McLean Hospital in Belmont, Massachusetts, and the Massachusetts Institute of Technology's Clinical Research Center in Boston are examining the metabolic regulation of acetylcholine synthesis and function in the AD brain. Uptake of choline-a precursor of acetylcholine-into the brain declines with age and may be an important contributing factor in AD, where acetylcholine neurons are susceptible to loss. Oral administration of CDP-choline (cytidine diphosphocholine), a metabolic intermediate that completely dissociates to form choline and cytidine, increases brain levels of choline, phospholipids, and acetylcholine biosynthesis in rat brain. In humans, CDP-choline (citicholine) has been shown to improve memory functioning in older people with well-functioning memory, as well as improving verbal memory (delayed recall) in older people with inefficient memory processing. Future studies will investigate the potential role of CDP-choline treatment in delaying the onset of cognitive impairment. Nerve cell decay that is related to aging may be caused or made worse by declines in circulating hormones such as estrogen, leading to the hypothesis that estrogen may have a protective effect in AD. NIA- and NIMH-funded researchers at Columbia University have been seeking to understand the molecular mechanisms through which hormones could affect brain function. They have shown that hormone receptors are heavily represented in some brain regions implicated in the pathology of AD, and that hormones act in combination with neurotrophic factors to promote cell survival. Although memory problems and cognitive impairment often are considered the primary symptoms of AD, psychiatric symptoms such as delusions, mood lability, apathy, irritability, agitation, disinhibition, and aggression also are key symptoms of the disorder. These non-cognitive symptoms are critical because they have been associated with more rapid disease course, caregiver distress, and earlier institutionalization. Patients with both AD and depression may have a more complicated course of AD and also may have other physical illnesses such as diabetes or heart disease. NIMH-funded researchers at the University of California at Los Angeles have found structural and functional correlates of psychiatric symptoms in the brains of AD patients. At the University of Pittsburgh, studies of brains at autopsy have indicated that AD patients who had depression had reduced levels of a neurotransmitter, serotonin, in the hippocampus. In NIMH-funded research at Stanford University, community-residing AD patients with the apoE4 allele showed greater behavioral disturbances than non-carriers of the allele, even when the level of cognitive impairment was taken into account. Further studies are under way to determine the replicability of these initial findings, which suggest that genetic variations in apoE may have a broader significance for the clinical symptoms of AD than has previously been recognized. All these studies are important because both psychiatric symptoms of AD and coexisting psychiatric disorders currently are more treatable than the cognitive symptoms of the disease, and their treatment can enhance quality of life for both patients and family caregivers. Neuroleptic medications (drugs that affect a person's thinking, behavior, and mood, which are designed to reduce agitation and confusion) remain a frequent treatment for AD patients who are agitated and/or exhibit psychotic symptoms of delusions and hallucinations. In addition to determining the efficacy of these medications, scientists are refining information about the risk of neuroleptic-induced tardive dyskinesia (TD)-a condition characterized by involuntary muscle rigidity and tremors. NIMH-supported researchers at the University of California at San Diego have studied older psychiatric patients, including AD patients, for their risk for TD. These scientists have found that cumulative exposure to neuroleptics, as well as advancing age, are among the greatest risk factors for TD. Older patients are six times more susceptible to developing TD compared to younger patients. Among middle- aged and older adults, cumulative exposure is the greatest risk for TD, regardless of dosage. These efforts have been refined to determine risk profiles for distinctive subtypes of TD (for example, facial rigidity versus body contortion and hand tremors). Efforts to find alternatives to these neuroleptic medications for managing disruptive and psychotic behaviors in AD patients include pharmacologic studies. Researchers at the University of Pittsburgh are looking at the effects of two different neuroleptics-perphenazine and melperone-to see how neuroleptics lead to changes in dopaminergic functioning in AD patients. The effects and actions of these medications are examined through drug challenge paradigms, where differences due to age and disease state can be studied. In addition to learning how to avoid TD when treating psychotic and behavioral symptoms in AD, these efforts aimed at understanding the dopamine-related system also will help scientists develop new drugs to treat the broader symptoms of AD. Over the past decade, a number of NIMH-supported researchers have documented the mental and physical health consequences of caregiving stress among family members with an AD patient. Family caregivers of loved ones with AD have been called the "second victims" due to their increased risk for depression, cardiovascular problems, and compromised immune (disease-fighting) function. Researchers at Ohio State University have found that stressed caregivers build up less antibodies in response to an influenza vaccination, indicating that they are at greater risk for influenza and its complications. Newer vaccine preparations now enable scientists to test whether repeated vaccinations may improve stressed caregivers' abilities to resist influenza. A second line of immune function studies by these researchers is examining how stress among caregivers affects cytokine production and wound