Progress Report on Alzheimer's Disease, 1999 Contents: * Introduction o The Impact of Alzheimer's Disease o Alzheimer's Disease: An Urgent National Health and Research Priority * The AD Research Effort * Alzheimer's Disease: A Puzzle Being Solved * What Are the Main Characteristics of AD? o Amyloid Plaques o Neurofibrillary Tangles o Genetic Factors in AD Development o Non-Genetic Factors in AD Development * What Do We Know About Diagnosing AD? * How Can Alzheimer's Disease be Treated? * 1999 AD Research Advances: Building on the Foundation * Understanding the Etiology of AD o Amyloid o Presenilins o Tauopathies and Tangles o Genetic Links to Late-Onset AD o Inflammation o Oxidative Stress o Brain Infarction o Diet * Improving Early Diagnosis o Mild Cognitive Impairment o Neuroimaging * Developing Drug Treatments o Treating Cognitive Decline o Slowing the Progress, Delaying the Onset, or Preventing the Disease o Treating Behavioral Symptoms * Future Considerations for AD Clinical Research o Improving Support for Caregivers o REACH o Special Care Units o Building a Research Infrastructure o Innovative Mechanisms for Funding AD Research * Support for AD Research by Other NIH Institutes o National Institute of Neurological Disorders and Stroke o National Institute of Mental Health o National Institute of Nursing Research o National Institute on Alcohol Abuse and Alcoholism o National Center for Research Resources o National Institute of Child Health and Human Development o National Institute of Environmental Health Sciences o National Institute on Deafness and Other Communication Disorders * Outlook for the Future * References (Abstracts From Medline) ------------------------------------------------------------------------ *_INTRODUCTION_* Alzheimer's disease (AD) is an irreversible, progressive brain disorder that occurs gradually and results in memory loss, behavior and personality changes, and a decline in thinking abilities. These 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 for 8 to 10 years after they are diagnosed, though the disease can last for up to 20 years. AD advances by stages, from early, mild forgetfulness to a severe loss of mental function. This loss is called dementia. In most people with AD, symptoms first appear after age 60. The earliest symptoms often include loss of recent memory, faulty judgment, and changes in personality. Often, people in the initial stages of 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, such as washing their hands. Eventually, people with AD lose all reasoning ability and become dependent on other people for their everyday care. Finally, the disease becomes so debilitating that patients are bedridden and likely to develop other illnesses and infections. Most commonly, people with AD die from pneumonia. Although the risk of developing AD increases with age, AD and dementia symptoms are not a part of normal aging. AD and other dementing disorders are caused by diseases that affect the brain. In the absence of disease, the human brain often can function well into the tenth decade of life. ------------------------------------------------------------------------ *The Impact of Alzheimer's Disease* AD is the most common cause of dementia among people age 65 and older. It presents a major health problem for the United States because of its enormous impact on individuals, families, the health care system, and society as a whole. Scientists estimate that up to 4 million people currently suffer with the disease, and the prevalence (the number of people with the disease at any one time) doubles every 5 years beyond age 65. It is also estimated that approximately 360,000 new cases (incidence) will occur each year, though this number will increase as the population ages (Brookmeyer et al., 1998). A number of research groups have examined differences in AD prevalence among racial and ethnic groups, and it appears from some studies that the risk is higher for African Americans and Hispanic Americans than it is for Caucasians, though not all studies provide similar results. These differences are important to study, not only because of the growing percentage of non-Caucasians in the older U.S. population (by the year 2050, the percentage of the population over the age of 85 that is non-Caucasian will have increased from 16 percent to 34 percent), but because the variations in prevalence may reflect different roles of particular genetic and environmental factors in the development of AD. AD puts a heavy economic burden on society. A recent study estimated that the annual cost of caring for one AD patient is $18,408 for a patient with mild AD, $30,096 for a patient with moderate AD, and $36,132 for a patient with severe AD. The annual national cost of caring for AD patients is estimated to be slightly over $50 billion (Leon et al., 1998). These numbers gain significance when they are placed against the backdrop of increasing life expectancy and changing demographics in the United States. Since the turn of the century, life expectancies have increased dramatically. More than 34 million people--13 percent of the total population of the United States--are now aged 65 and older. According to the U.S. Bureau of the Census, this percentage will accelerate rapidly beginning in 2011, when the first baby boomers reach age 65, and will reach 18 percent of the total population by the year 2025. Approximately 4 million Americans are 85 or older, and in most industrialized countries, this age group is one of the fastest growing segments of the population. The Bureau of the Census estimates that this group will number nearly 8.5 million by the year 2030; some experts who study population trends suggest that the number could be even greater. As more and more people live longer, the number of people affected by diseases of aging, including AD, will continue to grow. For example, some studies show that nearly half of all people age 85 and older have some form of dementia. Slightly more than half of AD patients receive care at home, while the remainder are in many different types of health care institutions. Many spouses, relatives, and friends take care of people with AD. During their years of caregiving, these families and friends experience emotional, physical, and financial stresses. They watch their loved ones become more and more forgetful, frustrated, and confused. Eventually, the person with AD may not even recognize his or her nearest and dearest relatives and friends. Caregivers--most of whom are women--must juggle child care, jobs, and other responsibilities with caring 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 difficult decisions about the long-term care of their loved ones. Frequently, they have no choice but to place their relative in a nursing home. The numbers of caregivers--and their needs--can be expected to grow significantly as the population ages and as the number of people with AD increases. ------------------------------------------------------------------------ *Alzheimer's Disease: An Urgent National Health and Research Priority* Given our aging population, the magnitude of AD as a national health problem is steadily increasing, making the disease an urgent research priority. Interventions that could delay the onset of AD will have an enormous positive public health impact because they will reduce the number of people with the disease at any one time. This in turn will reduce the costs associated with caring for them. A recent epidemiologic study provides a vivid illustration of the impact of delaying AD by even a short period of time: "If onset could be delayed, on average, 1 year, there would be nearly 210,000 and 770,000 fewer persons afflicted with Alzheimer's disease than projected 10 and 50 years after initiation of the intervention, respectively. If onset could be delayed, on average, only 6 months, there would be nearly 100,000 and 380,000 fewer persons afflicted with Alzheimer's disease than projected after 10 and 50 years, respectively....An average 1-year delay in disease onset would result in an annual savings of nearly $10 billion at 10 years after initiation of the intervention....Even a modest 6-month delay would correspond to an annual savings of perhaps $4.7 billion at 10 years after initiation of the intervention and nearly $18 billion annually after 50 years" (Brookmeyer et al., 1998). ------------------------------------------------------------------------ *The AD Research Effort* AD research supported by the Federal Government 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 also are looking for better ways to diagnose AD in the early stages and to identify the earliest brain changes that eventually result in AD. Investigators are striving to identify 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. Finally, scientists and many health care professionals are seeking better ways to help patients and caregivers cope with the decline in mental and physical abilities and the problem behaviors that accompany the disease and to support caregivers of people with AD. The National Institute on Aging (NIA), part of the Federal Government's National Institutes of Health (NIH), has primary responsibility for research aimed at finding ways to prevent, treat, and cure AD. The Institute's AD research program is integral to one of its main goals, which is to enhance the quality of life of older people by expanding knowledge about the aging brain and nervous system. The 1999 Progress Report on Alzheimer's Disease summarizes AD research conducted or supported by NIA and other components of NIH, including: * National Institute of Neurological Disorders and Stroke * National Institute of Mental Health * National Institute of Nursing Research * National Institute on Alcohol Abuse and Alcoholism * National Center for Research Resources * National Institute of Child Health and Human Development * National Institute of Environmental Health Sciences * National Institute on Deafness and Other Communication Disorders Other more modest AD research efforts not summarized in this report are supported by the National Cancer Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, and the Fogarty International Center. Twenty-five years ago, we knew relatively little about the processes in the brain that lead to Alzheimer's disease. Physicians assumed that AD dementia was merely an inevitable consequence of aging. Scientists have made enormous progress since then. Today, we know much more about Alzheimer's--what it is, who gets it, how it develops, and what course it follows. We have also made significant progress in the critical area of early diagnosis and have some promising leads on possible treatments. All of this research has deepened our understanding of this devastating disease. It also has expanded our knowledge about brain function in healthy older people and ways in which to minimize normal age-related cognitive decline. The 1999 Progress Report on Alzheimer's Disease is a window on this important research effort. It begins with a summary of our current knowledge about AD. This summary provides the backdrop for the next two sections, which present highlights of recent research conducted by NIA and other NIH Institutes. The report closes with a section called "Outlook for the Future," which describes the new NIH Alzheimer's Disease Prevention Initiative. AD research has progressed to a point where scientists, while still thinking about the basic biology of the disease, are increasingly able to consider strategies for slowing AD's progress, delaying its onset, or even preventing it altogether. The Prevention Initiative is designed to accelerate laboratory and clinical research and collaboration across the Federal Government and the private sector to make these strategies not a future possibility but a current reality. ------------------------------------------------------------------------ *_ALZHEIMER'S DISEASE: A PUZZLE BEING SOLVED_* In normal aging, nerve cells in the brain are not lost in large numbers. In contrast, AD disrupts three key processes--nerve cell communication, metabolism, and repair. This disruption ultimately causes many nerve cells to stop functioning, lose connections with other nerve cells, and die. At first, AD destroys neurons in parts of the brain that control memory, especially the hippocampus (a structure deep in the brain that helps encode memories) and related structures. As nerve cells in the hippocampus stop functioning properly, short-term memory fails, and often, a person's ability to do easy and familiar tasks begins to decline. AD also attacks the cerebral cortex, particularly the areas responsible for language and reasoning. Here, AD begins to take away language skills and change a person's ability to make judgments. Personality changes also may occur. Emotional outbursts and disturbing behavior, such as wandering and agitation, begin to happen and become more and more frequent as the disease runs its course. Eventually, many other areas of the brain are involved, all these brain regions atrophy (shrink), and the AD patient becomes bedridden, incontinent, totally helpless, and unresponsive to the outside world. ------------------------------------------------------------------------ *What Are the Main Characteristics of AD?* Two abnormal structures in the brain are the hallmarks of AD: amyloid plaques and neurofibrillary tangles. Plaques are dense, largely insoluble (cannot be dissolved) deposits of protein and cellular material outside and around the brain's neurons (nerve cells). Tangles are insoluble twisted fibers that build up inside neurons. Though scientists have known about plaques and tangles for many years, more recent research has revealed much about their composition, how they form, and their possible roles in the development of AD. *Amyloid Plaques* In AD, plaques develop first in areas of the brain used for memory and other cognitive functions. They consist of largely insoluble deposits of beta-amyloid--a protein fragment snipped from a larger protein called amyloid precursor protein (APP)--intermingled with portions of neurons and with non-nerve cells such as microglia (cells that surround and digest damaged cells or foreign substances that cause inflammation) and astrocytes (cells that serve to support neurons). Researchers still do not know whether amyloid plaques themselves cause AD or whether they are a by-product of the AD process. Certainly, changes in the APP protein can cause AD, as shown in the inherited form of AD caused by mutations in the APP gene (see p. 13 for more on inherited AD). APP is one of many 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. After it is made, APP becomes embedded in the nerve cell's membrane, partly inside and partly outside the cell, like a needle poking through a piece of fabric. Recent studies using transgenic (genetically engineered) mice show that APP appears to play an important role in the growth and survival of neurons. For example, certain forms and amounts of APP may protect neurons against both short- and long-term damage. In test tube studies, scientists have found that APP may play a role in making damaged neurons better able to repair themselves and help parts of neurons grow after brain injury. While APP is embedded in the cell membrane, proteases (a particular kind of enzyme, or substance, that speeds up or causes chemical reactions in the body--in this case, cutting proteins into fragments) act on particular sites in APP, cleaving it into protein fragments. One protease helps cleave APP to form beta-amyloid, and another protease cleaves APP in the middle of the amyloid fragment so that beta-amyloid cannot be formed. The beta-amyloid formed is of two different lengths, a shorter beta-amyloid that is more soluble and aggregates slowly, and a slightly longer, "sticky" beta-amyloid that rapidly forms insoluble clumps. While beta-amyloid is being formed, scientists do not yet know exactly how it moves through or around nerve cells. In the final stages of this process, the "sticky" beta-amyloid aggregates into long filaments outside the cell and, along with fragments of dead and dying neurons and the microglia and astrocytes, forms the plaques that are characteristic of AD in brain tissue. Many studies have centered on identifying the enzymes that cause beta-amyloid to be formed and on determining exactly how they work. By seeking clues in the beta-amyloid environment, scientists hope to understand just how beta-amyloid aggregates to form the plaques that build up in huge numbers in particular regions of the brain. Results from very recent research suggest that beta-amyloid is formed inside a part of the cell called the trans-Golgi network. Other work has found that certain organelles in the neuron, called early endosomes, are much larger in brains affected by some forms of AD than are endosomes in healthy brains, giving scientists clues about some intracellular processes affected by AD. It is logical to expect that as the disease progresses, more and more plaques will be formed, filling more and more of the brain. However, this is not necessarily the case. In fact, the amount of beta-amyloid often seems to be relatively constant over time. Studies with a confocal scanning laser microscope, which allows investigators to view the three-dimensional structure of plaques, have revealed that plaques are not solid, but have minute holes through them. It may be that the beta-amyloid is aggregating and disaggregating at the same time, in a sort of dynamic equilibrium. This raises the hope that it may be possible to break down the plaques after they have formed. Many scientists believe that beta-amyloid is toxic to neurons, perhaps by causing inflammation in the brain or by generating free radicals (a particular type of molecule that easily reacts with other molecules and that can be harmful if too many are produced). Another harmful effect of beta-amyloid may be that it makes neurons more susceptible to different kinds of damage, for example that caused by ischemia (poor blood flow). The neurons become more susceptible because beta-amyloid disrupts connections between cells in the immediate area around the plaque and reduces the ability of some blood vessels in the brain to dilate and compensate for the diminished blood flow. Beta-amyloid could also cause damage by increasing intracellular calcium. Calcium is an element that helps cells do many things, including carry nerve signals. However, too much calcium inside cells leads to cell death. ------------------------------------------------------------------------ *Neurofibrillary Tangles* This second hallmark of AD consists of abnormal collections of twisted threads found inside nerve cells. The chief component of tangles is one form of a protein called tau. In the central nervous system, tau proteins are best known for their ability to bind and help stabilize microtubules, which are one constituent of 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 axon, a long thin structure that extends far out from the cell body and forms a communicating bridge with other neurons. In cells affected by AD, the train track structures collapse. Tau normally forms the "railroad ties" or connector pieces of the microtubule tracks. However, in AD tau is changed chemically, and this altered tau can no longer hold the railroad tracks together, causing the microtubules to fall apart. This collapse of the transport system first may result in malfunctions in communication between nerve cells and later may lead to neuronal death. In AD, chemically altered tau twists into paired helical filaments--two threads of tau that are wound around each other. These filaments are the major substance found in neurofibrillary tangles. In one recent study, researchers found neurofibrillary changes in fewer than 6 percent of the neurons in a particular part of the hippocampus in healthy brains, in more than 43 percent of these neurons in people who died with mild AD, and in 71 percent of these neurons in people who died with severe AD. When they studied the loss of neurons, they found a similar progression. Evidence of this type supports the idea that the formation of tangles and the loss of neurons progress together over the course of AD. ------------------------------------------------------------------------ *What Causes AD?