Alzheimer's Disease and Related Dementias: Biomedical Update, 1995: PART 1
By Advisory Panel on Alzheimer’s Disease •
August 1, 1995
Advisory Panel on Alzheimer's Disease
The Advisory Panel on Alzheimer's Disease, congressionally mandated by Public Law 99-660 and reauthorized by Public Law 102-507, was appointed by the Director of the Office of Technology Assessment, a non-partisan analytical agency that serves the U.S. Congress. The Panel was charged to advise the Department of Health and Human Services (DHHS) and its Council on Alzheimer's Disease, as well as the Congress, on Alzheimer's disease research priorities and policy recommendations. Its chairperson was appointed by the Secretary of the HHS, and its activities have been administered through the DHHS. This report is submitted to the Congress, the Secretary of the HHS, and the DHHS Council on Alzheimer's Disease; it also is released to the general public.
While the final version represents the advice and effort of the entire membership, the Panel wishes to express particular appreciation to Laura Manuelidis, M.D., for her leadership and to Drs. Berg, Blass, Larson, and Price for their contributions to the development of this report. The opinions expressed herein are the views of the authors and do not necessarily reflect the official position of the U.S. DHHS or any of its components.
All material appearing in this volume is in the public domain and may be reproduced or copied without permission from the DHHS or the authors. Citation of the source is appreciated.
Biomedical research holds the promise of radically altering the present situation, in which Alzheimer's disease and related disorders cannot be prevented, slowed, or cured. In recent years, dramatic progress has occurred in research, to the extent that the field appears to be closing in on a biomedical understanding of the disease process in Alzheimer's disease and stands poised for additional breakthroughs that may lead to effective means of prevention or treatment for dementing disorders.
Each year, Alzheimer's disease (AD) and other dementias cast a shadow over a growing number of lives. Currently, an estimated 4 million Americans suffer from AD, while countless others are impaired by related dementing disorders. The financial burden of dementia, including direct care costs and lost productivity, has been estimated to be approximately 100 billion dollars annually. This estimate does not begin to take into account the immeasurable costs of care provided by family caregivers, many of whom are older spouses in poor health themselves or adult children in the midst of raising families of their own. Yet, the annual Federal biomedical research budget for AD comes to only 0.3 percent of the total cost of the disease to society.
AD does not simply affect the person with the disease. The lives of families, caregivers, and communities are significantly affected by the person's irreversible loss of cognitive and functional ability due to the disease. The man or woman who once was a vibrant, contributing member of society becomes increasingly dependent, faced with a "self" that fades as the disease progresses. As the size of the population of older Americans increases, so will the number of people at risk for diseases. Without an effective way to prevent or treat AD, the number of people with the disease is projected to spiral to 14 million by the middle of the next century. AD and related disorders pose a growing threat to the health and well-being of an expanding population of older Americans.
This Panel recognizes and appreciates the current difficulties for the Congress and the DHHS in setting balanced funding priorities, especially given our current national budget deficit. However, we remain convinced that funding for new initiatives in dementia research has a good chance of being repaid by reducing the human and economic costs of AD. Indeed, delaying the onset of AD by only 5 years will reduce by half both the number of people suffering from AD and the total national costs of the disease.
The Importance of Biomedical Research
Several critical questions concerning AD remain unanswered. What causes AD? How does it affect the brain? Why do some people get it, while others remain healthy late in life? What can we do to intervene in or prevent AD? The quickening pace of biomedical research efforts has provided tantalizing clues to the answers to these questions, yet a gap remains between our current knowledge and a complete understanding of dementing diseases. Three fundamental concerns underscore the need for a diversified research approach to dementia:
1. The expected increase in the number of older people in our society, particularly those over age 85, will promote additional late-onset cognitive disorders.
2. Because many older people never experience the cognitive impairment associated with dementia, studies of possible protective factors deserve support.
3. Because people with dementia may live in a dependent, non-functional state for more than 10 years, the costs of dementia are extraordinarily high.
The important role of biomedical research on AD has been clearly established. As recently as 20 years ago, AD was a poorly understood disorder receiving little or no attention from researchers. Today, entire textbooks on the disease illustrate the rapid pace at which knowledge about AD has grown. Because of the multifaceted nature of the disease, however, it will take a high level of effort and inevitable trial and error to more completely understand the processes at work in the brain. For this reason, sustained funding for biomedical research is essential to advance our ability to diagnose, treat, and ultimately prevent AD.
Scientists have taken diverse approaches to the study of AD. Much of our current knowledge comes from piecing together results from research areas such as amyloid protein studies, neurotransmitter system analyses, immunology, genetics, and epidemiology. By exploring a wide range of potential causes, researchers are moving closer to understanding the pathways that diseases like AD follow in the human brain. To illustrate the progress that has been made and the promise that exists if funding is sustained, the Advisory Panel on Alzheimer's Disease has highlighted some of the most innovative and exciting work in this report. Particular areas of interest include:
Scientists have long suspected that genetics may play an important role in the development of AD. These suspicions were confirmed by the identification of genetic mutations on chromosomes 14 and 21. Researchers are working with families who exhibit clear patterns of inheritance of a form of AD called familial Alzheimer's disease (FAD) to pinpoint the exact location of several of these mutations and to determine their functions.
A recent research finding in the field of genetics has shed new light on a potential factor in the development of AD. A gene on chromosome 19 appears to be associated with late-onset or sporadic forms of AD. This gene is responsible for the production of a cholesterol-transporting protein called apolipoprotein E (ApoE). Research indicates that inheriting certain forms of the ApoE gene may increase a person's risk for AD. Should ApoE prove to be a useful screening tool, ethical concerns regarding the effects and/or benefits of communicating information to patients and families must be addressed.