healing. Cytokines are proteins that react with certain foreign substances to mediate activities between cells, such as fighting disease. In an NIMH-supported long-term study at New York University, spousal caregivers of AD patients were randomly put in either a psychosocial intervention program designed to increase family involvement or a standard minimal support program (controls). The psychosocial intervention provided individual counseling and family counseling as well as participation in support groups. More than 40 percent of these caregivers had clinically significant levels of depressive symptoms at baseline. Over 12 months, those who took part in the intervention program remained stable, whereas control caregivers became more depressed. Caregiver gender and patients' severity of dementia did not significantly predict change in depression over time. On the other hand, the intervention program accounted for 23 percent of the explainable variance in caregivers' depression. These results suggest that while psychosocial programs may relieve some of the burdens of providing long-term care for chronically impaired AD patients, an effective intervention may need to use several strategies, be sustained over time, and involve families in the support process. National Human Genome Research Institute The National Human Genome Research Institute (NHGRI) (formerly the National Center for Human Genome Research) helps identify genes involved in human diseases and the function of these genes and their products. The Human Genome Project provides data, material resources, and technology that will improve the ability of scientists to conduct biological research rapidly, efficiently, and cost-effectively; and supports a vigorous research program on the ethical, legal, and social implications of human genome research. In the laboratories of the Division of Intramural Research, using the tools produced by the Human Genome Project, scientists are developing and using the most advanced techniques to study the fundamental mechanisms of inherited and acquired genetic disorders. The NHGRI supports researchers at Case Western Reserve University who are examining ethical and policy issues regarding current genetic susceptibility testing for late-onset AD, as well as the ethical aspects of ongoing genetic testing in families with early-onset AD. A Community Advisory Board and National Study Group were established to: examine current testing developments in AD genetics, their applicability to people before symptoms arise, and clinical usefulness consider costs of testing, potential groups of participants for testing, and justice in access to testing address the potential effect of susceptibility testing on the private long-term care insurance industry develop ethics guidelines for apoE susceptibility testing and APP autosomal dominant mutation testing develop recommendations for the Alzheimer's Association in ensuring public understanding of test developments In addition, a pilot questionnaire study of population attitudes toward apoE susceptibility testing, to be implemented in Chicago, Illinois, is included. This project proceeds in collaboration with the National Alzheimer's Association. To date, a book, The Moral Challenge of Alzheimer Disease, was published by the Johns Hopkins University Press, in December 1995. A second book on the findings of the National Study Group on ethics, genetics, and AD is being developed. In addition, a consensus manuscript from the National Study Group has been published in the Journal of the American Medical Association (March 12, 1997). National Center for Research Resources National Center for Research Resources (NCRR)-funded investigators are conducting AD research in the following areas: the structures of tangles in AD and related dementias, use of MRI to study cerebral blood flow in AD, use of CT scans to predict the rate of cognitive decline in AD, the effect of estrogen during menopause on risk and age at onset of AD, the way hyperinsulinemia may improve memory in AD, the role of apoE in APP buildup, and amyloid-related brain disease in older monkeys. The NCRR-supported resource center at the University of California at San Diego brought together neuroscientists from Japan and the Albert Einstein College of Medicine in an international collaborative effort to examine damaged regions of the hippocampus that are thought to play an important role in cognitive changes in AD and related disorders. Immunologically-based chemical and electron microscopic analyses of tissue from patients with primary degenerative dementias along with their age-matched controls were performed using a specially designed electron microscope to enable viewing of thick sections. Some of the tissue from AD patients and patients with related disorders (such as Lewy body dementia and progressive supranuclear palsy), but not from age-matched controls, reacted positively to the antibodies used. These findings indicate that neurofibrillary changes in all three of these neurodegenerative disorders have similar internal support structures. Investigators at the General Clinical Research Center (GCRC) at the New England Medical Center in Boston used a new imaging technique, called dynamic susceptibility contrast MRI, to discriminate older patients with AD. Older patients with AD had a much lower blood volume in some parts of their brains. These scientists concluded that this new MRI technique is a low-cost and safe method for evaluating AD. Some brain structures, such as the hippocampus and the amygdala, are severely affected even early in the course of AD. CT scans have shown a relationship between enlargement of the suprasellar cistern (SSC), a fluid-filled area in the base of the brain, and decline in cognitive function in AD patients. Investigators at Johns Hopkins University used this technique to predict future rates of cognitive decline. Twenty patients with diagnoses of probable AD received initial CT scans and then returned every 6 months for evaluation of their cognitive