* Knowing the clinical and behavioral characteristics of AD is one important part of solving the AD puzzle. Another is knowing the cause of the disease: What makes the disease process begin in the first place and what contributes to its development? Why does its prevalence increase with age? Some diseases, like tuberculosis, have clear-cut causes. Others, such as diabetes or arthritis, result from many interrelated factors, including genetic, environmental, and other factors. AD fits into this latter group of diseases. Scientists do not yet fully understand what causes AD, but it is clear that AD develops as a result of a complex cascade of events that takes place over time inside the brain. The disease can be triggered by any number of small changes in this cascade, and these events interact differently in different people. Researchers have come a long way toward elucidating the genetic and non-genetic factors that contribute to the development of AD. *Genetic Factors in AD Development* Two types of Alzheimer's disease exist: familial AD (FAD), which follows a certain inheritance pattern, and sporadic AD, where no obvious inheritance pattern is seen. Because of differences in the age at onset, AD is further described as early-onset (occurring in people younger than 65) or late-onset (occurring in those 65 and older). Early-onset AD is rare (about 10 percent of cases) and generally affects people aged 30 to 60. Some forms of early-onset AD are inherited and run in families. Early-onset AD also often progresses faster than the more common, late-onset form. All FAD known so far has an early onset, and as many as 50 percent of FAD cases are now known to be caused by defects in three genes located on three different chromosomes. These are mutations in the APP gene on chromosome 21; mutations in a gene on chromosome 14, called presenilin 1; and mutations in a gene on chromosome 1, called presenilin 2. Even if one of these three mutations is present in only one of the two genes inherited from the parent, the person will inevitably develop that form of early-onset AD. There is as yet no evidence, however, that any of these mutations play a major role in the more common, sporadic or non-familial form of late-onset AD. Scientists are now working to reveal the normal function of APP and presenilins and to determine how mutations of these genes cause the onset of FAD. Some evidence exists that the mutations in APP make it more likely that beta-amyloid will be snipped out of the APP precursor, thus causing either more total beta-amyloid or relatively more of the "sticky" form to be made. It appears that the presenilin mutations may contribute to the degeneration of neurons in at least two ways: by modifying beta-amyloid production or by triggering the death of cells more directly. Most people with early-onset AD and presenilin 1 and 2 mutations have more of the longer and "stickier" form of beta-amyloid in their brains than do those with the sporadic form. This suggests that mutations in the presenilins can in some way drive the production of this form of amyloid. Another theory about the possible roles for mutated presenilins in altering the production of beta-amyloid is that they interact directly with APP on the surface of neighboring cells, an interaction that eventually triggers beta-amyloid production. Other researchers suggest that mutated presenilins 1 and 2 may be involved in accelerating the pace of apoptosis, a name for one way in which cells are programmed to die. Genetics play a role in the development of late-onset AD as well as FAD. In the early 1990s, researchers at the NIA-supported Alzheimer's Disease Center at Duke University in Durham, North Carolina, found an increased risk for late-onset AD with inheritance of one or two copies of the apolipoprotein E epsilon4 (APOE e4) allele on chromosome 19 (Strittmatter et al., 1993). An allele is one of two or more possible versions of the same gene, each of which has a slightly different base sequence from the others (polymorphism). Different alleles produce variations in inherited characteristics, such as eye color or blood type. In this case, the variations are in the gene that directs the manufacture of the ApoE protein, which helps carry blood cholesterol throughout the body, among other functions. It is found in glial cells and neurons of healthy brains, but it is also associated in excess amounts with the plaques found in the brains of people with AD. AD researchers are particularly interested in three common alleles of the APOE gene: e2, e3, and e4. The finding that increased risk is linked with inheritance of the APOE e4 allele has helped explain some of the variations in age of onset of AD based on whether people have inherited zero, one, or two copies of the APOE e4 allele from their parents. The relatively rare APOE e2 allele may protect some people against the disease; it seems to be associated with a lower risk for AD and later age of onset if AD does develop. APOE e2 also appears to protect people with Down syndrome from developing AD-like damage. APOE e3 is the most common version found in the general population and may play a neutral role in AD. The mere inheritance of one or two APOE e4 alleles does not predict AD with certainty; that is, unlike early-onset FAD, a person can have one or two APOE e4 alleles and not get the disease and a person who develops AD may not have any APOE e4 alleles. The ways in which the ApoE e4 protein increases the likelihood of developing AD are not known with certainty, but one possible theory is that it facilitates beta-amyloid buildup and this contributes to lowering the age of onset of AD. Several new candidates for additional AD risk factor genes for late-onset disease have recently been identified, and this is an exciting avenue for new research. Building on the improving understanding of AD genetics, scientists can continue to look for clues as to which protein structures hasten the initiation of the disease process, what mechanisms cause AD, and what the sequence of events is. Once they understand these, they can then look for new ways to diagnose, treat, or even prevent AD. One of the most intriguing issues in this area is possible differences in risk among various racial and ethnic groups. Some recent studies have shown that carrying an APOE e4 allele is a greater determinant of risk of AD in Caucasians than it is in Hispanic Americans or in African Americans. However, African Americans and Hispanic Americans may have a higher overall risk of AD than do Caucasians (Tang et al., 1998). Other studies have found conflicting results (Fillenbaum et al., 1998). Clearly, further investigation is needed to examine the role that ethnic and racial differences play in determining the risk of AD and the contribution of APOE and other genes to this risk. Current NIA-funded studies should provide some answers. ------------------------------------------------------------------------ *Non-Genetic Factors in AD Development* Researchers have also investigated a number of avenues related to non-genetic factors involved in AD. Exploration of these factors may suggest new theories about the mechanisms involved in triggering or continuing the disease process. One promising area relates to a longstanding theory of aging. This theory suggests that the buildup of damage from oxidative processes in neurons causes a loss of function. Scientists believe that particular types of molecules, called free radicals, which are themselves short-lived and produced through normal metabolic mechanisms, play a role in several diseases, including cancer and AD. The body produces free radicals as a by-product of metabolism, and free radicals may help cells in certain ways, such as in fighting infection. However, too many free radicals can injure cells because free radicals are highly reactive and can readily modify other nearby molecules, such as those in the cell membrane or in DNA. The resulting, newly combined molecule can then set off a chain reaction, releasing additional free radicals that can further damage neurons. Oxidative damage due to free radicals may contribute to the development of AD by several means, including upsetting the delicate membrane machinery that regulates the flow of substances in and out of the cell, and altering the structure of certain proteins. Unique characteristics of the brain, including its high rate of metabolism and the long life span of its non-dividing cells, may make it particularly vulnerable to oxidative stress. Another promising possibility is that inflammation in the brain may play an important role in AD. Brain inflammation increases with age, but it is much more pronounced in AD patients. Investigators have both direct and indirect evidence that inflammation contributes to AD damage. Indirect evidence comes from the fact that in epidemiologic studies and in the NIA's intramural Baltimore Longitudinal Study of Aging, frequent use of anti-inflammatory agents is correlated with a decreased prevalence of AD (Stewart et al., 1997). More direct evidence comes from the fact that various compounds known to be involved in inflammatory processes can be found in AD plaques, and a number of studies suggest ways in which inflammatory pathways could destroy neurons in an ever-repeating vicious cycle (Griffin et al., 1998). Many scientists are currently conducting studies to understand this process more fully and to explore possible therapeutic approaches that involve anti-inflammatory medications. In a third area, investigators at the Sanders-Brown Center on Aging and the NIA-supported Alzheimer's Disease Research Center at the University of Kentucky in Lexington have demonstrated a possible link between brain infarction (stroke) and AD. A brain infarction is an area of injury in brain tissue that usually occurs when the blood supply to that area is interrupted, depriving neurons of essential oxygen and glucose. The researchers have been working with a group of 678 elderly nuns from the School Sisters of Notre Dame who live in convents throughout the United States. In this long-term study of aging and AD, each participating sister agrees to have a yearly physical and cognitive examination and to donate her brain to the study at her death. Results from this ongoing work show that study participants who had had infarctions in certain brain regions had more clinical symptoms of dementia than could be explained by the number of plaques and tangles in their cerebral cortex (Snowdon et al., 1997). These findings suggest that some brain infarcts, which may not themselves be sufficient to cause dementia, may play an important role in increasing the severity of AD's clinical signs. Other diseases related to the brains' blood vessels or blood supply, such as atherosclerosis, also may be involved in the development of AD. Finally, it is becoming clear that there are important parallels between AD and other neurological diseases, including prion diseases, Parkinson's disease, Huntington's disease, and fronto-temporal dementia. All involve deposits of abnormal proteins in the brain. Dr. Stanley Prusiner won the 1997 Nobel Prize in Physiology or Medicine for his discovery of prions, a novel and controversial infectious type of protein. AD and prion diseases, such as Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy ("mad cow disease"), cause dementia and death, and both are associated with the formation of insoluble amyloid fibrils, but from membrane proteins that are different from each other. Findings from studying amyloid formation in prion diseases may be useful in studying the similar process in AD. In 1997, scientists studying Parkinson's disease, the second most common neurodegenerative disorder after AD, discovered the first gene linked to the disease. This gene codes for a protein called synuclein, which, intriguingly, is also found in the amyloid plaques of AD patients' brains. Investigators have also discovered that genetic defects in Huntington's disease, another progressive neurodegenerative disorder that causes dementia, cause the Huntington protein to form into insoluble fibrils very reminiscent of the beta-amyloid fibrils of AD and the protein fibrils of prion disease. Thus, research into each of these neurologic disorders is yielding unexpected insights into the other diseases. ------------------------------------------------------------------------ *What Do We Know About Diagnosing AD?* Currently, clinicians use several tools to diagnose "possible AD" or "probable AD" in a patient who is having difficulties with memory or other mental functions. These tools include a patient history, physical exam, laboratory tests, brain scans, and a series of tests that measure memory, language skills, and other abilities related to brain functioning. However, in these patients, AD can be diagnosed conclusively only by examining the brain after death in an autopsy to determine the presence of characteristic plaques and tangles in certain brain regions. The earlier an accurate diagnosis of AD is made, the greater the gain in managing symptoms and determining the natural history of AD. 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 can still take part in making decisions. Researchers have made significant progress in developing accurate diagnostic tests and techniques that can be used in living patients. In specialized research facilities, clinicians can now diagnose AD with up to 90 percent accuracy. For example, work is underway to develop new tests of mental status that might be used to distinguish between people who might have very early AD symptoms and those experiencing age-related normal memory loss. Other investigators have explored the utility of analyzing cerebrospinal fluid for levels of "sticky" beta-amyloid and tau for diagnosing AD. Researchers also have used positron emission tomography (PET) scans, an imaging method in living patients, to see whether they can detect changes in the way glucose is metabolized in parts of the brain that are most affected by AD. Another imaging method, known as single photon emission computed tomography (SPECT), also has been combined with genetic and psychological testing to predict which people with memory problems eventually will develop clinically diagnosed AD. A particularly exciting area of work involves yet another imaging technique in the diagnosis of AD. This technique uses magnetic resonance imaging (MRI) to measure the size of various structures in the brain. Many studies have shown that AD causes some brain structures, particularly the hippocampus, to shrink early on in the disease, and scientists are exploring exactly how early this shrinkage, or atrophy, can be detected. Several teams of NIA-funded scientists have established the usefulness of MRI as a tool to help determine which people with memory problems are in the earliest stages of AD; to identify people who will later be diagnosed with AD; and to measure hippocampal volume to distinguish between people with mild cognitive impairment (MCI) and those with no memory or learning problems, and between people without AD and those with very mild AD. ------------------------------------------------------------------------ *How Can Alzheimer's Disease be Treated?* For those who are already suffering from the effects of AD, the most immediate need is for drugs to control their symptoms, including problem behaviors such as verbal and physical aggression, agitation, wandering, depression, sleep disturbances, and delusions. Treatments are needed that work on many patients, stay effective for a long time, ease a broad range of symptoms, improve patients' cognitive function and ability to carry out activities of daily living, and have no serious side effects. Eventually, scientists hope to develop drugs that attack fundamental AD processes, preventing them from damaging function and quality of life. The Food and Drug Administration has approved two medications for AD. Both act by inhibiting acetylcholinesterase, an enzyme that normally breaks down acetylcholine, a key neurotransmitter in cognitive functioning. This neurotransmitter is produced by one set of neurons that are lost in AD. The first of these medications, approved in 1993, was tacrine (Cognex). The second, approved in 1996, was donepezil hydrochloride (Aricept). This drug has less severe side effects than does Cognex and is now commonly used to treat mild to moderate symptoms of AD. However, the drug does not stop or reverse the progression of AD, and it appears to help only some AD patients for a period of time ranging from months to about 2 years, so its usefulness is limited. The growing understanding of the variety of factors involved in AD's development, including oxidative damage and inflammation, have suggested new potentially fruitful avenues for drug treatment research to modify disease progression or to halt it early on. The NIA's intramural Baltimore Longitudinal Study of Aging and NIA-supported epidemiologic studies are showing that use of estrogen replacement therapy (ERT) and regular use of some non-steroidal anti-inflammatory drugs (NSAIDs) are associated with lower risks of developing AD. Scientists caution, however, that individuals should not take these medications just in hopes of preserving cognitive function or reducing the chances of developing AD. Results from epidemiologic studies do not mean a cause-and-effect relationship, and much research still needs to be done in studies involving human AD patients (clinical trials) to determine whether the treatments are safe and effective and to see whether they have a beneficial effect on AD development or progression. < > ------------------------------------------------------------------------ *1999 AD RESEARCH ADVANCES:BUILDING ON THE FOUNDATION* As can be seen from the previous section, one of the primary characteristics of the NIH AD research effort over the last 25 years has been support for a wide range of studies on many topics by many researchers. Some of these investigations have developed to the point of suggesting new ways of treating AD. All have contributed to building the solid base of knowledge that exists today. This base is pointing scientists in several potentially productive research directions. It is also helping investigators ask better questions about the issues that still remain unclear. During the last year, researchers supported by NIA and other NIH Institutes made advances in a number of areas important to Alzheimer's disease, including: * understanding the etiology of AD--the biological events that cause the changes in brain cells and tissues that lead to AD; * improving early diagnosis; * developing drug treatments; * improving support for caregivers; * and building the research infrastructure. ------------------------------------------------------------------------ *Understanding the Etiology of AD* In the last year, scientists continued to improve their understanding of the complex ways in which aging and genetic and non-genetic factors affect and damage brain cells over time and eventually lead to AD. For example, investigators made progress in unraveling such questions as how and why amyloid plaques form and cause neuronal death; the relationship between various forms of tau and, possibly, impaired function leading to neuronal death; the roles of inflammation and oxidative stress; and the contribution of brain infarctions to the disease. Answers to these questions about the fundamental nature of the disease and the way in which it evolves will help investigators create improved methods for diagnosing AD before a patient has any behavioral symptoms, develop effective treatments, or perhaps someday, even prevent this devastating disease. ------------------------------------------------------------------------ *Amyloid* Scientists know that amyloid in the brain, formed by the aggregation of individual fragments derived from a larger protein, APP, is a prominent feature of AD. Understanding the function of the APP protein itself, apart from its role as the precursor of amyloid, should provide clues to whether APP is involved in the development of the disease. This is a central question that still confronts researchers: Just how does APP biology affect the onset and development of AD? Are APP and beta-amyloid central factors in most forms of the disease or is the disruption of APP metabolism and beta-amyloid deposition only a secondary consequence of some other, more immediate factor? A number of NIH-supported research advances this past year helped reveal some answers. For example, researchers at the University of California at San Francisco (Xu et al., 1999) may have pointed to a possible role of APP in the brain through its involvement in preventing apoptosis. Apoptosis is a series of carefully regulated cellular events that lead eventually to cell death. This biological process is an important part of the normal functioning of developing and adult organisms. However, when this process goes awry, it can have devastating consequences, especially when it occurs in generally irreplaceable cells such as neurons. Activation of the apoptosis process may play a role in AD and other neurological diseases that are characterized by abnormal rates of cell death, so it is an important topic to investigate. In this study, the research team compared the ability of mutant and normal, or "wild-type," forms of APP to protect neurons in tissue culture against apoptosis. The researchers induced apoptosis in the neurons using two well-established methods (stauro-sporine and ultraviolet radiation) and found that wild-type APP inhibited cell death, whereas mutant APP did not. The investigators established that APP worked by interfering with p53 activation. P53 is a tumor suppressor protein that is involved in cell cycle control and apoptosis. In additional experiments, neurons were infected with p53 to directly induce apoptosis. Neurons with wild-type APP survived, whereas those with mutant APP had increased levels of cell death. The researchers conclude that APP can protect neurons by preventing p53 activation and they proposed several different ways in which this could happen. Other NIA-supported investigators have attempted to shed light on the ways in which beta-amyloid deposits in plaques might actually disrupt brain cell function and cause neuronal death. For example, one team of Harvard Medical School researchers used triple immunofluorescent confocal microscopy and three-dimensional reconstructions of specially treated brain tissue samples to study two groups of deceased patients who had been treated at the Massachusetts General Hospital Alzheimer's Disease Research Center. One group had clear clinical histories of AD dementia; the other group had no history of neurological disease. The researchers found that neurites that pass through amyloid deposits in AD lose their normal straight shape and become twisted and longer (Knowles et al., 1999). This lengthening causes tiny delays in the normal communications between nerve cells. The researchers postulate that these delays, occurring over widespread areas of the brain affected by amyloid plaques, could significantly disrupt the cell-cell signaling essential for the particular cognitive functions related to memory, resulting in cognitive impairment and the clinical manifestations of AD. Given that increased beta-amyloid generation, its aggregation into plaques, and the resulting neurotoxicity may lead to AD, scientists are interested in investigating conditions under which beta-amyloid aggregation into plaques might be slowed or blocked. Scientists at the New York University School of Medicine showed that, in test tube studies, a small peptide similar in structure to part of the beta-amyloid itself inhibited beta-amyloid aggregation. Other studies in rats showed that this peptide dissolved preformed fibrils (the thread-like structures at the core of the amyloid plaques) and prevented fibril-induced death of special types of neurons in tissue culture (Soto et al., 1998). Importantly, injection of high levels of the peptide into the brains of rats that had beta-amyloid deposition resulted in smaller beta-amyloid deposits than in control rats that were not injected with peptide. The use of such peptides, which mimic the region of the protein involved in aggregation and prevent it, may be a useful strategy to treat not only AD but also a number of other neurodegenerative diseases involving abnormal protein aggregation. In another study, which also focused on the formation of amyloid, scientists at Evanston Northwestern Healthcare Research Institute used an atomic force microscope to study beta-amyloid in the process of forming fibrils. They found precursors to insoluble amyloid, which were freely diffusible small amyloid aggregates. The experiments suggested that these precursors might actually be more toxic than plaque amyloid (Lambert, M.P. et al., 1998). These results were obtained in tissue culture and it is not yet certain whether those small aggregates actually exist in the human brain and, if they do, whether they are actually more toxic than the insoluble plaque amyloid. In another study examining APP's and amyloid's role in the development of AD, the University of California at San Francisco research team used a transgenic mouse model to show that overproduction of a human mutant APP in hippocampal neurons causes damaging neurophysiologic changes in the synapse and synapse loss well before any amyloid plaques build up (Hsia et al., 1999). These results underscore the fact that deposits of amyloid plaques outside the cells may not be necessary for the function of neurons to become severely impaired. The investigators note that caution has to be exercised when extrapolating these animal findings to human AD. However, both this study and that of Lambert and colleagues suggest that therapeutic drugs that only target plaque deposition might not be as effective as drugs that prevent build-up of newly formed beta-amyloid. Other recent studies have attempted to gain further insights into the APOE gene itself and how it affects a person's risk of developing AD. For example, one large non-Federal study conducted in France examined the impact of several APOE polymorphisms in the regulatory region of the APOE gene and found that these differences also can have an impact on the development of AD quite apart from the APOE e4 risk (Lambert, J.C. et al., 1998). Two of the three polymorphisms examined by this research team may have a deleterious effect, while the other may be protective. The investigators conclude that these and other differences, together with whatever risks are associated with the different APOE alleles (e2, e3, or e4) themselves may contribute to the overall risk of developing late-onset AD. Another study, conducted by researchers at the Washington University Medical Center, St. Louis, Missouri, used a well-developed transgenic mouse model to show that certain factors, such as the ApoE protein, can indeed influence AD-like plaque formation (Holtzman et al., 1999). This study lays the foundation for further studies to elucidate the mechanisms that underlie the clearance or aggregation of beta-amyloid plaques under pathological conditions. This year, scientists published evidence showing that the different degrees of risk associated with inheritance of the APOE alleles might be related to more than just their effect on amyloid deposition. A study conducted by investigators at the University of California at San Francisco, presents compelling evidence to suggest that the presence or absence of particular APOE alleles affects the way neurons respond to injury (Buttini et al., 1999). In these studies, mice whose own APOE gene had been removed from their DNA ("knockout" mice) were made transgenic for one or the other human APOE alleles. The knockout transgenics made only human ApoE e3 or ApoE e4 proteins at high levels. The researchers showed that the human ApoE e3 protein protected the brains of these mice against injury due to overexcitation or aging but that the ApoE e4 protein did not. The significance of this finding is that it may help to explain why the APOE e4 gene is a risk factor for the development of AD, and, if confirmed, might suggest useful therapeutic strategies that could be started before any cognitive impairment occurs in at-risk individuals. Finally, a recent study conducted by NIA intramural AD investigators may shed light on future therapeutic strategies for AD. In this tissue culture study, the researchers observed an increase in death of hippocampal neurons in cells that they had engineered to over-express mutated forms of human APP compared to neurons over-expressing the normal human APP (Luo et al., 1999). The death caused by mutant APP over-expression appeared to be apoptotic and led to the generation of more intracellular terminal fragments of APP. These results suggest that abnormal metabolism of APP leading to more beta-amyloid or terminal fragments of APP may be toxic to cells. ------------------------------------------------------------------------ ** *Presenilins* In the past year, researchers also took several big steps toward a better understanding of the role of presenilins in AD development. Naturally occurring mutations in presenilin 1 are found in about 40 percent of people with early-onset familial Alzheimer's disease (FAD). Previous studies have suggested that these inherited gene mutations increase the total amount of beta-amyloid clipped out from the larger APP or of the longer and "stickier" form of beta-amyloid, but no one had determined how that clipping occurred, though they knew that an enzyme was involved. Researchers named this elusive enzyme gamma-secretase. Working with nerve cells grown in tissue culture, an NIA- and NINDS-supported research team at Harvard Medical School and the Brigham and Women's Hospital, Boston, gained an important insight into this process (Wolfe et al., 1999). When the investigators altered the normal sequence of presenilin amino acids (the building blocks of the presenilin protein) in two critical locations buried within the cell membrane, they found that beta-amyloid formation was reduced. This evidence strongly suggests that presenilin 1 is either gamma-secretase itself, or a unique cofactor required for gamma-secretase activity. This study is important because if its findings prove to be true, it could lead to significant advances in therapeutics research by showing investigators one exact place to intervene before plaques form. A second, supporting study from a research team at the University of Pennsylvania, used a particular Drosophila fruit fly model to demonstrate a similar link between the presenilin protein and another protein called Notch (Ye et al., 1999). The Notch protein is a large transmembrane receptor protein involved in cell-cell interactions, especially during development. These two proteins appear to share a mechanism of regulated proteolysis (the process by which proteins are clipped to create small chains of amino acids). The researchers showed that in this fruit fly model, a proteolytic cleavage, required for Notch activity, did not occur in the absence of presenilin. Proteolysis of the human APP has similarities to Notch receptor processing and so a better understanding of presenilin function in Notch proteolysis may yield enormous dividends with respect to understanding APP processing and may lead to new insights into the development of AD. In a collaborative study with scientists at The Johns Hopkins University and the University of Chicago, NIA intramural AD researchers also examined the effects of a deficiency of presenilin 1 on tissue culture neuronal cells isolated from genetically engineered mice (Naruse et al., 1998). They found that a lack of presenilin 1 in cortical neurons eliminated the secretion of beta-amyloid. Furthermore, this deficit in presenilin 1 caused an increase both in the accumulation of a secreted form of APP and in the buildup of certain fragments of APP within the cells. The processing of several other proteins also was affected. These results suggest that presenilin 1 plays an important role in the movement and metabolism of selected membrane and secretory proteins within cells, and this has implications for the function of presenilin 1 beyond its role in the modulation of APP processing. NIA-supported investigators at the University of Kentucky have been exploring the role that presenilin mutations play in the death of neurons and the development of AD. In this study, the investigators used transgenic mice to demonstrate a link between a mutation in presenilin 1 and an increased susceptibility of cultured hippocampal neurons to excitotoxic injury stemming from a dose-dependent challenge with a particular kind of neurotransmitter called glutamate (Guo et al., 1999). The researchers suggest that the mechanism involved may be to increase intracellular levels of free calcium resulting in oxidative stress and the dysfunction of mitochondria. Thus, by changing the normal balance of calcium in the cells, presenilin 1 mutations may predispose neurons to multiple forms of cell death. ------------------------------------------------------------------------ *Tauopathies and Tangles* Several neurodegenerative diseases, including AD, are characterized by the aggregation of tau into insoluble filaments in neurons and glia, leading to dysfunction and death. Until now, there was no evidence that changes in the tau protein itself could actually initiate neuronal degeneration in humans with any forms of dementia. Rather, the tangles of Alzheimer's disease were seen as secondary to some other insult or genetic change, for example, the buildup of beta-amyloid. Determining exactly what relationship exists between plaques and tangles is a major goal of AD research. Very recently, several groups of NIA-supported researchers at the University of Pennsylvania, Mayo Clinic, University of Washington, and Cambridge University, who were studying families with a variety of hereditary dementias other than AD, found the first mutations in the tau gene on chromosome 17 (Clark et al., 1998; Hutton et al., 1998; Poorkaj et al., 1998; Spillantini et al., 1998). In these families, mutations in the tau gene cause neuronal cell death and dementia. These disorders, collectively called "frontotemporal dementia and parkinsonism linked to chromosome 17" (FTDP-17), share some characteristics with AD but differ in several important respects. Patients with FTDP-17 differ from AD patients in the cognitive and behavioral problems they exhibit, for example. They also differ in the area of the brain most affected (frontotemporal dementia disorders primarily affect the frontal cortex). In addition, only neurofibrillary tangles made up of abnormal tau proteins form--there are usually no amyloid plaques in these diseases. However, a recent scientific article describes a 55-year-old individual with FTDP-17 who did have plaques in his brain, suggesting the possibility that tau mutations could sometimes result in beta-amyloid deposition (D'Souza et al., 1999). These studies describing tau mutations are important because they support the idea that tau in and of itself can be an important contributor to neurodegeneration. Researchers speculate that these families have slightly different mutations, but that they all work in one of two ways to kill neurons--either by preventing tau from binding to the microtubules, which provide support for cellular structures such as axons (Dayanandan et al., 1999; Hong et al., 1998) or by causing tau to aggregate to form neurofibrillary tangles (Nacharaju et al., 1999). These disruptions to the cell's basic function and structure could lead to its death. The benefits of this research lead far beyond FTDP-17, for a better understanding of the impact of tau mutations in this disease may well provide clues to other age-dependent neurologic diseases that also are characterized by abnormal aggregation of tau protein, such as AD, Parkinson's disease, some forms of amyotrophic lateral sclerosis, corticobasal degeneration, progressive supranuclear palsy, and Pick's disease. ------------------------------------------------------------------------ *Genetic Links to Late-Onset AD* Scientists are continuing to pursue research into the relationship between genetics and late-onset AD. In the early 1990s, researchers discovered that the APOE gene on chromosome 19 was associated with late-onset AD, and the APOE e4 allele remains the single most significant risk factor gene in this form of the disease, accounting for about 50 percent of the genetic effect in the development of late-onset AD (Strittmatter et al., 1993). Recently, one team of investigators at The Johns Hopkins University suggested that the APOE e4 allele influences when susceptible individuals might develop Alzheimer's disease, but in those who survive to very old age (older than 84), it has no bearing on whether a person might develop AD (Meyer et al., 1998). These results suggest that late-onset AD is a genetically complex disorder involving some, perhaps many, genes apart from APOE e4. A number of different methods are being employed to find these other risk factor genes. All these genetic studies involve looking at the occurrence of specific polymorphisms in individuals or groups and comparing them with the occurrence of particular diseases in those groups. For example, scientists supported in part by NIA recently used a methodology called genome scanning, in which all the chromosomes are scanned for genes that are inherited in families along with a particular disease, to search for candidates for risk factor genes in AD other than APOE e4. Researchers at five sites (Jacksonville, Florida; St. Louis, Missouri; Cardiff, Wales; London, U.K.; and Lille, France) conducted a genome scan on 292 sibling pairs, each of whom had AD, and