Beta-Amyloid and Tau Protein Studies--The plaques seen in the brains of people with AD are composed primarily of beta-amyloid protein. While it is not yet clear whether deposits of beta-amyloid cause or result from AD, researchers suspect that the way beta-amyloid originates from the amyloid precursor protein (APP) and is processed or deposited may be important to a complete understanding of AD.
Research on amyloid has significant implications for developing an effective treatment for AD. A recently developed transgenic mouse model may help provide important clues. Diagnosis of AD in the very early stages, even before actual symptoms appear, someday may enable researchers to intervene before beta-amyloid accumulates and harms brain cells. Researchers also are looking at chaperone proteins, which are involved in processing both beta-amyloid and APP, as potential targets for intervening in the disease's development.
While amyloid is a primary component of plaques, other proteins are deposited in the brains of people with AD as well. Scientists are looking at other dementing diseases for clues, hoping that changes taking place in the brain in those diseases will shed light on how and why brain cells die in AD. In some less common dementing diseases, such as kuru and Creutzfeldt-Jakob disease (CJD), a protein known as prion protein, or PrP, is deposited into plaques in the brain. Like beta-amyloid, PrP can be toxic to brain cells. Understanding the way PrP affects the brain in some dementing diseases may help researchers better understand the function of beta-amyloid in AD.
Scientists also are studying the role of tau, a normal brain protein that is the major component of the neurofibrillary tangles (NFT's) noted in AD. Understanding how tau is produced and processed is important to researchers as they attempt to understand how AD unfolds in the human brain. Tau processing also may serve as a target for the development of new therapies to treat the disease.
Inflammatory Changes and Therapies
Some researchers are pursuing the role of inflammatory or autoimmune processes in late-onset dementias. These processes can be triggered by a variety of environmental causes, including toxins or viruses. Certain types of cells in the brain can interact with or produce inflammatory molecules that destroy healthy brain cells. Researchers are seeking to understand how this process may occur in AD and what might be done to prevent it. Studies are underway with anti-inflammatory drugs, which researchers hope will minimize cell damage and slow or prevent the brain changes that occur in AD.
Electrophysiological, Metabolic, and Neurotransmitter Studies--In addition to the cell changes that take place in dementia, changes occur in the brain's metabolic, electrophysiological, and neurotransmitter systems that affect functional ability. For example, the neurotransmitter glutamate, necessary for cells to work correctly, can be toxic to cells at higher levels.
Researchers are studying glutamate and other excitatory neurotransmitters to determine if chronic, low-dose exposure to them may have a toxic effect. They also speculate that some substances produced when certain brain receptors are stimulated excessively, such as nitric oxide, may play a role in the sequence of events leading to AD.
Studies are underway to develop potential treatments for dementing diseases based on what scientists are learning about neurotransmitter changes. Researchers hope to identify drugs that prevent neurotransmitter damage and cell death. Some scientists are exploring proteins called neurotrophic factors that may help keep brain cells healthy during adult life, thus protecting them from damage due to changes in the various systems of the brain.
Epigenetic DNA Studies
For cells to function properly, deoxyribonucleic acid (DNA) must be intact. Epigenetic changes are changes, usually due to some sort of damage, that occur after DNA is inherited. Recent research indicates that calcium may activate certain enzymes in the brain that cause healthy DNA to fragment. In addition, free radicals, environmental toxins, and some proteins can damage DNA, which, in turn, may affect how cells work. Damage to DNA may accumulate over time and be compounded by the aging cell's decreased ability to repair the destruction.
Persistent and Latent Virus Studies
Some scientists have suggested that a subset of patients with symptoms of dementia may have latent viral infections. These infections do not cause the white blood cell reactions seen in typical viruses. Thus, they may be able to evade the body's immune systems, eventually leading to cognitive and functional impairment, although lying dormant for many years before symptoms appear.
Older people may eat poorly, particularly if they live alone. Damage to DNA and other brain functions may be accentuated when poor nutrition compromises the health of brain cells. Inadequate nutrition also may tip the balance toward the breakdown of brain cells seen in dementia. Researchers are using animal models to see if environmental toxins cause the brain to change prematurely in those with poor nutrition.
Epidemiologic studies play a critical role in dementia research and are central to policy development. These studies help identify who gets dementia and suggest reasons why. For example, studies of twins who have identical genes suggest that it is unlikely that AD is a purely genetic disease. One or more environmental factors may be necessary for AD to develop.
Recent epidemiologic studies have suggested new avenues for research. For example, AD affects more women than men, even when taking into account that a higher proportion of women survive into old age. Scientists want to know why. One study indicates that post-menopausal women taking estrogen supplements may have a delayed onset or reduced incidence of AD.
These findings indicate that a broad range of exciting research opportunities exist. The explosion of new information, innovative technologies, and improved research resources provides great possibilities. While the next important discoveries cannot be predicted with confidence, some areas of research appear especially promising. These include:
a. Pursuing the cellular pathways specified by mutant genes in AD and other dementias.
b. Identifying mechanisms of amyloid formation and neurotoxicity.
c. Developing cell culture and animal models of disease.
d. Conducting epidemiologic studies to determine environmental risk factors and to definethe interactions between genetics and environment.