function. The interval between the initial testing and the most recent evaluation ranged between 12 and 67 months (the mean was 40.5 months). The investigators found that the size of the SSC correlated with a decline in cognitive function as measured by several mental tests, indicating that CT measurement of the SSC can predict the rate of decline in cognitive function in AD patients. Estrogen use by postmenopausal women has many health benefits, but its effects in women with AD are not clear. Researchers at the Columbia University GCRC explored whether the use of estrogen could lower the risk of AD in 1,124 older women. (For more information about this research, see Estrogen Replacement Therapy and Alzheimer's Disease.) Growing evidence suggests that disruption of glucose regulation accompanies AD and may contribute to the severe memory impairment associated with the disease. NIA- and NCRR-funded investigators at the Washington University GCRC in St. Louis, Missouri, studied the effects of insulin and glucose in 22 patients with AD and 13 healthy adults. They found that raising insulin levels in the blood stream improved memory in the AD patients even when glucose levels did not change. Higher levels of glucose in the blood stream also improved memory, but not to the same extent as the higher insulin levels. These scientists also report that patients with AD have abnormal levels of some hormones that regulate glucose, and suggest that neuroendocrine factors play an important role in the development of AD. Researchers at the University of Alabama are using a laboratory cell culture system to study the effects of genetically-induced overexpression of apoE. The researchers have discovered that apoE overexpression in this cell system significantly inhibits the aggregation of a protein fragment of beta-amyloid, indicating that apoE may be involved in the regulation of amyloid buildup. Brains from 81 rhesus monkeys were collected to study the incidence and cerebral regional distribution of beta-amyloid plaques and amyloid-related blood vessel disease in the brains of autopsied rhesus monkeys. Different age groups were collected from autopsy cases performed at the University of Wisconsin Regional Primate Research Center during the past 14 years. Beta-amyloid and APP in the plaques were detected by chemical staining. No amyloid plaques were found in the brains of 16- to 19-year-old monkeys (8 cases). In aged groups, the average rates of the plaque or blood vessel lesions were 20.8 percent in the 20 to 25 year group (24 cases), 60.9 percent in the 26 to 31 year group (41 cases), and 100 percent in the 33 to 39 year group (8 cases). Among 38 cases showing amyloid plaque lesions, 10 were accompanied by amyloid-related damage in the cerebral and meningeal blood vessels. No neurofibrillary tangles were detected in these brain lesions. Twelve cases in the aged monkeys had an involvement of visceral amyloidosis in the liver, adrenal, or the islets in the pancreas; and 7 of 12 had cerebral amyloidosis. The amyloid in the visceral organs showed no cross reactivity with beta-amyloid and precursor proteins. It appears that there is no disease-based correlation between cerebral and visceral myloidosis. As in the aged human population, the aged monkey also spontaneously develops AD-type brain lesions. National Institute of Nursing Research The National Institute of Nursing Research (NINR) supports research on the biobehavioral aspects of AD and related dementias. The primary focus has been on dealing with behavioral, physical, and functional problems, such as wandering, agitation, and sleep disturbances. NINR-supported researchers at the University of Iowa in Iowa City have developed a caregiver training protocol that focuses on the setting in which caring for people with AD occurs. The program is based on the need to deal with the caregiver's increasing inability to cope with both environmental and internal stressors because of the patient's progressive cerebral pathology and associated cognitive decline. The model, the Progressively Lowered Stress Threshold, seeks to reduce stress by changing environmental demands to promote adaptive behavior. The model can be used in a variety of settings, including the home, and can be taught to family caregivers. The family caregiver training protocol consists of two 2-hour sessions and a 1-hour in-home followup session 1 week later. Preliminary data have shown increased socialization; stable weight or gain in weight; and a reduction of psychotropic or neuroleptic medications, sedatives, and tranquilizers among patients whose caregivers received training. In addition, agitation and wandering episodes were decreased. Initial findings in another study at the University of Texas Health Sciences Center at San Antonio indicate an alternative approach for managing problem behaviors. The strategy was based on a cognitive functional age approach to dementia. It has been noted that patients seem to lose their cognitive and functional abilities in a reverse order to that followed during the acquisition of those abilities. Researchers designed the interventions using a Piagetian model for assessment of cognitive functioning in conjunction with existing staging and assessment models. Preliminary findings show a decrease in problem behaviors while reducing the number of psychotropic medications. Outlook Investigators do not know yet how the various factors that may play a role in AD interrelate. In the next year, researchers will continue to study known genes and other risk factors and look for other genes and risk factors that might be linked to AD. Epidemiology studies will compare and identify environmental and genetic risk factors in diverse populations. Scientists also will study other disorders, such as strokes, to see if they affect the development or symptoms of AD. Identification of genes implicated in AD provides new opportunities for analysis of the initiating cellular events, how the protein products affect these events, as well as how the