results do suggest that there are other risk factor genes in addition to APOE e4 (Kehoe et al., 1999). Other types of studies, called family- and population-based association studies, look at polymorphisms in specific genes that frequently occur along with the disease but not in unaffected individuals. In particular, scientists are using these research methods to focus on a small region of chromosome 12, which studies have suggested is a potential area of susceptibility to AD. Using a family-based association method, investigators at Massachusetts General Hospital and Harvard University found that a common polymorphism in a protease inhibitor gene that makes a protein called alpha 2-macroglobulin (a2M) may be a major risk factor determining whether Alzheimer's disease will develop in later life (Blacker et al., 1998). There is some biological evidence to support a role of a2M in AD. a2M can act to prevent beta-amyloid from accumulating by binding to it and degrading it, and ApoE e4 may interfere with this process, thus allowing amyloid plaques to accumulate (Blacker et al., 1998; Rebeck et al., 1998). However, there is no evidence that the a2M polymorphisms have different biological activities. Moreover, results from other laboratories in this country, the United Kingdom, and Canada (Rogaeva et al., 1999) have not confirmed this association and suggest that another, entirely different, risk factor gene may reside on chromosome 12. Other associations, suggesting new risk factor genes, have been found in population-based studies. Many of these may be spurious, caused by differences in genetic backgrounds and in environment between the control and AD groups other than the polymorphism being tested. Because families share the same genetic and often the same environmental backgrounds, family-based analyses reduce the possibility that associations with the disease may be related to the genetic or environmental differences that exist between unrelated persons. The statistical and other family-based methods for detecting risk factor genes in genetically complex diseases such as AD are still evolving. Only as additional families are tested and as the various research groups share their raw data will it become clear exactly which gene on chromosome 12 is a risk factor gene for AD. The NIA will hold a workshop on the genetics of AD and related dementias at the end of 1999 to address these issues. The workshop will provide an opportunity for many genetic researchers to come together to discuss their different findings and assess the various techniques being used to hunt for risk factor genes in diseases such as AD. ------------------------------------------------------------------------ *Inflammation* Work on the links between inflammation and AD continue to bear fruit. For example, a recent study by University of Arizona scientists compared the effects on a specific area of rat brain that contains cholinergic neurons, lost in AD, of short-term, high-dose injections of an inflammatory agent with the effects of longer-term, lower-doses of the agent (Willard et al., 1999). They found that both treatments were deleterious but that the chronic inflammation caused more damage to the cholinergic neurons that are vulnerable in AD than did the short-term, intense inflammation. These results suggest that neuro-inflammation over a longer period of time has the potential to underlie the genesis of some of the cellular damage seen in healthy aging as well as in AD. ------------------------------------------------------------------------ *Oxidative Stress* Investigators continue to tease out the ways in which oxidative stress, which occurs as a result of over-production of free radicals, may play a role in neuronal damage and death. For example, one research team from Case Western Reserve University in Cleveland, Ohio, has attempted to distinguish the particular cell types in the brain that are most vulnerable to oxidative stress (Nunomura et al., 1999). They found that most of the oxidative damage to DNA and RNA in vulnerable neurons of AD involves RNA, not DNA. The several classes of RNA molecules, which are chemically similar to DNA, play essential roles in carrying genetic information from DNA in the nucleus to the outer portion of the cell, where the information serves as a blueprint for the manufacture of specific proteins. RNA also plays a critical role in the actual synthesis of the proteins. Oxidatively damaged RNA may interfere with these processes, and this may cause a malfunctioning protein to be made (one that has either gained a toxic function or lost a normal function). In turn, this could be one cause of the neuronal death that characterizes AD. Other recent studies, conducted by scientists at the Sanders-Brown Center on Aging and the NIA-supported Alzheimer's Disease Research Center, have built on previous work detailing the direct evidence for free radical damage to neurons in AD. In one of these studies, scientists confirmed that certain types of free radicals, called 4-hydroxynonenal (HNE), which are toxic to neurons, are increased in several regions of the brain that have the most AD damage (Markesbery and Lovell, 1998). This study, in conjunction with cell culture studies and previous studies showing HNE elevation in cerebrospinal fluid of AD patients, suggests that HNE may also be important in the development of neuron damage in AD. In a review of many studies on oxidative stress, the same team of investigators present evidence that the oxidative process damages brain fats, carbohydrates, proteins, and DNA, and also summarize the evidence for inflammatory processes in the brains of AD patients (Markesbery and Carney, 1999). They suggest that it is these two processes, working in concert, that contribute to the death of brain neurons and the consequent decline in mental function seen in AD patients. ------------------------------------------------------------------------ *Brain Infarction* The interest in studying a possible association of brain vascular disease and AD pathology has grown with the publication of results from a study of patients with autopsy-proven AD who were enrolled in the NIA-supported Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (see p. 45 for a more detailed description of CERAD). Confirming results from the earlier Nun Study (Snowdon et al., 1997, see p. 14), these researchers found that AD patients who also had evidence of a brain infarction at autopsy had more severe clinical dementia and poorer performance on specific tests of language and cognitive function and higher frequency of dementia than did those with AD alone (Heyman et al., 1998). These results are spurring collaborative efforts by the NIA and other NIH institutes, such as the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, and the National Heart, Lung, and Blood Institute, to explore the interrelationships among age-related cognitive decline, dementia, cerebrovascular disease, and cardiovascular disease in order to develop better methods to identify early those people at risk of dementia and to provide new approaches to treatment and prevention. The NIA is funding epidemiologic studies to uncover possible interactions among these various entities. It is also funding an add-on component to two clinical trials to measure cognitive decline in elderly women both with and without cardiovascular risk factors. These cognitive components are being added to the ongoing NIH Women's Health Initiative and the Women's Anti-oxidant Cardiovascular Study (see page 44 for more on these studies). ------------------------------------------------------------------------ *Diet* A 1998 study provides another intriguing clue to the origins of AD. This study, conducted by scientists from Oxford University and Norway's University of Bergen showed that blood levels of homocysteine (an amino acid) were significantly higher and blood levels of folate were lower in patients with diagnosed AD than in controls (Clarke et al., 1998). The study's authors suggest that high levels of homocysteine might be a risk factor for AD. Recent findings from the Nun Study also suggest a link between folate and brain dysfunction. In this research, investigators determined blood levels of folate and other nutrients from selected nuns living in a convent in Mankato, Minnesota (Snowdon et al., in press). They then compared these folate levels with the degree of AD pathology present in the brains of any nuns who died. All of the participating nuns ate from the same kitchen and lived similar lives. Examinations of the brains of 30 nuns who have died since the beginning of the study showed that the neocortex--one of the primary regions of the brain affected in AD--of those who had low blood folate levels showed significant shrinkage, and that the correlation was particularly evident among 15 nuns who had many AD plaques and tangles. None of the other nutrients examined showed the same correlations. Folate, also called folic acid, plays an important role in the development of the central nervous system (CNS) and may play a role in maintaining its integrity throughout life. One of folate's functions, along with vitamins B6 and B12, is to convert homocysteine to the more useful amino acid methionine. High levels of homocysteine have been linked in epidemiologic studies to risk of heart disease, and, in the study by Clarke and colleagues, to risk of AD. ------------------------------------------------------------------------ *Improving Early Diagnosis* The clinical diagnosis of AD has improved significantly in recent years. However, important gaps in knowledge remain, and work continues on the search for reliable, valid, and easily attained ways to identify cases very early in the course of the disease, when treatment may be most effective. Tests are also needed that can reliably separate people with incipient Alzheimer's from those with cognitive problems that stem from other causes. In the last year, researchers made significant progress in several areas related to early diagnosis, including increasing their focus on mild cognitive impairment with memory loss, which may be an early stage of AD, and improving neuroimaging techniques for diagnostic purposes. ------------------------------------------------------------------------ *Mild Cognitive Impairment* Individuals who have a memory problem but who do not meet the generally accepted clinical criteria for AD are considered to have mild cognitive impairment (MCI). They are becoming an increasingly important group for AD researchers because it is now known that about 40 percent of them will develop AD within 3 years. A recent study, conducted by researchers at the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease Patient Registry in Rochester, Minnesota, broke new ground in this area by confirming that MCI is a distinct clinical entity different from mild AD and from normal age-related changes in memory (Petersen et al., 1999). This study involved three groups: healthy older people, people with MCI, and patients with mild AD. The groups were followed over time and compared on demographic factors and on several different measures of cognitive function. Results showed that the main difference between the healthy study participants and those with MCI was in memory abilities. The MCI participants and the AD patients had similar memory impairments, very much worse than the healthy participants, but the AD patients had other cognitive impairments as well. Over time, the cognitive performance of individuals with MCI declined more rapidly than that of the healthy participants and more slowly than that of the AD patients. However, some patients diagnosed with MCI did not progress to AD, suggesting that the MCI group is composed of two subgroups, only one of which is sure to progress to AD. The findings from this study will enhance clinicians' ability to diagnose this particular impairment as well as AD and has provided a firm foundation for NIA's new Memory Impairment Study (see page 36 for a full description of this study). ------------------------------------------------------------------------ *Neuroimaging* One of the most exciting developments in neuroscience research during the past 10 years has been the refinement of techniques that allow scientists to visualize the activity and interactions of particular brain regions as they are used during cognitive operations such as memorizing, recalling, speaking, reading, learning, and other sorts of information processing. This window on the living brain can help scientists measure early changes in brain function or structure to identify those individuals who are at risk of Alzheimer's disease even before they develop the symptoms of the disease. These imaging techniques include positron emission tomography (PET) scans and single photon emission computed tomography (SPECT), which produce "maps" of the brain that give information about activity in particular regions as a person responds to a task or stimuli, and magnetic resonance imaging (MRI), which provides a way to look at the size and characteristics of brain structures. Three different recent studies using MRI show how it may be useful in the early diagnosis of AD and in evaluating its progression. Eventually, clinicians may be able to use imaging techniques to assess a patient's response to treatment over time. Researchers at the Mayo Clinic have conducted several important studies in the use of MRI to measure shrinkage in the volume of the hippocampus. The initial studies were cross-sectional studies, which compared groups of individuals with various levels of mental function, from healthy to diagnosed AD. In their newest study, the team actually followed a group of men and women with MCI over time (a longitudinal study) to test the hypothesis that MRI-based measurements of hippocampal volume could predict the risk of future development of AD (Jack et al., 1999). The team followed the patients for nearly 3 years, providing annual clinical exams and tests of mental function. Twenty-seven of the 80 MCI patients developed dementia over the course of the study, and the investigators found that there was indeed a clear association between hippocampal shrinkage at the beginning of the study in these patients and later conversion to AD. In a second study, investigators at the New York University School of Medicine hypothesized that changes in the size of the entorhinal cortex (EC), a part of the brain important in recent memory and the site where tangles first begin to appear as AD develops, could be potentially useful in the early diagnosis of the disease (Bobinski et al., 1999). Using brain tissue from deceased individuals with and without AD, the researchers first developed and validated a way to measure EC size using MRI. Then they applied the method in living study participants to compare those with mild AD with age-matched healthy individuals. Using three different types of measurements, the researchers showed that the size of the EC was smaller in mild AD patients than in the healthy individuals, suggesting that this use of MRI could also be useful in the early diagnosis of the disease. A third study using MRI was a follow-up to an earlier study of individuals at risk of AD. All of the individuals had a family history of AD; some also carried the APOE e4 allele. In the earlier study, which used PET, a group of investigators at the University of Arizona showed that compared to those without the APOE e4 allele, those with the allele had significantly reduced glucose metabolism in particular brain regions (Reiman et al., 1996). In the new study, the team used MRI to compare hippocampal volume in the same two groups of patients (Reiman et al., 1998). They found that although the individuals with the APOE e4 allele tended to have smaller hippocampal volumes, this was not statistically significant. However, the smaller volumes were associated with lower scores on a test of long-term memory. The researchers suggest that perhaps the results seen in the PET scans indicate changes occurring before the onset of memory decline, whereas the changes in hippocampal volume seen with MRI occur at the same time as memory declines. ------------------------------------------------------------------------ *Developing Drug Treatments* Improvements in our understanding of AD are making it possible to design new therapeutic strategies to intervene at multiple stages of the disease process. Insights into the neurochemistry and neurobiology of the disease and epidemiologic studies pinpointing risk factors have resulted in a marked expansion of the types and numbers of drugs that are now being tested or may be tested in the future. Today, it is estimated that NIA, other NIH Institutes, and a number of pharmaceutical companies are or will be testing 50 to 60 compounds in human trials. They focus on three major aspects of AD--treatments for the cognitive decline associated with AD; treatments to slow the progress of the disease, delay its onset, or prevent it; and treatments for AD-associated behavioral problems. ------------------------------------------------------------------------ *Treating Cognitive Decline* A number of drugs that maintain the cholinergic system have been developed or are now being tested to treat the cognitive decline experienced by Alzheimer's patients. For example, the current drug of choice for AD, donepezil, acts by slowing down the metabolic breakdown of acetylcholine. These agents do not, however, alter the underlying course of the disease. Another clinical trial to investigate potential cholinergic treatments for AD cognitive decline is being supported by the Belgian pharmaceutical company, Janssen Pharmaceutica. In this study, to be conducted in the United States, researchers will investigate the effect on cognitive performance of galantamine, an experimental medication that is thought to increase the amount of acetylcholine available in the brain. Galantamine does this both by inhibiting the enzyme that breaks down acetylcholine and by stimulating certain receptors in the brain to release more acetylcholine. ------------------------------------------------------------------------ *Slowing, Delaying, or Preventing the Disease* Scientists are working at a stepped-up pace to examine a number of compounds that might delay the onset of AD, slow its progress, or prevent it altogether. These compounds include: /Anti-Inflammatory Agents/--One of the hallmarks of AD is inflammation in the brain, but whether it is a cause or an effect of the disease is not yet known. Epidemiologic evidence strongly suggests that anti-inflammatory agents, such as prednisone (a steroid) and nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen and indomethacin, are associated with a decreased risk of AD. NIA has supported a study to compare the effects of prednisone versus a placebo (inactive pill) on patients with diagnosed AD to see whether progression of the disease can be slowed. This study, the results of which are presently being analyzed, was conducted through the Alzheimer's Disease Cooperative Study (see p. 46 for a description of the ADCS). Another ADCS study with AD patients, which will begin at the end of 1999, will compare treatment with a traditional NSAID to treatment with a COX2 inhibitor, a more specific type of NSAID with pain relieving qualities but without some of NSAIDs' side effects on the gastrointestinal