Given the broad areas of significant research outlined in this report, the Panel emphasizes the need for a diversified research portfolio that combines well-established projects and innovative hypotheses. Encouraging innovative scientific approaches from many disciplines is critical. Already, major advances have been derived from lines of inquiry initially thought to be unrelated to dementia. Specifically, the Panel encourages support for research with the following goals:
a. To identify the various causes of dementia.
b. To clarify the specific processes in the brain that cause cell damage and death to expose the entire chain of events that unfolds to cause cognitive and functional impairment.
c. To better understand why some older people do not experience cognitive decline, even in very advanced ages. Research also is needed to identify protective factors and to understand higher rates of AD among women as compared to men.
d. To develop cell culture and animal models of disease that can be used to evaluate novel mechanisms of disease and new therapies.
e. To suggest and test potential treatments for the disease and for the cognitive and behavioral symptoms that accompany it to reduce the human toll of AD.
Research is the best weapon we possess to fight the devastation of AD and related dementias and to decrease the prevalence of the disease in our population. The biomedical community is poised for rapid and relevant advances at all levels of investigation. This opportunity should not be lost. A diverse program of biomedical research during the next 10 years will save resources by delaying the need for full-time care of people with AD both at home and in long-term care institutions. The Panel proposes the following steps to provide adequate resources for AD research:
a. Increase investigator initiated awards in addition to large, collaborative projects.
b. Expand awards to include more disciplines.
c. Recruit young and talented scientists to the field.
d. Encourage senior investigators to use their resources and expertise to train new scientists.
e. Enhance investigator ability to evaluate new treatments, particularly those using drugs that are already well studied for other conditions.
This Panel believes that a long-term commitment to a multidisciplinary research approach is the best way to identify, treat, and care for people with AD.
The Advisory Panel on Alzheimer's Disease, established under Public Law 99-660 (amended by Public Law 102-507), was charged with the following mandate:
The Panel shall assist the Secretary of the HHS and the Council on Alzheimer's Disease (an intra-governmental task force also established under the same statutes) in identifying priorities and emerging issues with respect to Alzheimer's disease and related dementias and the care of individuals with such disease and dementias. The Panel shall advise the Secretary and the Council with respect to the identification of:
1. emerging issues in, and promising areas of, biomedical research relating to Alzheimer's disease and related dementias
2. emerging issues in, and promising areas of, research relating to services for individuals with Alzheimer's disease and related dementias and their families
3. emerging issues and promising initiatives in home and community-based services, and systems of such services, for individuals with Alzheimer's disease and related dementias and their families
4. emerging issues in, and innovative financing mechanisms for, payment for health services and social services for individuals with Alzheimer's disease and related dementias and their families, particularly financing mechanisms in the private sector. (Sec 922 [a])
This report is submitted to the Congress, the Secretary of the HHS, and the DHHS Council on Alzheimer's Disease; it also is released to the general public.
Why We Must Be Concerned About Alzheimer's Disease. Currently, there are 4 million Americans with AD. Society is aging, and prevalence of the disease increases dramatically with age. Unless we identify measures to prevent or delay AD, the number of people with this disorder will rise to between 12 and 14 million by the year 2050. It now is estimated that AD costs the country more than 100 billion dollars annually, leading to major emotional, physical, and financial strain on families and caregivers.
What Is AD?
AD is the most common among many forms of dementia. It is characterized by loss of memory, decreased intellectual function, and deterioration of personality. Eventually, a person with AD becomes unable to perform even the most basic self-care activities. These symptoms result from loss of function of nerve cells (neurons) in the brain. Microscopically, the brain shows atrophy and loss of neurons, as well as characteristic NFT's and amyloid-containing senile plaques. Functional and molecular changes not visible through the microscope precede these end-stage changes and are likely to be important targets for therapy.
Recent Research Results and Their Implications.
Exciting and potentially high-impact findings have emerged from biomedical research. Scientists have identified several genes linked to AD. Some genes are associated with early-onset FAD, while still another gene has been identified as a risk factor in the far more common late-life form of AD. Recent research also has led to a better understanding of the mechanisms underlying the formation of plaques and NFT's, which may play a role in other dementias. Another research theme focuses on maintaining the viability of neurons and protecting them from a wide variety of damaging factors. Although effective ways to prevent, delay, or treat AD presently do not exist, researchers are building on current studies and recent advances to develop new therapies.
Encouraging innovative approaches from many scientific disciplines is critical. Already, major advances have been derived from lines of inquiry initially thought to be unrelated to dementia. For example, researchers recently identified a cholesterol-transporting protein that may play a role in AD. Furthermore, study of several late-life dementing diseases may provide information that is pertinent to the basic mechanisms underlying AD. Research findings already point the way toward therapies with potential to benefit patients, their families, and society. It therefore is essential to sustain and accelerate funding for both basic and applied research.
AD and other progressive dementias exact a terrible toll on individuals, their families, and health and community services. The problem of dementia has been brought to the attention of the public by the enormous number of people who have observed the full extent of mental deterioration in their relatives. Courageously, Ronald and Nancy Reagan recently highlighted these issues. Over the past decade, the Congress authorized a major initiative to address the problem of dementia by creating an Alzheimer's-specific research program. This targeted funding has had a significant impact on the field, and is central to alleviating the family and societal burdens of AD. The Panel continues to emphasize the importance of basic biomedical research. This is the single most effective way to elucidate the causes and mechanisms of these devastating diseases, to implement effective preventive measures, and to design treatments to reduce the increasing prevalence of dementia in our population. Given the great cost of dementing diseases to society, research on these disorders is seriously underfunded. Currently, the annual Federal biomedical research budget for AD amounts to only 0.3 percent of the costs of the disease to society.