initiating events lead to the well-recognized pathology of AD. For example, many questions exist about the relationships of presenilin mutations to the development and production of amyloid in AD. Current challenges include finding and understanding additional mutations; determining how presenilins 1 and 2 are produced and processed, how they interact with cellular systems, and whether they play a role in nerve cell death and the development of late-onset AD; learning the effect of different presenilin mutations on APP metabolism and other cellular events; and comparing how presenilin 1 and 2 levels in cells change over the lifespan of healthy people and those with AD. Mutations in the APP gene were discovered prior to those in the presenilins, and the knowledge base on the regulation and function of this precursor of beta-amyloid is correspondingly greater. Now, important steps for AD researchers will be to search for more receptors affected by beta-amyloid; understand the pathways involved in and look for substances that fight oxidative stress and beta-amyloid production; and determine the relationship between amyloid deposits and the other neuropathologies of AD. Much work also is being done to discover why cells stop functioning properly and die in AD. Ongoing research to produce transgenic animal models (e.g., for the various genetic forms of FAD) will aid researchers' understanding of the molecular mechanisms involved in AD development and help them identify treatments to retard disease progression. For example, comparing behavioral and anatomical approaches, researchers will be able to determine if the appearance of the plaques in transgenic mice carrying human APP mutations comes before or after the learning and memory problems. Scientists also are trying to develop ways to stop plaque formation and determine whether plaque formation is linked causally to cognitive changes. So far, older transgenic mice with defects in the presenilin genes have not developed plaques or memory impairment. The challenge is to breed mice that develop AD-like symptoms so that investigators can study the mechanisms underlying their development. Plausible theories and evidence link both the presenilins and apoE to ways the body handles APP. Whether this is solely linked to beta-amyloid deposition or is, as well, related to the biological activity of APP is being investigated. What researchers are able to learn from the mouse model may help bring all of these findings together to form a coherent explanation of what causes AD, both in FAD and in late-onset AD. In the clinic, scientists working to improve the diagnosis of AD seek to: validate and refine current recommended procedures; establish if differences in disease patterns in AD reflect genetic- and gender-based factors; determine how age affects the clinical and pathological criteria; find tests to determine which people with mild cognitive impairment will progress to clinical AD; develop biochemical and molecular methods for quickly diagnosing AD and compare the results to data obtained from currently recommended methods; standardize diagnostic methods and agents used at autopsy; develop and standardize quantitative methods; and determine the nature and significance of white matter pathological changes in AD. ADCS investigations of estrogen, anti-inflammatory agents, and AIT-082 are examples of many efforts to test promising new treatments for AD. Preliminary data suggest that AIT-082 stimulates the production of neurotrophins, natural proteins that protect nerve cells from damage and enhance the regrowth of damaged nerve tissue. AIT-082 also stimulates cognitive function and memory in aged animals. As with other promising agents, the effectiveness of AIT-082 will only become known after lengthy and costly clinical trials. One future direction for ADCS scientists is to test the effectiveness of vitamin E in people with mild cognitive impairment to determine whether this vitamin can reduce the number of people who would otherwise progress to more advanced stages of AD. This will be the first study to identify people at risk and bring them into a clinical trial. Eventually, the goal is to identify people at risk before they develop any signs of the disease and treat them with a drug (or a combination of drugs) that will slow or halt development of clinical AD. Studies also continue to aid people who currently have AD and their caregivers. The ADCS plans additional studies of drugs used to treat the behavioral symptoms of AD. Members of the consortium currently are analyzing data from a clinical trial of the effectiveness of trazodone, haldol, and behavioral management in preventing or reducing agitation. In addition to further studies of SCUs in nursing homes and special care in other residential settings, researchers seek to develop a framework for evaluating non-institutional care. Two recently funded NIA studies are using measures similar to those developed in the original SCU Initiative to examine the outcomes of residential care for people with dementia. Research also will continue into caring for special populations to understand factors that influence minority and ethnic families, rural caregivers, employed caregivers, and male caregivers. In addition, scientists will study changing care structures; the interplay among older people, their families, and care settings; and the effects of these factors on an older person's ability to stay mentally and physically healthy. Major recent advances in our understanding of AD hold promise for an accelerated pace of discovery into the causes and processes of this tragic disease. Recent findings also increase our ability to delay the progression of symptoms and bring us closer to being able to prevent and perhaps cure AD. For further information about Alzheimer's disease, please contact: Alzheimer's Disease Education and Referral (ADEAR) Center PO Box 8250 Silver Spring, Maryland 20907-8250 800-438-4380 301-495-3334 (fax) http://www.alzheimers.org Published in November 1997