system. /Estrogen and Estrogenic Compounds/--Estrogen use also has been associated in epidemiologic studies with a decreased risk of AD and with enhanced cognitive function. It has both antioxidant and anti-inflammatory effects and enhances the growth of select neurons that release acetylcholine. Researchers hope that three current estrogen and AD studies may be able to determine whether estrogen actually affects development or progression of AD. The first is a small ADCS study of estrogen replacement therapy (ERT) in post-menopausal women who have had a hysterectomy. Results of this study, which evaluated the effects of ERT on cognitive decline in AD, are now being analyzed. The second study, called the Women's Health Initiative Memory Study, is a component added to the NIH's Women's Health Initiative. This component, which is being supported by Wyeth-Ayerst Laboratories, will determine whether hormone replacement therapy decreases the incidence of cognitive decline and dementia. The third study, which is in the patient recruitment phase, is a multi-site, NIA-supported clinical trial to determine whether the use of estrogen in women without AD but with a family history of the disease may prevent the development of AD. Scientists at Columbia University are coordinating this study. Estrogen replacement therapy is limited to women because of its potential feminizing effects in men. In women, compliance is limited by side effects, including increased risk of cancer. Researchers are developing synthetic compounds, such as those called selective estrogen receptor modulators (SERMS), that mimic the positive effects of estrogen on various organ systems, including the brain, without having the negative side effects of estrogen itself. The first SERM to be approved by the Food and Drug Administration (FDA) for replacement therapy is raloxifene. A recently awarded NIA grant has added analysis of age-related cognitive decline and onset of dementia onto an ongoing Eli Lilly and Company-supported study that is testing the effects of raloxifene on osteoporosis. /Antioxidants/--Over-production of free radicals, produced in normal levels during metabolism, can result in oxidative damage to cells. Researchers hypothesize that free radicals may play a role in the Alzheimer's disease process, and they are studying agents that inhibit and protect against oxidative damage. One of the most important antioxidants is vitamin E (alpha-tocopherol), which was shown in a recent study to delay by about 7 months several important dementia milestones, such as patients' institutionalization or progression to severe dementia (Sano et al., 1997). Many Alzheimer's patients are currently taking vitamin E, and a new NIA-supported study--the Memory Impairment Study--will examine this agent further to see if it can prevent patients with mild cognitive impairment from developing AD (see the accompanying box for a description of this trial). Another potentially promising compound is ginkgo biloba, an extract derived from the leaves of the ginkgo tree. It appears to have antioxidant properties as well as anti-inflammatory and anticoagulant properties, and a recent meta-analysis of previously published clinical trials suggested a slight positive effect on AD symptoms (Oken et al., 1998). The NIH's National Center for Complementary and Alternative Medicine is supporting a new clinical trial of this compound to determine whether it can delay or prevent dementia in older individuals. /Nerve Growth Factor (NGF) and Other Neurotrophic Factors/--NGF is the best known of a class of compounds known as neurotrophic factors and has been well studied in animal models for its regenerative properties. NIA is currently supporting a clinical trial of AIT-082, a promising neurotrophic factor (see sidebar on p. 43 for more on AIT-082) /Cholinergic Agents/--Novartis Pharmaceuticals, a company based in Switzerland with U.S. headquarters in New Jersey, is sponsoring a clinical trial to compare the length of time of progression from MCI to a clinical diagnosis of AD in participants taking a placebo or an experimental cholinesterase inhibitor called rivastigmine. This drug is under review with the FDA as a treatment for AD. Participants in the 3-year study will be assessed every 3 months for any adverse reactions to the drug as well as for vital signs, ability to carry out activities of daily living, and signs that they may have converted from MCI to dementia. ------------------------------------------------------------------------ *Treating Behavioral Symptoms* Behavioral symptoms--agitation, aggression, wandering, and sleep disorders--are common in AD patients and can be serious. Physicians now have several treatments for these symptoms, such as antidepressants, antipsychotic drugs, and sedatives, but researchers continue to search for better treatments, including non-drug approaches. One new ADCS clinical trial is focusing on alleviating sleep disturbances, a common problem for AD patients. Nighttime wandering and agitation can result in injury for patients and disrupted sleep for caregivers. In this study, groups of patients will be given either a slow-release preparation of melatonin (a naturally occurring hormone that induces sleepiness), an immediate-release preparation of melatonin, or a placebo. This trial is now in progress. Another ADCS study focuses on agitation, a problem affecting 70 to 90 percent of AD patients and one that can make caring for a patient at home very difficult. Drugs are commonly used to control signs of agitation, but they can have distressing side effects. This study compared, over a 4-month period, non-drug behavior management techniques with traditional medication approaches and no intervention to see which were more effective. The trial has been completed and results are now being analyzed. ------------------------------------------------------------------------ *Future Considerations for AD Clinical Research* Scientists engaged in the design and development of clinical trials to test potential treatments for AD face a number of challenges. One is the need to recruit large numbers of participants--those with diagnosed AD, those earlier in the course of the disease (before clinical diagnosis), and healthy elderly--so that the effects of the drug being tested and its safety and effectiveness can be measured with confidence. Close collaboration with existing research and treatment facilities, such as the Alzheimer's Disease Centers and Alzheimer's Disease Cooperative Study sites, help to ensure a sufficient pool of potential study participants. Recruitment strategies being developed for trials such as the Memory Impairment Study will also help to ensure strong participation. A second challenge is the need to incorporate into study designs the special characteristics of people with AD. In many respects--cognitively, behaviorally, psychologically, and medically--this patient population is different from patients who participate in clinical trials for other diseases. Because of their dementia, many may not even be fully aware that they are participating in clinical research. Extra care must be taken to accommodate AD patients and protect their interests and rights. Their condition also means that family members and other caregivers need to be included as full partners in the research effort if participation of the patient is to be successful. Finally, the fact that several therapeutic drugs, such as donepezil and vitamin E, are now available to treat AD has raised an important ethical issue about study designs in which one group of participants is given the investigational drug and the other group is given a placebo (Farlow, 1998; Karlawish and Whitehouse, 1998; Knopman et al., 1998). Researchers are discussing whether this type of design should be abandoned in AD research in favor of designs that compare new drugs against these existing therapies, or whether placebo-controlled trials should be continued because these therapies are not yet considered definitive standards of care for AD. ------------------------------------------------------------------------ *Improving Support for Caregivers* Perhaps one of the greatest costs of Alzheimer's disease is the physical and emotional toll on family, caregivers, and friends. As Alzheimer's disease makes inroads into a person's memory and mental skills, it also begins to alter his or her emotions and behaviors. Patients can experience extreme agitation and feelings of anger, frustration, and depression. They can begin to exhibit bizarre behaviors such as pacing, wandering, screaming, and physical or verbal aggression. These changes in a loved one's personality and the need to provide constant, loving attention for years on end are major reasons for caregiver exhaustion and depression, and for why AD patients are placed in nursing homes. A recent study analyzing data from more than 1,500 caregivers who participated in the 1996 National Caregiver Survey provides details on the physical and other costs of caregiving (Ory et al., 1999). These data show that dementia caregivers spend significantly more time on caregiving tasks than do people caring for those with other types of illnesses. In addition, they report that this type of caregiving has a greater impact in terms of employment complications, caregiver strain, mental and physical health problems, time for leisure and other family members, and family conflict than do other types of caregiving. The authors suggest that these findings point to a need for programs and support services tailored to the unique challenges faced by AD caregivers. This suggestion is supported by research conducted at Cornell University, which demonstrated the effectiveness of peer support programs that link caregivers with trained volunteers who have also been dementia caregivers (Pillemer et al., 1999). Not surprisingly, the researchers found that these programs were especially effective for those caregivers whose social support networks were weak before the program began. They also found that the intervention had the strongest positive effects on the psychological well-being of caregivers who were in the most stressful situations. Other research conducted at the University of Washington, Seattle, and at the University of California at San Diego has attempted to fill gaps in our understanding of the psychological and physiological responses of caregivers to the chronic stress of taking care of an AD patient. These studies suggest that there is not a generic response to caregiving burdens, but that certain caregiver characteristics (being male), a lack of respite from caregiving responsibilities, and the presence of preexisting illnesses (such as heart disease), make some caregivers especially vulnerable to the stresses associated with dementia care. These vulnerabilities include increases in heart disease risk factors, such as cholesterol levels and blood pressure, and decreases in immune function indicators (CD4 counts) (Mills et al., 1999; Vitaliano et al., 1998). ------------------------------------------------------------------------ *REACH* In 1995, the NIH established a major 5-year initiative to carry out social and behavioral research on interventions designed to help caregivers of patients with AD and related disorders. Resources for Enhancing Alzheimer's Caregiver Health (REACH) is co-sponsored by NIA and the National Institute of Nursing Research (NINR). Participating researchers are from universities and medical centers around the country: * University of Alabama and University of Alabama at Birmingham; * Veterans Affairs Medical Center and University of Tennessee at Memphis; * Center on Adult Development and Aging at University of Miami, Florida; * Veterans Affairs Palo Alto Health Care System and Stanford University, California; * Center for Collaborative Research at Thomas Jefferson University in Philadelphia, Pennsylvania; * Hebrew Rehabilitation Center for the Aged and Boston University; and * University Center for Social and Urban Research at the University of Pittsburgh. REACH projects focus on characterizing and testing the most promising home- and community-based interventions for helping caregivers, particularly in minority families. The interventions include psychoeducational support groups, behavioral skills training programs, family-based interventions, environmental modifications, and computer-based information and communication services. An important outcome of this initiative will be a shared database that will enable investigators to answer key questions about the best intervention strategies for maintaining and improving the health and quality of life of caregivers of dementia patients. Investigators are particularly interested in exploring issues related to depression among caregivers, but they are also assessing the effects of caregiving on health status, health practices, and use of health care services. To date, over 1,000 families with diverse ethnic backgrounds have entered the study (57 percent are White; 22 percent are African American, and 20 percent are Hispanic American); preliminary outcome findings are expected in the next year. Information about the project is available on the REACH website (http://www.edc.gsph.pitt.edu/reach/). Results are being published in the scientific literature and in a book entitled Handbook of Dementia Caregiving Intervention Research. ------------------------------------------------------------------------ *Special Care Units* As the population ages and the number of people with AD grows, the issues surrounding caring for dementia patients in nursing homes become ever more important. Special care units (SCUs) are separate sections in nursing homes for residents with dementia. It is estimated that in the U.S. today there are 16,840 nursing homes, with 1.65 million residents (Rhoades et al., 1998). The past decade has witnessed a tremendous growth in the number of SCUs in licensed nursing facilities; as of 1996, nearly one in four nursing homes had at least one organized dementia care unit, wing, or program. The idea behind SCUs is that people with dementia might benefit from specially designed programs or environments that are different from those provided in a traditional nursing home setting. Dementia-oriented programs include small group activities, short programs, and activities arranged by functional or cognitive ability levels. Dementia-oriented environmental design features include secured exits, small dining rooms, single-occupancy rooms, and special indoor or outdoor areas for wandering. The rapid proliferation of SCUs has underscored the need for research into their organization, services, and effectiveness. In 1991, NIA began an SCU Initiative, a set of collaborative research projects located at ten sites around the country. These projects were designed to examine the nature and effectiveness of SCU care in institutional settings using state-of-the-art research methods. Results from these studies have made a significant contribution to current knowledge about the organization and impact of these settings. For example, the lack of a standard definition of what constitutes an SCU has meant an enormous variability in the care provided by units that identify themselves as SCUs. A recent study supported through the SCU Initiative has addressed this problem by developing and testing a method for classifying unit types that serve dementia residents in nursing homes (Grant, 1998). This classification system will help to standardize the attributes that define SCUs and will serve as a useful tool for researchers to use in comparing different models of Alzheimer's care in nursing homes. It contains seven attributes of care that distinguish SCUs from other types of care: 1) a greater degree of separation between dementia residents and cognitively intact residents in physical space and social activities; 2) a greater effort to eliminate noxious auditory stimulation, such as radios and door alarms; 3) a greater number of simple activities planned for residents; 4) a greater tolerance of problematic behaviors; 5) a greater degree of dementia patient participation in organized recreational programs; 6) less participation by residents in therapeutic programs aimed at promoting activities of daily living, such as eating and dressing; and 7) more methods used to train staff about dementia care. ------------------------------------------------------------------------ *Building a Research Infrastructure* An important component of the success of NIH's AD research effort is its vibrant network of research institutions and investigators who work together, as well as independently, to further the process of discovery in AD. Building this research infrastructure is an ongoing effort and it ranges from developing a variety of innovative mechanisms for funding research to sponsoring research conferences on cutting-edge issues (such as the September 1999 workshop on imaging and biological markers and the December 1999 conference on the genetics of AD and other dementias). ------------------------------------------------------------------------ *Innovative Mechanisms for Funding AD Research* Because of the cost, time, and effort involved, relatively few medications or treatment strategies are tested in full-scale clinical trials. However, it is important to provide as many opportunities as possible to explore the potential of multiple compounds and strategies. NIA has therefore developed a number of mechanisms for funding research aimed at each stage of drug development, from efforts to identify useful drugs, through testing in animals and pilot clinical trials, to full-scale clinical trials. At each step, the NIA is fostering and developing industry participation. The accompanying sidebar gives one example of how these mechanisms work together to further the process of AD drug development. /Small Business Innovation Research Grants (SBIRs )--/SBIRs are grant mechanisms designed to establish the merit and feasibility of ideas that may eventually lead to commercial products or services, and to support in-depth development of those whose feasibility have been established. A number of these grants have been funded in the area of AD research and they provide an important way for small businesses to participate in the research process. They also serve as a bridge between laboratory work and commercial development. Recent examples include projects to explore the feasibility of using a training program to improve the sleep of older adults with insomnia and co-existing diseases, including AD; develop individualized interventions to enhance patient-family interactions in the later stages of the disease; isolate the active ingredient from cat's claw (a plant whose extract seems to inhibit amyloid formation); and test compounds from marine microbes for plaque-inhibiting activity. /Drug Development Contract--/NIA maintains a contract mechanism for funding investigators or small companies who have a potentially interesting candidate AD treatment drug but who lack the means to begin the formal drug testing process. This contract, Investigational New Drug Toxicology for Drugs to Treat Alzheimer's Disease, funds contractors to conduct animal studies to evaluate drugs for toxicity. If the toxicology screening is successful, the data generated are used to file a request to the Food and Drug Administration for approval to carry