As a central part of the AD initiative, a network of 28 federally funded Alzheimer's Disease Centers (ADC's) provides a valuable resource for in-depth evaluation of well-studied patients. Researchers can analyze clinical and epidemiologic data, collect appropriate tissue samples for neurobiological analysis, and study new therapeutic initiatives in a scientifically controlled manner. Investigator-initiated research flourishes in the interdisciplinary Center setting. However, innovative science requires funding for qualified and independent investigators. To use the resources of the Centers effectively, the Panel considers it most fruitful to recruit additional talented investigators from a broad array of disciplines. While the funding of Centers continues to be an important goal, the Panel recommends that supporting investigator-initiated basic science research be a priority.
The detailed progress report below highlights only a few of the new findings that are especially remarkable. The success of several novel approaches underscores the need for increased funding. It would be unwise to limit these advances or to narrow the scientific scope of dementia research. There are many facets to dementing disease, requiring differing but complementary approaches--from clinical and experimental animal studies through basic investigations to penetrate cellular and molecular mechanisms of disease. Together these can yield a rational approach to prevention and therapy. This report encourages pursuit of the most fundamental knowledge necessary for an effective attack on dementing diseases to benefit the largest number of people, reduce societal costs, and alleviate suffering.
The ultimate goals of dementia research are to elucidate potential causes, to define their mechanisms, and to prevent these diseases. Great strides have been made in sorting out familial forms of dementia and in uncovering the link between genetic makeup and the development of familial disease. However, many adult dementias appear to be spontaneous or sporadic and may have no established or clear single genetic cause. Therefore, other approaches deserve attention, including environmental and host co-factors that may contribute to dementing disease.
It is crucial to understand what factors cause dementia or contribute to its progression. Information on potential factors comes from a variety of different research pathways, and ultimately may allow scientists to delay the onset of dementia or halt the progression of cognitive symptoms. Genetic risk factors, complex inflammatory responses, and the formation of potentially toxic amyloid in the brain all may play a role in the development and progression of dementia. The field of neuroprotection also may hold significant promise, as nerve cell plasticity or remodeling may be affected when neurotrophic factors required for brain cells to survive are depleted. Our current human immunodeficiency virus (HIV) epidemic illustrates that persistent viral infections also may play a role in dementia. It is important to note, however, that basic science already has suggested therapeutic applications for dementia. For example, detection of inflammatory components in the brains of people with AD has provided an impetus for pilot therapeutic trials (see below).
Although the initial events that cause dementing diseases are not yet completely clear, it is notable that a subset of common cellular pathways appear to be involved in many neurodegenerative processes, regardless of their cause. These pathways can be targeted in a more generalized approach to preventing progression of the disease. Studies implicate a few key complementary avenues that are shared by many dementing diseases, including cellular processes involved in amyloid deposition and indirect mechanisms of neuronal damage by cellular factors.
The Panel recognizes that investigative avenues are linked and strongly recommends a diversified portfolio of research in dementia. Scientific progress will be unnecessarily confined if funding is only provided for a very few themes. Without sufficient support, original investigations that are so crucial for unanticipated progress may be lost entirely. Identifying more than one factor provides positive opportunities to combine different strategies for preventive and therapeutic success. Furthermore, each piece of the puzzle is likely to be not only complementary, but vital to unifying the entire picture.
While it is essential to sustain funding for promising areas of research currently under investigation, it also is important to support more innovative lines of inquiry. These novel research approaches may seem risky at first glance, but often have the potential to lead to critical breakthroughs. In addition, recruiting more scientists with substantial expertise (for example, in pharmacology, immunology, virology, protein chemistry, and basic biology) will assure a diversified effort and maximize the chances of success in preventing and treating dementia. Continued development of animal models of neurodegeneration and application of newer imaging techniques to explore early stages of human dementia also are critical avenues for any multidisciplinary effort to reduce the incidence and prevalence of dementia.
Rationale for Supporting Diversified Approaches
The reasons for expanding the research support in dementia include the following:
1. To understand the nature and magnitude of the problem of dementia, it is important to understand that neurons do not multiply. Over a lifetime, our neurons steadily accumulate the effects of damage from environmental insults. This damage, which begins long before symptoms are apparent clinically, may lead to a loss of neurons and the development of dementias of the elderly. Therefore, efforts to identify significant environmental factors that contribute to dementia, such as chemicals, toxins, nutritional deficiencies, and infectious agents, should be encouraged. The expected increase in our elderly population will promote additional late-onset cognitive disorders.
2. As the human lifespan increases, an increasing number of people will show the consequences of nerve cell damage. However, some older people remain remarkably intelligent and creative, while others experience a tragic loss of mental capacity. It is important for researchers to understand the differences in susceptibility between these different groups of individuals. In other words, studies of the protective factors that allow some older people to sustain mental acuity deserve support.
3. People with dementia typically do not show deterioration of other organs. Because individuals with severe dementia can live in a dependent, non-functional state for more than 10 years, the costs of dementia are extraordinarily high. The costs to families are even greater, as they encompass emotional and physical burdens that reach far beyond the financial issues.
Achievable Goals of Fundamental Research
The purposes of basic research include the following aims:
1. to identify the various causes of dementia
2. to define the mechanisms of degenerative brain changes
3. to develop and refine experimental models of disease, both in cultured cells and in living animals, that can be used to test existing and new drugs.
Understanding the causes and mechanisms underlying dementia will provide new avenues for prevention and treatment.
Scientific Background and Perspectives
Despite the public expectation that dementia will be cured with a simple, fast-acting prescription drug, AD and other dementing diseases are not simple disorders. Unraveling the mysteries of dementing diseases requires a thorough assessment of research goals and strategies. To date, knowledge gleaned from basic research has provided sometimes unexpected and often important breakthroughs.
Ultimately, neurons fail to function and communicate with each other in dementing diseases. Because neurons die in a limited number of ways, a descriptive clinical or pathological classification of dementing illness is only a rough approximation of the final common mechanisms leading to death. It remains unknown why some neurons, such as those of the motor cortex of the brain, remain resistant to this process in many dementing diseases.
Furthermore, the end-stage changes associated with dying neurons do not indicate the original cause(s) of injury. Several different causative and intrinsic susceptibility factors need to be considered in dementia research.
End-stage changes in the brain often are used to classify disease, but there are limitations to this approach. One type of neuronal change, known as a NFT, is common to several neurodegenerative diseases. Many factors can cause this type of lesion. For example, repeated head injury leads to the well-described dementia of boxers (dementia pugilistica). In this condition, NFT's can be prominent. NFT's also are found in subacute sclerosing panencephalitis, a disease caused by a measles-like virus. The same tangles are seen in post-viral late-onset forms of Parkinson's disease as well as in AD. Thus, strategies that help us understand the common processes involved in neurofibrillary degeneration may be useful in explaining several causally unrelated conditions. Different factors may lead to the same final pathway for injury, underscoring the need to identify common pathways. Similarly, drugs designed to interrupt the general processes involved in amyloid plaque formation may be of use in several conditions that have a different primary cause, but which share common final mechanisms of damage. As discussed below, there are several protein derivations of amyloid. In all cases, however, membrane products and aggregation mechanisms are involved. Therefore, research on basic mechanisms already provides essential information for new therapeutic strategies.
Studies on these two pathological changes illustrate the importance and potentially wide application of different initiatives and hypotheses. Recent work implicates a diversity of causes and contributory co-factors in AD. Genetic studies have identified several pertinent genes. However, when specific genetic and environmental factors can be used to define different subsets of progressive dementia, treatments may be optimized for each group. Such fundamental definitions may illuminate the reasons why only a modest number of patients with AD respond favorably to treatment with a given drug, such as tacrine. A different subset of patients may respond to other novel therapies. For example, DNA therapy designed to correct a genetic defect eventually may benefit people with dementias caused by a mutant gene.
Identifying the major causes of dementia also will lead to a better understanding of different mechanisms of progressive disease and suggest new preventive strategies. In this context, the association of several different persistent viruses with cognitive loss deserves attention. It is conceivable that appropriate vaccines may be able to prevent infections that cause or contribute to some dementias. Similarly, information on additional environmental toxins that affect neuronal survival may be applied to disease prevention. The study of less prevalent forms of neurodegenerative dementing disease also has suggested possibilities for treatment and prevention that may have broad application. For example, natural neurotrophic or growth-enhancing factors that promote the survival and growth of neurons are being developed to treat several neuronal diseases (Barinaga 1994b; Mitsumoto et al. 1994). Some of these eventually may be of value in counteracting the progressive atrophy of neurons in AD. Additionally, comparisons of individual cases of Huntington's disease in siblings have shown large differences in the age of onset. These differences appear to derive from "imprinting," where the chemical structure of DNA is modified during development. This leads to a change in the activity of the gene (Surani 1993). These molecular observations suggest new ways to uncover and exploit the natural ways the organism retards its own destruction.
The recent explosion of information from molecular, genetic, and cell biology research and brain imaging provides an extraordinary opportunity to identify not only the critical underlying mechanisms in dementia, but also the ultimate causes of disease.
Overview of Research Opportunities
1. Genetic research has begun to clarify differences among AD patients. The mechanisms of these genetic influences now can be pursued in an experimental setting. The continued development of animal models as well as cell culture systems is crucial for initial tests of pharmacological agents.
2. Protein and cell biology studies have elucidated relevant protein pathways. Changes in the normal cytoskeletal protein tau appear to be critical in the formation of the NFT. Additionally, proteins that induce cell death have been described. For example, membrane-derived proteins that form amyloid plaques have been shown to be neurotoxic in an experimental setting (Forloni et al. 1993). Proteins that cause rapid cell death or apoptosis, and death-preventing proteins recently have been defined (Lam et al. 1994; Tomac et al. 1995; Bredesen 1994). Because some of these proteins are important in brain development, it would be surprising if they were not recruited abnormally in a subset of dementing processes. Researchers have just begun and must continue to study such proteins in dementing disease.
3. Unsuspected persistent viruses causing demen-tia are being defined now that increasingly sensitive molecular nucleic acid techniques have become available. Recent molecular amplification strategies have made it possible to detect several persistent or latent viruses in the brains of many individuals (White et al. 1992). The possible role of such persistent viruses in dementing diseases has been considered (Manuelidis 1994a), but not tested empirically.
4. Important new studies of inflammatory changes in AD and pilot therapeutic anti-inflammatory approaches (McGeer and Rogers 1992; Rogers et al. 1993; McGeer et al. 1992; Chui et al. 1994) deserve further study.
5. Powerful new functional imaging technologies for the brain have only recently been applied to the study of various dementias (Budinger 1994).
These studies may define new aspects of the failing intellect found in dementia that have not been fully explored. Using non-invasive imaging techniques may assist in the classification of different types of dementia, clarify forms of cognitive impairment, and suggest more general targets for therapy. Such studies also may help clarify the acknowledged discrepancies between specific brain lesions and cognitive disorders.