out initial tests for safety and efficacy in humans. This contract mechanism has already yielded several potentially promising compounds, and applications to test several more drugs are in process. /Pilot Trial and Trial Planning Grants/--These grant mechanisms give investigators funding to plan future clinical trials and conduct smaller-scale clinical trials aimed at treating AD's cognitive and behavioral symptoms. The trials allow investigators to develop recruitment strategies and diagnostic procedures, test drug responses, and generate data necessary to apply for funding of a full-scale clinical trial."Add-on" Research Components to Ongoing Clinical Trials--One efficient way to conduct AD clinical trials is to add a cognitive or dementia component onto an ongoing trial. For example, NIA recently added two cognitive components to existing NIH trials. In one trial (The Women's Health Initiative), healthy older women are taking aspirin or the antioxidant vitamin E; in the other (The Women's Antioxidant Cardiovascular Study), older women at high risk for cardiovascular disease are taking either antioxidants or a combination of folate and vitamins B6 and B12. In both of these trials, investigators are testing the effects of these compounds on age-related cognitive decline. /Alzheimer's Disease Centers (ADC)/--The NIA supports a number of Centers that conduct research; provide investigator training and patient care; and support the research process through the development of centralized databases, research tools and instruments, and clinical trials. In 1984, Congress authorized and NIA funded the first five ADCs to promote research, training and education, technology transfer, and multi-center and cooperative studies of AD diagnosis, etiology, pathology, and treatment. At present, there are 28 NIA-supported centers across the United States. ADCs also receive funding to perform specific research studies on AD or have a particular focus on techniques such as neuroimaging or data analysis. In addition, a number of the ADCs participate in the Satellite Diagnostic and Treatment Clinics program. This program, established in 1990, is designed to extend the ability of ADCs to offer diagnostic and treatment services to minority, rural, and other underserved communities. As well, it provides an opportunity for these Americans to participate in clinical drug studies and other clinical research efforts. This benefits the participants because of the care they receive, and it benefits the ADCs because a broad diversity of research volunteers helps to ensure that answers to research questions apply to a wide group of people. Much of the success in AD research in the last 15 years can be attributed to the work of the ADCs. These advances include identifying the links between genes of chromosomes 1, 14, and 21 to FAD and identifying the inherited gene risk factors related to APOE. ADC researchers also have helped to lay the groundwork for studying how the proteins that make up amyloid plaques and neurofibrillary tangles are processed. They have also contributed significantly to the understanding of normal aging processes and how they differ from the changes seen in AD. Besides providing well-characterized populations of healthy individuals and AD patients who can be studied over time to determine healthy aging as well as the clinical course of the disease, the ADCs have developed banks of brain tissue for analysis. These tissue banks have been instrumental in helping researchers understand the pathological course of the disease and how it relates to the clinical symptoms. The Centers provide a valuable patient and tissue resource for a vast array of separately funded projects throughout the United States. The Centers also have played an important role in educating and training physicians, nursing home staff, and family members, and have worked closely with local Alzheimer's Association chapters in education and training initiatives. The result of these various projects is state-of-the-art care provided to many thousands of AD patients--more than 37,000 patients have been seen at Centers since the inception of the program. /Consortium to Establish a Registry for Alzheimer's Disease (CERAD)/--CERAD was a 24-site research consortium of NIA-sponsored Alzheimer's Disease Centers and other university medical centers in the United States engaged in dementia research. It was first funded in 1986 by the NIA for the purpose of standardizing procedures for the evaluation and diagnosis of patients with AD. Since then, participating researchers have worked with more than 1,500 carefully screened AD patients and healthy elderly control volunteers to develop such standardized diagnostic rating tests as a Behavior Rating Scale for Dementia, family history interviews, and assessments of services needs, and tests to assist in neuropsychology, neuroimaging, and neuropathology. CERAD tests have been translated into several languages to meet increasing demands for their use in a variety of clinical and research settings. Versions of selected assessments and supporting materials exist in French, Spanish, Italian, Portuguese, Dutch, Korean, Chinese, Japanese, Bulgarian, Hebrew, German, and Finnish. The data obtained with these tests have been pooled and compiled on a CD-ROM that is available to investigators. This CERAD database contains up to 7 years of longitudinal data on the natural progression of the disease and it has become a major resource for research in AD. /Alzheimer's Disease Data Coordinating Center (ADDCC)/-- As research on AD has progressed, it has become increasingly clear that many factors contribute to its development and that the dementias of aging (including AD) are a family of diseases with a variety of overlapping characteristics. The ability to pool data on patients from many ADCs will help investigators understand these complexities in AD and other dementias as well as help in diagnosis, monitoring, and treatment. For 2 years, NIA has funded an interim ADDCC to systematically collect data from all of the ADCs. In July 1999, NIA awarded a grant to the University of Washington in Seattle to establish a permanent ADDCC. This will make it possible to address important and novel research issues that are not feasible with the resources and patient populations available in any one Center. Many of these issues relate to distinguishing among the subtypes of AD and the interface between normal age-related cognitive decline, AD, and other dementias. The existence of the ADDCC will also encourage standardized methods of data collection and management and of tissue collection and dissemination. These standardized methods will help in building a coordinated and smoothly functioning research infrastructure. Alzheimer's Disease Cooperative Study (ADCS)--NIA established the ADCS in 1991 to build an organizational structure so that many Centers could cooperate in investigating promising drugs for AD and develop and improve tests for evaluating AD patients in clinical trials. The studies funded by the ADCS are carried out largely through the clinical cores of ADCs. During the first 5-year grant period, the ADCS began four drug studies and two studies of cognitive impairment assessment tests for Alzheimer's disease clinical trials (one each in English and Spanish). In 1996, NIA funded the ADCS for another 5 years. The new studies include work to develop a written test to measure MCI; the Memory Impairment Study; a study of two different kinds of anti-inflammatory compounds; the study of melatonin and sleep disorders in AD; and research on divalproex sodium (Depakote), an antiseizure drug, as a possible therapy for agitation and dementia in nursing home residents. Tests developed by the ADCS have become the benchmarks for clinical trials on AD carried out by both the private and public sectors. /Exploratory Centers on the Demography of Aging: Alzheimer's Disease/--NIA also supports research at nine collaborating Exploratory Centers on the Demography of Aging. The goal of these centers is to provide innovative and public policy-relevant research on issues related to the health, long-term care, and economic aspects of aging. Each center brings experts from different backgrounds together to conduct the research. 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 individuals and society. This program supports a variety of projects that examine aspects of AD in relation to demographic factors. For example, researchers at Duke University are trying to forecast the life expectancy of older people and their health service needs, studying how life expectancy can be extended, and measuring the rate of disease and disability in the U.S. population. They are also looking at the costs and benefits of different medical treatments for older people. In another exploratory center study, scientists at the University of Chicago are investigating the well-being of spouses of institutionalized AD patients. They are also 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. Researchers at the University of Pennsylvania in Philadelphia are studying AD and life in nursing homes. These investigators are working to develop new measures of AD progression so that they can more accurately project future population and disability rates. They also are examining relationships between members of different generations, measuring death rates of African Americans from 1930 to the present, comparing English and Spanish versions of a test that measures the severity of dementia, and looking for ways to encourage minority researchers to address research issues in aging. ------------------------------------------------------------------------ *SUPPORT FOR AD RESEARCH* *BY OTHER NIH INSTITUTES* *National Institute of Neurological Disorders and Stroke (NINDS)* Scientists supported by the NINDS are conducting a variety of studies aimed at increasing knowledge about the causes of AD and at finding new and better interventions for AD. In studying the causes of AD, investigators are looking at the organization of memory 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. For example, an NINDS- and NIA-supported research team at The Johns Hopkins University School of Medicine in Baltimore, Maryland, tested the relation between the severity of dementia and loss of brain volume, comparing autopsy findings from individuals without AD to those from patients diagnosed with AD (Mouton et al., 1998). Cortical atrophy in patients with AD was 20 to 25 percent greater than in controls. In addition, AD patients who died at older ages showed less severe cortical atrophy than did those who died at younger ages. For all patients with AD, cognitive performance was strongly correlated with cortical volume loss. These findings confirm earlier studies that have identified cortical degeneration as the major basis for cognitive decline in patients with AD, and the investigators believe that the currently unknown mechanisms that lead to cortical atrophy may play a key role in the progression of AD. This research is an excellent example of patients followed by an NIA-funded Alzheimer's Disease Research Center participating in research funded by another Institute. Another team of NINDS-supported scientists used new biophysical and molecular techniques to examine the steps that take place between the cleaving of APP to form beta-amyloid and the deposition of the beta-amyloid protein in plaques (Dewji and Singer, 1998). Confirming an earlier hypothesis that the formation of beta-amyloid in AD might involve an unspecified pair of cells in the brain first adhering (joining) to one another through the binding of APP to one of the presenilin proteins, the investigators suggest that a process may be stimulated in which vesicles (small sacs) containing intact APP and presenilin molecules bound to one another are pinched off the adherent cell surface of the APP-expressing cell and taken into the cell's interior. These vesicles fuse with other bodies inside the cells, where proteases break down the APP, forming beta-amyloid. The beta-amyloid then travels to the outside of the cell, where it accumulates into plaques. Further studies in this area will help to determine whether this process results in the production of the forms of beta-amyloid that are important in AD. NINDS-supported investigators are also conducting studies on potential new treatments for AD. For example, one new study is investigating the safety and effectiveness of an agent called CX516 to improve mental function in patients with mild to moderate AD. In earlier studies with healthy animals and human volunteers, CX516 was shown to improve memory. ------------------------------------------------------------------------ *National Institute of Mental Health (NIMH)* NIMH supports research on the causes of AD, its clinical course, and treatment and services for AD patients. In the last year, researchers supported by NIMH have made advances in a number of areas, including the use of advanced imaging techniques, improvements in understanding depression in both caregivers and AD patients, and the basic molecular underpinnings of the disease. NIMH-supported researchers have conducted several different studies using techniques that permit scientists to visualize brain regions as they are being used during certain cognitive operations. In one study, researchers at the University of Pittsburgh used positron emission tomography (PET) to study the semantic memory system of people with AD. Semantic memory is the knowledge of words, word meaning, and the relationships among these concepts. Many of the processes required for semantic memory may be found in the temporal lobe--predominantly in the left (language-dominant) hemisphere when words are used, and on both sides (bilaterally) when pictures or drawings of objects are the stimuli. Specific regions of the temporal lobes are responsible for specific aspects of semantic memory processing. Available evidence suggests that as a person ages, the normal activation in the temporal lobe is reduced--in AD, this activity is reduced even more. In addition, activity in other brain regions is also decreased as an AD patient performs semantic memory tasks. By contrast, when people age, or have AD, and are to perform certain types of memory tasks (for example, recalling lists of words), brain activity can actually increase, suggesting that these regions may be trying to overcome functional limitations. These data suggest that in AD the way that the brain responds to the developing abnormality differs depending at least on what cognitive operation is being performed, and perhaps as a function of the specific brain region involved. This is important because it may have implications for how to treat the disease: Are there specific brain regions (or brain neurochemical systems) that seem better able than others to respond to cognitive challenge? Further research will better delineate how AD affects these brain systems and whether they respond to specific therapeutic interventions. In other imaging studies, a second group of scientists at the University of Pittsburgh used PET to test the hypothesis that cognitive and behavioral symptoms of AD represent a failure of acetylcholine to modulate other functionally linked neurotransmitters, specifically dopamine and serotonin. These investigators found that the ability of acetylcholine to affect dopamine function is not impaired in healthy older people, but is impaired in AD. This suggests that healthy older people are able to compensate for age-related changes in brain function, whereas AD patients have difficulty doing so. Measuring cholinergic modulation of other neurotransmitter systems provides a more comprehensive way to think about the complex neurochemical systems and multiple symptoms of AD and may have implications for the future treatment of symptoms such as agitation, apathy, and psychosis, which are affected by multiple neurotransmitters. Another team of University of Pittsburgh scientists have used a technique called magnetic resonance spectroscopy (MRS) to examine the naturally occurring chemicals present in the brains of patients who have died with AD. This technique can also be used to measure many of the same chemicals in the brains of living patients. Much more detailed information can be obtained from studying tissue extracts than from studying living brains, however, so these data are extremely helpful in interpreting the information obtained from living patients. The sum of the two techniques--one more detailed and one more representative of the disease in living patients--is more powerful than either in isolation. Ultimately, knowledge of metabolic abnormalities will be critical in determining the pathology of AD. To date, these studies have shown that the AD brain shows evidence for breakdown of cell membranes, loss of a marker of healthy neurons, and loss of inhibitory and excitatory neurotransmitters. The data have also shown that genetic risk factors (APOE genotype) are related to increased metabolic abnormalities and that subtypes of AD show different metabolic patterns. Related studies ongoing in this same laboratory are aimed at developing small molecule probes that can enter the brain and specifically label the amyloid plaques located there. Some of these probes are fluorescent and can be visualized. Others are radiolabeled so that investigators can carry out quantitative studies of amyloid deposition. The probes developed so far have been able to bind specifically to all of the common pathological structures in AD brain. Future plans involve combining these two areas of research by comparing previously determined metabolic abnormalities to quantitative measurements of pathological AP deposits. Ultimately, both of these techniques could be applied in living individuals to study the causes of AD, provide very early diagnosis, and follow response to treatment. NIMH is also providing extensive support to scientists to investigate aspects of depression, an important problem that affects both AD patients and caregivers. It is estimated that as many as 20 to 25 percent of patients with Alzheimer's disease suffer from major depression, and an additional 25 to 30 percent suffer minor depression. The Depression in Alzheimer's Disease Study (DIADS), currently ending its second year, was developed to investigate further the treatment of depression in patients with Alzheimer's disease. The purpose of the trial is to determine whether sertraline, a selective serotonin reuptake inhibitor, may help to ameliorate depression in these patients. The trial, which was conducted at The Johns Hopkins Medical Institutions and the Copper Ridge Institute, also is investigating the specific benefits of depression reduction for patients and caregivers. It is anticipated that depression reduction will lead to improved memory, better functioning with activities of daily living, and less caregiver burden. The study already has produced several findings regarding depression in AD. For example, researchers have documented a strong link between depression and physical aggression in patients with dementia. This finding offers the theoretical possibility that depression treatment may reduce aggression in patients with dementia. DIADS investigators also have found notable differences in the relationship between cognitive and functional impairment and depressive features among