These are only a few of the reasons why the Panel emphasizes the need for substantial long-term funding for a well-diversified group of projects in dementia research. This Panel recognizes and appreciates the current difficulties for the Congress and the DHHS in setting balanced funding priorities, especially given our current national budget deficit. However, we remain convinced that funding for new initiatives in dementia research has a good chance of being repaid by reducing the human and economic costs of AD. Indeed, delaying the onset of AD by only 5 years will reduce by half both the number of individuals suffering from AD and the total national costs of the disease (Katzman 1993).
Rather than emphasizing a single dramatic new finding that will lead to instant success, we offer a more balanced view that draws on many different disciplines and ideas. Differing views about the causes and mechanisms of dementia are to be expected in a relatively new and dynamic field. Indeed, progress on several fronts signifies vital growth and development. This report predicts an enormous peak of significant discoveries that lie before us. We have good reason for optimism, especially in the next 5 to 10 years.
Pertinent Scientific Findings
1. Genetic Studies
Studies as far back as the 1920's suggested that AD might have a hereditary component. Chromosome 21 originally was implicated in AD because amyloid plaques and NFT's accumulate consistently in older people with Down syndrome (Trisomy 21). The discovery of the amino acid sequence of the beta-amyloid protein fragment (Glenner 1992) also provided sufficient details to locate and retrieve the entire gene of the APP. This gene resides on chromosome 21 and is the source of the major component (beta-amyloid) deposited in senile plaques of AD patients (Beyreuther et al. 1993). The same plaques also are found in older people with normal thought patterns; however, the plaques are less numerous.
Within the last 4 years, several relevant genes have been localized and/or identified. These studies relied on the observation that rare families inherited AD in an autosomal dominant pattern (i.e., with 50 percent of family members afflicted). These families, also called kindreds, became a major resource for molecular studies of the genome. In 1991, specific mutations in the APP gene were identified in a few families with early-onset FAD. Single DNA base changes at position 717 and a double mutation at codon 670/671 soon were identified in families under study (Goate et al. 1991; Charteir-Harlin et al. 1991; Mullan et al. 1992a). With rare exceptions, individuals in those families who inherit the mutations develop AD, and those without the mutation do not. It therefore became pertinent to discover whether the mutations were widespread in these kindreds. However, these particular mutations were seen infrequently. Even in FAD, fewer than 20 families with APP mutations have been found in the hundreds of kindreds screened thus far.
In 1992, four research groups reported genetic linkage of other families with early-onset FAD to a locus on chromosome 14 (Schellenberg et al. 1992; Mullan et al. 1992b; St. George-Hyslop et al. 1992; Van Broeckhoven et al. 1992). Close to 70 percent of FAD kindreds in which dementia symptoms begin before the age of 65 have this chromosome 14 linkage. Several research groups currently are identifying the specific gene and the precise mutation(s) in this locus that are linked to early-onset FAD. The identification of specific genes in this region, and more importantly, the elucidation of their functions, will be quite informative. It may be possible, for example, to correlate specific biochemical reactions with changes in these gene functions. Similar changes related to proteins and their functions also may be induced in the more common non-familial forms of AD. Environmental insults may contribute to changes in gene functions, and should be explored further to develop therapeutic strategies.
Hereditary abnormalities appear to play an important predisposing role in the more frequent sporadic forms of AD, in which an autosomal dominant or familial inheritance pattern is not obvious. Past studies of older-onset AD patients suggested that genetic factors might have been overlooked because of premature death in earlier generations. Thus, a great effort was made to find additional genes that might define or contribute to the expression of late-onset sporadic AD. A locus on chromosome 19 was identified in late-onset FAD (Pericak-Vance et al. 1991), and in 1993, a gene within this region was specifically implicated (Corder et al. 1993; Saunders et al. 1993; Strittmatter et al. 1993; Nalbantoglu et al. 1994). This gene codes for ApoE and has several alleles, or sequence variants. ApoE is a protein made by various types of cells of the body; and it normally is localized in oligodendroglia, astrocytes, and microglia, the supporting and defensive cells of the brain. The amino acid sequence of the protein is essentially identical in many species. Thus, it is likely to be a protein essential for life functions. In fact, ApoE is used in the transport of cholesterol and was first identified and studied extensively in the context of atherosclerosis and coronary artery disease. Therefore, the Panel recognizes that therapies targeting ApoE may be difficult to achieve without accompanying, possibly detrimental, side effects.
Different forms of the ApoE gene are associated with differences in the risk of developing late-onset sporadic AD and FAD. One form of the ApoE allele, known as E4, appears to increase the risk of AD. Studies to date indicate that the likelihood of developing AD is several times higher in people who have only the E4 allele (homozygote E4/E4). It appears that the presence of the E4 allele is associated with an earlier age of onset. Further studies using the network of National Institute on Aging (NIA) funded ADC's and other resources currently are used to define the proportion of American AD patients with this E4 allele. Studies of patients and families from a variety of ethnic groups also are underway, as there are different interpretations about the relative importance of ApoE in AD (Roses 1994; Selkoe 1994).
Should a marker like E4 prove to be an index for the risk of developing AD in population-based samples, it may be useful in the future as a screening tool to help assess the risk of developing AD. The Panel recognizes that there are several problems with genetic screening studies. Without a cure or preventive approach for AD, screening poses several concerns, including choices about the desirability of communicating information to families and associated ethical, emotional, and financial problems. Guidelines for dealing with the ethics of such counseling have been discussed extensively and evaluated in other adult neurodegenerative diseases of genetic origin, such as Huntington's disease. The NIA also has sponsored research to define more thoroughly the effects and/or bene-fits of genetic counseling in AD once molecular genetic technology for risk assessment becomes widely available. Notably, there are special problems for late-onset dementias (or late-onset diseases in general) that have not been completely addressed by the evolving guidelines in the genome project.
2. Amyloid Protein Studies
Because amyloid-containing senile plaques are a prominent feature in the brains of people with AD, researchers have focused on them for more than a decade, especially studying APP processing. A cleaved peptide portion of this protein becomes the beta-amyloid in plaques. Molecular studies on APP continue to be conducted in a systematic fashion. Although this membrane protein gives rise to beta-amyloid, the precise mechanisms and steps involved in the process are not understood fully. Plaque deposition may involve complex pathways, many of which are undefined (Wisniewski et al. 1994).
Several investigators have suggested that beta-amyloid deposition is the essential first step leading to a sequence of destructive brain changes (Selkoe 1993). Other investigators suggest that such plaques are the result, rather than the cause, of brain cell devastation. At present, both concepts can be accommodated by the possibility that some forms of the beta-peptide may accentuate or contribute to progressive neuronal destruction.
The beta-amyloid peptide has been reported to exert both destructive and growth-enhancing effects as determined by cell culture and brain inoculation studies (Whitson et al. 1989; Kosik and Coleman (eds) 1992). Some portions of the wild type normal and mutant APP genes also have been used in an attempt to generate a plaque-producing animal model of AD. Appropriate animal models, produced by transgenic strategies, will be critical for the following: (1) understanding the pathogenesis of neuronal damage, (2) evaluating useful pharmacological agents that prevent or halt amyloid deposition and/or amyloid-induced destruction, and (3) defining fundamental mechanisms and common pathways implicated in many types of dementia. Until recently, the lack of a valid animal model of AD has been a hindrance to the development of effective drug therapies. Recent transgenic models made with a mutant form of APP have led to beta-amyloid plaque formation in the mouse brain (Games et al. 1995). Although not a model of natural disease in humans (where APP expression is eighteenfold lower), this model holds considerable promise for testing drugs designed to minimize plaque formation.
Several of metabolic studies also have defined how APP may be processed in a dementing disease. For example, the APP protein is not overproduced by the cell in AD. Rather, the essential step for the generation of beta-amyloid seems to involve a modification after APP production and/or a change in cellular processing of APP. Several enzymes as well as metallic ions (e.g., zinc (Bush et al. 1994)) also may be involved in the deposition of insoluble amyloid plaques.
Amyloid plaques in AD are not constituted by a single protein derived from APP. Many proteins, such as proteases, protease inhibitors, and microtubule-associated proteins (e.g., tau), are deposited in plaques. ApoE also associates with AD plaques. These additional plaque-associated proteins may contribute to the aggregation of the beta-peptide into fibrils and the formation of insoluble beta-amyloid arrays within the extracellular space. Amyloid plaques are not restricted to AD, but also can be found in CJD, a dementia caused by an unconventional virus. Plaques in these diseases also contain ApoE and tau, and ApoE is deposited within the cell body of astrocytes in these infections (Brion et al. 1987; Namba et al. 1991; Diedrich et al. 1991). In these infectious dementias, however, a different altered host protein known as PrP is the major plaque component. PrP protein, like beta-amyloid protein, derives from a host-encoded membrane protein and can have similar toxic effects on neurons. Thus, there are parallels and possibly common mechanisms of membrane damage that may be present in both AD and CJD. In this context, the use of rodent models of CJD also may be informative.
Studies of the host-encoded PrP membrane protein have provided insight into mechanisms of neurodegen-eration and plaque formation that may be relevant for AD. For example, one or two peptide regions of the PrP protein are neurotoxic (Forloni et al. 1993). These peptide regions spontaneously form amyloid fibrils. Other types of amyloid fibrils, such as those of the pancreatic amylin-type in Type 2 diabetes mellitus, also are toxic (Lorenzo et al. 1994). This provides a paradigm for potential toxic effects of amyloids in general, regardless of their origin.
Genetic overexpression of PrP in transgenic mice creates a neurodegenerative phenomenon that is remarkably similar to that seen in infectious human CJD. These changes can occur without any significant infectious titer and therefore can be induced genetically (Hsiao et al. 1990; Hsiao et al. 1994). The paradigm of similar brain pathology evoked by an infectious agent, and in a smaller number of cases, by a genetic change, is not unlike the situation in sporadic AD and FAD. This suggests that only the common sporadic form of AD may be predominately environmentally dependent.
3. Common Mechanisms of Amyloid Damage
Studies of amyloid diseases have brought together a group of different disorders and implicated convergent pathways for toxic changes. These data demonstrate the validity of targeting common final pathways in a variety of dementias. Various amyloid studies also show that similar end-stage changes in the brain can derive from different causes (e.g., infectious and genetic). The variety of models and observations in this area have illuminated both possibilities and paradoxes, and have emphasized overlapping disease processes caused by different factors. Thus, initiatives to define the originating causes in adult dementias will be best approached by systematic study of several relevant models.
In summary, both beta-amyloid and APP remain a major focus of AD research. A majority of investigators now work under the assumption that beta-amyloid holds the key to understanding AD pathophysiology. This view is by no means universal, and it is known that clinical disabilities in AD do not correlate well with the degree of plaque formation. However, earlier identification of AD will allow researchers to prevent amyloid deposition and toxicity, although the functional benefit of such a strategy remains unknown. Chaperone proteins including ApoE (Wisniewski and Frangione 1992), involved in the processing of both APP and PrP, also may provide targets for intervention.