patients with AD, vascular dementia, and undifferentiated dementia. These results suggest that the mechanisms underlying AD depression may be different from those of other types of dementia. The DIADS study also has supported the development of a new bedside global measure that can assess the presence of other specific diseases in patients with dementia. This scale is now being used by DIADS and will be available for use in many clinical and research settings, where it is important to quantify the seriousness of other medical conditions in patients with dementia. In other work on depression associated with AD, scientists at Ohio State University, Columbus, have been evaluating the longer-term effects of dementia caregiving by examining depressive symptoms among caregivers whose spouse died several years previously with AD (Glaser et al., 1998). These "former" caregivers continue to have elevated levels of depressive symptoms even 5 to 6 years after the loss of the spouse. In fact, the former caregivers are, on average, indistinguishable from current caregivers, with both groups reporting significantly greater depression than controls. These data are not typical of bereaved spouses in general. Research on bereavement shows that the average person recovers within 1 to 2 years and thus, this long-term change is not simply a reflection of the loss of the spouse. These scientists are trying to find out why AD caregivers do not recover as quickly as other bereaved spouses. One possible reason is that these former caregivers also continue to report higher levels of loneliness and lower social support than do controls. The multiple sacrifices made during caregiving, such as those related to jobs, finances, social activities, and hobbies, may be difficult to redress when caregiving ends, and this may effectively accelerate diminution of some facets of their social networks. The continued elevations in depressive symptoms also appear to have immunologic consequences. Data on influenza vaccine responses showed that both former and current caregivers showed significantly poorer immune system response to influenza vaccine than did controls. This suggests that both groups of caregivers were at greater risk for influenza and perhaps other infectious diseases. Another important area of AD work supported by NIMH is identifying the reasons why particular sets of neurons are vulnerable and die while other neuron types are spared. In other types of dementia, different populations of neurons from those in AD are vulnerable and again, the cause is unknown. In the case of AD, neuronal death is likely to be caused by a number of stresses, including oxidative stress and neuronal over-excitation. Researchers working on studies at the University of Southern California School of Medicine suggest that these stresses may have additive effects that converge through a common cell signaling pathway, ultimately exceeding a threshold and killing the cell. At the same time, neuroprotective factors also may operate through these pathways. Stress-activated protein kinases (SAPKs), especially c-Jun N-terminal kinases (JNKs), are prime candidates to mediate these effects. The team has found JNK3, a neuron-specific kinase, is activated either by the oxidant stress caused by beta-amyloid or by hypoxia/ischemia followed by reperfusion. This activation results in cell death. Using neural cell and tissue culture systems and mouse models, the investigators are examining very early steps in this cell-death process, including JNK interactions with other proteins, especially in the cell nucleus. They are characterizing and testing molecules such as human JNK interacting protein (hJIPI/IBI), which acts at an early stage in the process before cell death becomes inevitable. These studies may ultimately lead to intervention strategies early in the disease course. Another NIMH-supported area of research deals with the chronic inflammatory state that appears to exist in the AD brain. This state is thought to injure nerve cells and contribute to decline in memory and other brain functions. One NIMH-supported research team at Stanford University is working to identify factors that initiate and perpetuate this inflammatory state. Microglia, specialized inflammatory cells found in the brain, are thought to be key in this process. Normally, microglia are beneficial because they can rapidly initiate an inflammatory response that protects the brain against invading microorganisms or tumor cells by secreting toxic compounds. In AD, however, microglia are chronically activated and over time, the secretion of toxic compounds injures nerve cells. One stimulus that activates microglia in AD is beta-amyloid, although the effects of beta-amyloid alone on microglia are insufficient to account for the degree of nerve cell injury that occurs in AD. Augmenting factors must also be present. The researchers have identified macro-phage colony stimulating factor (M-CSF), a protein found at increased levels in the brain in AD, as an important co-activator of microglia along with beta-amyloid. When microglia grown in the laboratory were treated with beta-amyloid and M-CSF, the production of toxic compounds was dramatically increased. Other activating compounds were tested, but none was as effective as M-CSF in conjunction with beta-amyloid in activating microglia. Further, the investigators have shown that activated microglia themselves can produce beta-amyloid. Thus, in AD, microglia activated by beta-amyloid and M-CSF may produce more beta-amyloid, which further activates nearby microglia, thus initiating a vicious cycle of microglial production of toxic compounds. Currently, these scientists are studying animal brain tissue to learn more about the role of M-CSF, beta-amyloid, and microglia in AD. To visualize the densely packed cells in the brain tissue, the researchers use a laser scanning confocal microscope, a special type of microscope that allows them to differentiate among the many cell types present. They are also developing ways of introducing mutated genes known to be important in causing AD in humans into the animal brain tissues. By genetically engineering the brain tissue to produce abnormal proteins found in the brain in AD, including beta-amyloid, they can simulate the inflammatory process that occurs in AD under the controlled conditions of the laboratory. The team is also conducting studies using cerebrospinal fluid donated by patient volunteers with AD. Preliminary results show that M-CSF levels in cerebrospinal fluid from AD patients are correlated with levels of tau. Thus, patients with high levels of M-CSF also show high levels of an important marker for nerve cell injury in AD. These clinical studies will allow these scientists to test the relevance of laboratory models to the actual AD process in patients. A group of investigators at the Massachusetts Institute of Technology (MIT) have been studying what controls the rate at which brain cells make APP and what controls whether the APP is broken down to beta-amyloid or to soluble APP, a molecule derived from APP that may help neurons grow and function normally. They have discovered that certain neurotransmitters promote, or inhibit, APP formation, and other neurotransmitters promote, or block, its breakdown to beta-amyloid. With this information, the team has "cured" APP generation of beta-amyloid in tissue culture cells. Now they are developing animal models to see whether the same neurotransmitters, or drugs that mimic them, also work in the brains of intact animals. If these studies are successful, they may lead to tests of these compounds in patients. Patients with AD vary considerably in the clinical characteristics of their disease, including the age at which symptoms appear; the rate at which the disease progresses; the emergence of disturbances of mood, thought, perception, and behavior; the development of parkinsonian features; and the presence of a family history of AD-like dementia. This clinical variability suggests that AD, as currently defined, may more closely resemble disorders such as mental retardation or anemia, which have multiple contributing causes, rather than a disease with only one cause. In research supported by NIMH and NIA, a group of investigators at Carnegie Mellon University's Western Psychiatric Institute and Clinic are teasing out the reasons behind this clinical variability by searching for genetic and other biological factors, demographic characteristics, and environmental exposures that may influence the susceptibility of individuals to developing AD. Identifying these AD risk factors will provide clues about the causes of the disease and lead to the development of effective treatments. Furthermore, because the degeneration of brain cells that leads to AD appears to begin decades before the first symptoms emerge, risk factor profiles will be important in identifying asymptomatic individuals who are in the earliest stages of developing AD. Such individuals are the most likely to benefit from preventive treatments. In this research, the investigators recruited over 300 healthy first-degree relatives (brothers, sisters, or children) of patients who suffer from AD. These relatives, who are at risk of developing AD, were carefully evaluated for numerous characteristics that might contribute to their increased susceptibility. The study team also established a library of cell lines from most of this group so that the search for genetic and biological risk factors for AD could continue indefinitely even after the study was concluded. This at-risk group has now been followed for approximately 10 years and, so far, 18 have developed AD-like dementia. As this number grows, the team will continue to search for traits that contribute to the risk of developing AD. The research team also has conducted studies on the brains of patients who have died with AD to learn more about the development of depression and related behavioral disturbances in patients with dementia. These studies have shown that the death of neurons in the brain that release particular neurotransmitters is associated with the development of serious depression (more subtle dysfunctions of these neurons may contribute to the development of clinical depression in nondemented patients). This finding may partially explain why depression in AD is more difficult to treat with antidepressant medications. Moreover, the recurrent nature of major depression in AD may reflect the progressive loss of these brain cells over time. Current studies are focusing on the molecular and cellular processes that lead to the death of aminergic neurons in the brains of patients with AD as well as other aspects of the clinical biology of depression and related behavioral disturbances in AD. Advances in this area may suggest interventions that spare these and other brain cells in AD and other neurodegenerative disorders. These efforts are an example of including ADC patients in a study funded by another Institute, for the research is being pursued by a consortium of four NIA-funded Alzheimer's Disease Centers (University of California at Los Angeles, Indiana University, Baylor School of Medicine, and Mount Sinai School of Medicine) as well as the Geriatric Psychiatry Branch of the NIMH. *National Institute of Nursing Research (NINR)* NINR supports research on biobehavioral aspects of AD and related dementias. The primary focus of current studies is on behavioral, physical, and functional problems such as wandering, agitation and aggression, and maintaining activities of daily living. Disruptive behaviors by nursing home residents occur frequently, and nursing home staff need to manage these behaviors more effectively with nonpharmacologic methods. Unfortunately, conventional behavioral management training for nursing assistants does not ensure that they translate their training into practice, especially over time. NINR-funded researchers from the University of Alabama at Birmingham have developed a formal staff management system that helps to maintain taught skills (Stevens et al., 1998). This system includes monitoring of skills by supervisors, a weekly lottery for those who maintain the skills, and a monthly feedback letter to the nursing assistant summarizing his or her performance. Although nursing assistants who participated in conventional and the new training system improved their behavior management skills with AD patients immediately after the training, more of those in the formal management system were still using the skills 22 weeks after training. In two other NINR-supported studies, researchers examined some of the approaches used by caregivers of patients with Alzheimer's disease. The first study, conducted at Florida Atlantic University in Boca Raton, was designed to try to find evidence that patients in the middle and late stages of AD are able to maintain a sense of self or of personal identity (Tappen et al., 1999). A diminishing sense of self is a commonly-held belief about AD in both the popular and professional literature. Investigators conducted 30-minute conversations with nursing home residents who had been diagnosed with probable AD. Analyses of these taped interviews indicate that the patients did continue to maintain a sense of self into the middle and late stages of the disease. They were aware of their cognitive decline, but did not have an explanation for the changes. The study authors suggest that patients should be told of their AD diagnosis and be offered an explanation of what the diagnosis means for them. The second study was designed to investigate whether AD patients in the late stages of the disease can still develop a therapeutic relationship with their caregivers (Williams and Tappen, 1999). This issue is of practical importance because a common caregiver approach is to avoid most communication with AD patients except for task-oriented conversations. These University of Miami School of Nursing investigators found that most moderate- to late-stage AD patients were able to develop new relationships with the study's nurse practitioners. The study authors conclude that strategies are needed to encourage communication and the development and maintenance of relationships between caregivers and AD patients. These strategies may help to prevent the dehumanization that may occur as individuals progress through the later stages of Alzheimer's disease. *National Institute on Alcohol Abuse and Alcoholism (NIAAA)* Researchers supported by the Division of Clinical and Biological Research in the NIAAA are conducting a large, 5-year study to investigate the cognitive changes and dementia that are induced by alcohol consumption in order to differentiate clearly alcohol-related dementia from Alzheimer's or other conditions. Dementia in older adults with a history of alcohol abuse can be caused by a number of factors, including Alzheimer's disease, vascular disease, or alcohol. Alcohol-related neurotoxicity may be causally related to 20 to 25 percent of dementia cases in the elderly population (Smith and Atkinson, 1995). Because alcohol dementia is thought to be at least partly reversible with abstinence, its prognosis is very different from that for Alzheimer's disease. Establishing criteria for differential diagnoses of these two dementias thus has major practical and public-health implications. In a separate study, NIAAA-supported researchers are using proton magnetic resonance spectroscopy to characterize the longitudinal course of metabolic changes in regions of the brain that are sensitive to alcohol-induced damage, including the cerebellar vermis, frontal cortex, and frontal white matter. Cognitive functions, such as memory, are being evaluated simultaneously. NIAAA-supported scientists also recently developed a novel strategy for identifying cognition-enhancing drugs. This strategy has potential implications for treating a variety of diseases, including AD. Working with awake, freely moving rats and using a technique called microdialysis-coupled place-cell detection, the research team simultaneously linked a cognitive behavior --visually triggered memories of spaces--with directly measured neurotransmitter and electrophysiological responses of nerve cells exposed to pharmacologic agents in an area of the brain involved in memory. Other studies using techniques such as the one developed by these researchers may allow scientists to evaluate the potential of various cognition-enhancing drugs in treating AD. *National Center for Research Resources* NCRR develops and supports critical research technologies and shared resources that underpin research across the NIH. NCRR supports the development and use of sophisticated instrumentation and technology, new animal models for studies of human disease, and enhanced clinical research environments. NCRR also supports efforts to enhance the research capacity of minority institutions and of scientists who belong to minority groups. In a major study of the incidence of AD in ethnic groups, Columbia University scientists supported by NIA and an NCRR-funded General Clinical Research Center, found that African Americans and Hispanic Americans are at greater risk of developing AD than Caucasians (Tang et al., 1998). The new finding of the study was that African Americans and Hispanic Americans had an increased frequency of AD regardless of their APOE genotype. African Americans and Hispanic Americans with an APOE e4 allele were as likely as Caucasians with an APOE e4 allele to develop AD. However, in the absence of an APOE e4 allele, African Americans and Hispanic Americans were 2 to 4 times more likely than Caucasians to develop AD. These observations provide evidence that, in addition to the APOE e4 allele, previously unidentified genes and/or other risk factors apparently contribute to the etiology of AD among African Americans and Hispanic Americans. In another study, NCRR-supported investigators at Boston's Brigham and Women's Hospital used single photon emission computed tomography (SPECT) to determine whether regional cerebral perfusion was a preclinical predictor of AD (Johnson et al., 1998). Regional decreases in perfusion in several key brain areas (the hippocampalamygdaloid complex, the posterior cingulate, the anterior thalamus, and the anterior cingulate) were most prominent among study participants who may have had AD at the beginning of the study and who definitely converted to AD over time (these participants were called "converters"). Three of the four brain regions important for discriminating converters from healthy participants involve a distributed brain network pertaining to memory, suggesting that this network may be selectively affected in the earliest stages of AD. NCRR-supported investigators at the University of Pennsylvania School of Medicine also examined the role oxidative stress plays in the pathogenesis of AD by measuring isoprostane levels in AD and control brains (Pratico et al., 1998). The levels of both isoprostanes (iPF2-III and iPF2-VI) were markedly elevated in both the frontal and temporal cortex, but not in the cerebellar cortex (a relatively unaffected region), of the brains of people who had died with AD. Levels were also elevated compared to corresponding areas of brains from patients who had died with schizophrenia, Parkinson's disease, or from non-neuropsychiatric disorders. These data suggest that specific isoprostane levels may reflect increased oxidative stress in AD. Researchers at the University of Connecticut General Clinical Research Center evaluated the allele frequency for polymorphisms in six different genes of neuropsychiatric interest in six different populations (Gelernter et al., 1998). One of these six genes is the APOE gene, which has been shown to be a genetic risk factor for AD. The results revealed significant allele frequency variation among populations at all six loci. These results will provide a global framework of normal variation at these loci that might have functional significance or otherwise be related to susceptibility to various disorders or behavioral phenomena. Knowledge of this variation can be important for study design and data interpretation when individuals from various population groups are participating in research, and may eventually help lead to a better understanding of behavioral changes resulting from these variations in gene structure. The delivery of human nerve growth factor (NGF) by gene transfer to the brain has shown promise as a means of preventing cholinergic neuronal degeneration in human disorders such as Alzheimer's disease. In 1996, NCRR-supported investigators affiliated with the California Regional Primate Research Center (CRPRC) showed that NGF could rescue 80 to 100 percent of basal forebrain cholinergic neurons in nonhuman primates (NHPs) and reverse spontaneous age-related cholinergic neuronal atrophy. However, preliminary studies indicated that NGF also upregulates expression of APP, which could lead to an increase in the deposition of mature beta-amyloid in brain plaques. To examine this prospect in NHPs, the CRPRC scientists more recently studied aged rhesus monkeys treated with NGF (Tuszynski et al., 1998). After 3 months of treatment, the investigators found no significant increases in amyloid plaque formation in the treated monkeys over that found in healthy aged controls. This finding therefore supports NGF as a potential ameliorating agent in the treatment of AD and other dementias. NCRR-supported investigators at the University of Alabama at Birmingham have found that overexpression in transgenic mice of a specially engineered portion of APP resulted in vacuolation and increasing accumulation of beta-amyloid and APP fragments in skeletal muscle fibers during aging (Fukuchi et al., 1998). This pathology has similarities to the disease called inclusion body myopathy, and the results suggest that these transgenic mice may be a useful model for studying this disease. *National Institute of Child Health and Human Development (NICHD)* NICHD supports research related to AD primarily through its research programs involving neurobiology and mental retardation and developmental disabilities. NICHD-supported advances in basic neurobiology stem from the Institute's efforts to understand the processes underlying both normal and abnormal human development. These advances are helping researchers understand how brain functions, such as memory and thought processing, are established in early embryonic development, and may ultimately lead to therapeutic drugs that can address the gradual loss of memory function in patients with AD. For example, NICHD researchers recently confirmed the role of a substance known as brain-derived neurotrophic factor (BDNF) in sustaining memory. Using genetically engineered mice, NICHD-supported researchers demonstrated that BDNF, acting in concert with electrical impulses within the brain, enhances the ability of brain cells to store information. While there is no solid evidence that BDNF and other neurotrophic factors are involved in the development of AD, BDNF and its derivatives may one day serve as potential therapeutic agents for a variety of learning and memory deficits. Through research on Down syndrome (DS), NICHD-supported investigators are making other new inroads into understanding AD. While adults with DS are believed to be at increased risk for the type of dementia that is associated with AD, the natural history of dementia in these individuals is not well understood. Thus, researchers are comparing adults with DS to those with other forms of mental retardation to understand the differences and similarities in their neuropsychological and behavioral functioning. These efforts should contribute to improved diagnosis, treatment, and prediction of risk for all types of dementia, including AD. The NICHD also supports several studies that are directed at characterizing the cellular and molecular biology of presenilin genes and developing molecular and animal models to profile patterns of degeneration in AD. Many of these studies are designed to complement larger AD initiatives at various NIH Institutes. Finally, a recent breakthrough supported by NICHD may one day offer better prevention and treatment options for women with AD. Researchers at Yale University have used functional magnetic resonance imaging (fMRI), to show that estrogen alters brain activation patterns in postmenopausal women as they perform memory tasks. The fMRI produces computer-generated images of blood flow in the brain during such tasks as thinking, reading, or remembering. Researchers in the Yale study compared brain activation patterns in postmenopausal women when they were taking estrogen and when they were taking a placebo. The women were then asked to perform simple tasks, such as remembering a telephone number, which were designed to test their ability to store verbal information and hold it in memory for brief periods of time. The researchers found that estrogen changed the brain activation patterns of the postmenopausal women and that the changes resembled brain activation patterns typically seen in younger people. These findings show that it is possible to alter brain organization in older women, indicating that the memory systems of mature women are responsive to external stimuli rather than being fixed or immutable. In addition, these results suggest that the use of functional imaging, coupled with protocols examining proper dosing regimens for estrogen, may yield important new information concerning the effects of estrogen on cognitive function in postmenopausal women. *National Institute of Environmental Health Sciences (NIEHS)* Scientists supported by NIEHS are examining the ways in which metals and other compounds found in the environment may affect brain tissues and possibly contribute to the development of AD. For example, in studies in rat cerebrocortex, investigators working at the University of California at Irvine have shown that the neurotoxic peptide fragment from beta-amyloid is able to enhance the ability of metal ions such as iron, copper, and aluminum to produce free radicals (Bondy et al., 1998a). This may explain one mechanism underlying beta-amyloid-induced degeneration of nerve cells. This same research team also has studied the mechanism by which aluminum interacts with iron and other transition metals in protein-free systems (liposomes) (Bondy et al., 1998b). They were able to show that aluminum-induced potentiation of iron-effected oxidation was not dependent on the presence of protein and thus could not be attributed to membrane protein configurational changes. Although aluminum salts in biological tissue do not have any direct oxidation capacity, it has been shown that aluminum is able to increase the ability of iron salts to promote reactive oxygen species formation, which may be an important mechanism of nerve cell damage. Both iron and aluminum are present at high concentrations in the neurofibrillary tangles associated with Alzheimer's disease, but it is still unclear whether their accumulation is a cause of neurodegeneration or a result of it. In other work, NIEHS intramural scientists have found evidence for a new role for a specialized neurotransmitter receptor, the nicotinic receptor, in a subset of nerve cells in the hippocampus, a region of the brain important in learning and memory processes (Jones and Yakel, 1997). The receptor's function may be a key to understanding AD, and it may also be important in other diseases such as Parkinson's or depression. Alterations of nicotinic binding sites in the hippocampus have been reported in neurodegenerative disorders such as AD, and nicotine enhances cognitive function in some Alzheimer's patients. This discovery provides a molecular mechanism that may help explain some of the pathology of these disorders as well as of nicotine addiction. Activation of glial cells in the brain stimulates the expression of several cytokines and is believed to contribute to the pathogenesis of a variety of neurodegenerative diseases, including Alzheimer's. In other research, NIEHS intramural scientists have investigated the effects of several cytokines (interleukin-1, interferon-gamma, and tumor necrosis factor-alpha) in mouse cell cultures of neuronal and glial cells (Jeohn et al., 1998). These cytokines were shown to act as triggering signals for glia-mediated nerve cell injury. *National Institute on Deafness and Other Communication Disorders (NIDCD)* This NIH institute has focused its AD research on changes in the ways patients communicate with each other and understand and process information as their disease progresses. For example, several teams of researchers supported by NIDCD have investigated the semantic memory impairment in patients with probable AD. One team at the University of Pennsylvania School of Medicine has used a threshold oral word reading task to assess priming of different word relationships (Glosser et al., 1998a). Another team at the University of Pennsylvania Medical Center has worked with AD patients who have semantic memory difficulties and AD patients with relatively preserved semantic memory to determine whether the two groups differ in the way they name pictures and judge the category membership of words and pictures of natural kinds and manufactured artifacts that varied in their representativeness (Grossman et al., 1998a). Only semantically impaired patients were insensitive to representativeness in their category judgments. In other NIDCD-supported research, the University of Pennsylvania Medical Center scientists have used high-resolution single photon emission computed tomography in patients with neurodegenerative conditions to see how profiles of language comprehension difficulty are related to patterns of reduced cerebral functioning (Grossman et al., 1998b). This team found different patterns of reduced relative cerebral perfusion (blood flow) in patients with frontotemporal degenerative (FD) diseases and patients with AD. Cognitive assessments also showed different patterns of impaired comprehension in patients with FD and those with AD. Grammatical comprehension difficulty in FD correlated with relative cerebral perfusion in left frontal and anterior temporal brain regions; impaired semantic processing in AD correlated with relative cerebral perfusion in the inferior parietal and superior temporal regions of the left hemisphere. These findings are consistent with the hypothesis that a neural network distributed throughout the left hemisphere, rather than a single brain region, is responsible for understanding language. NIDCD-supported investigators also have evaluated the spontaneous communicative hand-arm gestures in older patients with probable AD (Glosser et al., 1998b). Patients with AD produced proportionately more referentially ambiguous gestures, fewer gestures referring to metaphoric as opposed to concrete contents, and fewer conceptually complex bimanual gestures. Other NIDCD investigators have focused on basic science issues, including studies to demonstrate the feasibility of using olfactory receptor neurons (ORNs) from biopsies to study changes in aging and neurodegenerative diseases (Rawson et al., 1998) studies to show that increased numbers of APOE-immunoreactive ORNs in AD patients compared to nondemented subjects demonstrates another manifestation of AD-related neuropathology that parallels changes in neurons in the AD brain (Yamagishi et al., 1998) and studies that have used MRI to gather and compare data on age-related changes within specific areas of the brain such as the insular cortex and the lateral ventricles of the brain (Foundas et al., 1998). ------------------------------------------------------------------------ *OUTLOOK FOR THE FUTURE* Alzheimer's is an old disease. Ancient Greek and Roman writers described symptoms similar to those that we know as AD. In the 16th century, Shakespeare wrote about very old age as a time of "second childishness and mere oblivion," suggesting that the symptoms of AD, or something quite like it, were known and recognized then. For many years, the clinical signs and symptoms of Alzheimer's disease were seen as an inevitable part of growing older. In the last 25 years, scientists have produced an extraordinary body of research findings on AD. Many of these findings have defined the genetic and biologic changes that underlie AD and offer possible targets for treatment. Researchers have identified drugs and other agents that could potentially counteract or compensate for the pathologic changes that occur in AD. They have made gains in identifying the means of detecting persons at high risk of developing AD. As methodologies are refined, scientists and clinicians will be able to investigate and understand the very earliest pathological and clinical signs of AD--perhaps 10 to 20 years before an actual clinical diagnosis is made. A variety of approaches also have been applied to improve methods of providing quality care for AD patients, reduce caregiver burden, and decrease the need for institutionalization. In seeking to understand AD, investigators are also describing normal aging. The research is beginning to shed light on healthy cognition and how to minimize normal age-related cognitive decline. Federal support of AD research has been the foundation of many of these breakthroughs in our understanding of the disease. This funding has also helped establish an infrastructure that will continue to facilitate research advances. Novel grant award mechanisms, such as the Alzheimer's Disease Centers Program and the Leadership and Excellence in Alzheimer's Disease award, have attracted distinguished scientists to AD research promoted interdisciplinary research collaborations enhanced coordination of research data from multiple studies developed patient examination facilities and biologic resources that are necessary for research on the disease and enabled patient outreach efforts. These scientific advances, and the research infrastructure that supports them, have made it possible for the NIH to launch a new initiative that builds on current activities and gives a new focus to future work. This initiative, the NIH Alzheimer's Disease Prevention Initiative, is designed to expedite the progress toward finding effective medications and other approaches to delaying or preventing the onset of Alzheimer's disease. In collaboration with other Federal agencies and the private sector, this initiative is moving forward on several fronts simultaneously: * fostering new approaches to basic biologic and epidemiologic research; * increasing the focus on drug discovery and development; * improving methods to identify early those people who are at increased risk of developing AD; * facilitating movement of possible new treatments into the clinic for testing in clinical trials; and * actively pursuing research into drug and non-drug strategies for treating behavioral disturbances in AD patients. Potential targets for AD prevention have been identified. These include estrogen-like compounds, anti-inflammatory agents, and antioxidants, as well as drugs that target cell death, the accumulation of abnormal insoluble molecules, and other harmful processes involved in AD. These targets were completely unknown only a few years ago, and the pace of discovery is accelerating. The AD Prevention Initiative will stimulate laboratory and clinical research in these areas. Some of the clinical trials that are part of the AD Prevention Initiative are already underway, and many more are planned. For example, the first NIH clinical trial aimed at preventing or delaying the onset of clinically diagnosed AD in persons at risk--the Memory Impairment Study--was launched in March 1999. Other trials will be added onto already ongoing trials that are investigating treatments or prevention strategies for other conditions. This "piggy-backing" approach will produce results much more swiftly and cost-effectively than will newly initiated, freestanding studies. Importantly for those who now have the disease, NIH also is intensifying its AD research and information efforts on issues related to supporting patients and the family members, friends, and providers who care for them. These efforts will include a special emphasis on the needs of a diverse patient population. A defining aspect of the AD Prevention Initiative is collaboration among NIH institutes and with other Federal agencies, private pharmaceutical companies, and the private sector. The major NIH funders of AD research-- the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, and the National Institute of Nursing Research--make up the NIH AD Working Group that will coordinate and direct the Prevention Initiative. Other NIH institutes that fund AD research also will be closely involved in the initiative. For several years, NIA staff have worked with other Federal agencies, including the Health Care Financing Administration, the Department of Veterans Affairs, the Food and Drug Administration, and the Centers for Disease Control and Prevention on various areas related to AD. These areas include developing data sets for research purposes, collaborating in research, developing appropriate standards for testing drug efficacy, and pursuing outreach and education efforts. NIH will continue this collaboration, as well as efforts to develop relationships with State and local agencies so that effective AD prevention and treatment strategies can be successfully carried out in the community. The NIH also will continue to cooperate with pharmaceutical companies in basic research, drug development, and testing and, in particular, will continue to encourage small companies to apply for drug development grants. As part of this aspect of the Prevention Initiative as well as for other future research initiatives, NIH will continue to identify partners for collaboration and to encourage its grantees to build collaborative research relationships with the private sector. Last, but by no means least, the NIH will continue to work closely with voluntary organizations such as the Alzheimer's Association. One example of this partnership is NIH/Alzheimer's Association co-sponsorship of conferences on different aspects of AD research. The Alzheimer's Association also collaborates in research, education, and outreach at the local and national levels with Alzheimer's Disease Centers, NIH-supported AD investigators, and the NIA's ADEAR Center. Executives of the Institute for the Study of Aging, Inc., a non-profit organization recently established primarily to facilitate development and testing of effective drugs for AD, also will be discussing possible joint initiatives with the NIH. The AD Prevention Initiative will work to expand and strengthen these interactions. 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