Many additional chaperone-associated proteins (such as heat shock protein 70 and ubiquitin) and other structural proteins (such as tau) clearly are involved in the formation of amyloid in hereditary, sporadic, and infectious neurodegenerative diseases. Finally, it should be noted that Congo red, a dye that binds to beta-amyloid and other proteins that form beta-pleated sheets, prevents the formation of more insoluble or resistant forms of PrP in scrapie-infected cultures (Caughey and Race 1994). Compounds of this class (including sulfated polyanions) also may be effective in blocking plaque formation in AD. Several research groups are testing polysulfated polyanions for their potential usefulness in the therapy of AD and CJD. In summary, amyloid studies have emphasized that convergent pathways may be involved in a variety of dementias. These pathways remain to be explored for potential therapeutic benefit.
4. Analysis of Neurofibrillary Tangles
NFT's, fibrillar inclusions with new cells, are one of the microscopic hallmarks of AD. Because the presence of NFT's is essential for establishing a diagnosis and because the burden of the lesion correlates with the presence of dementia, abnormalities in neurons are regarded as a key part of the brain pathology of AD.
A major component of NFT's is the normal cyto-skeletal protein tau, which accumulates excessive numbers of phosphate groups (hyperphosphorylation) in AD. This abnormal phosphorylation of tau appears to lead to the formation of insoluble paired helical filaments (PHF's) and then to NFT's (Trojanowski et al. 1993; Matsuo et al. 1994). Recent biochemical, molecular biological, and immunologic studies recently have defined the site of phosphorylation of tau, which appears to be important for the formation of PHF's. More recently, studies have shown that some of these sites also appear to be phosphorylated in some central brain cells. It now is thought that hyperphosphorylation of tau may result from the down-regulation of phosphates. Thus, either hyperphosphorylation or failed phosphorylation would have the same outcome. Phosphorylation sites on tau are positioned in that their phosphorylation reduces the ability of tau to bind to microtubules; and this may cause these critical organelles to collapse, a process that may interfere with trafficking/transportation within neurons. In turn, defects in intracellular transport can lead to degeneration of nerve cells. Thus, the abnormal processing of normal neuronal proteins appears to lead to the accumulation of lesions characteristic of AD. The balance between these two opposing actions may be critical to the neuronal integrity and may serve as a potential target for developing new therapeutic interventions.
Finally, preliminary investigations suggest that different ApoE4 alleles bind to tau differently. ApoE3 binds to the microtubule binding domain of tau, whereas ApoE4 does not. It has been hypothesized that the interactions of ApoE3 with tau may protect against the tau phosphorylation that leads to the formation of PHF's.
5. Inflammatory Changes and Therapy
Some investigators believe that inflammatory or autoimmune processes may play a role in late-onset dementias (e.g., McGeer and Rogers 1992). Several different environmental agents, including toxins and viruses, are capable of initiating this type of process. AD is generally viewed as a non-inflammatory disease because there are no lymphocytic (white blood cell) infiltrates. Nonetheless, detailed studies of immune-associated molecules in AD brains support an inflammatory process. These molecules are not related to the classical cellular lymphocytic responses and/or antibody production. Instead, they are derived from non-neuronal cells in the brain.
Specialized cells in the brain appear to be involved in these inflammatory responses, which are unique to this site. Most important are astrocytes and microglial cells. These glial cells can secrete toxic as well as growth-enhancing molecules, and appear to be necessary for the health and survival of surrounding neurons (Travis 1994). They may play a role in virtually all progressive neurological diseases, including those caused by slow viral infections that do not elicit a lymphocytic response (Mucke and Eddleston 1993; Epstein and Gendelman 1993). Microglial cells and astrocytes apparently take over some protective functions, but their responses eventually may be destructive. Microglial cells, which ingest toxic and other harmful materials, also may have an important role in amyloid plaque deposition and neuronal destruction in AD. The basis for an anti-inflammatory approach in AD patients was the observation that microglial cells appear to be recruited along with complement (immunologic-associated) molecules (Itagaki et al. 1994). Thus, indirect and glial-mediated mechanisms of damage are important opportunities for novel research strategies in AD and related neurodegenerative diseases.
Astrocytes and microglia accentuate each other's actions by producing inflammatory molecules. Such molecules include cytokines (soluble factors that induce changes in another cell), which play a role in inflammatory and destructive processes. Cytokines are important in the elimination of neurotoxins and often are produced during brain infections (e.g., Mucke and Eddleston 1993). The role of specific cytokines in dementia deserves systematic study, as some parallels have been drawn between AD and other dementias that reveal specific cytokine profiles. Additionally, the immune-related class of major histo-compatibility (MHC) antigens has been detected in the brains of people with AD, but not in those of control subjects. These MHC antigens arise in microglial cells and signify part of an antigen presentation or inflammatory response. Molecules of the complement cascade, which are important mediators of inflammation, also were detected in AD brains and were clearly abnormal (Itagaki et al. 1994). Furthermore, the complement complexes identified are capable of initiating cell lysis or destruction.
These complement cascade and MHC results led one group of investigators to an original therapeutic proposal for AD. These researchers hypothesized that anti-inflammatory agents could be used to minimize self-inflicting mechanisms of damage. They postulated that this approach would retard at least some of the progressive or slowly neurodestructive changes in AD. Positive outcomes have been noted in pilot studies of AD patients being treated with the widely available anti-inflammatory drug Dapsone. A study of 50 pairs of elderly twins gives further credence to this anti-inflammatory therapeutic approach. Twins taking anti-inflammatory drugs lived for longer periods free of dementing disease, as compared to their untreated siblings with AD (Breitner et al. 1994).
In a recent study of people chronically treated with Dapsone for leprosy, the incidence of dementia was less than 50 percent of the expected level. There was a marked reduction of AD plaques in the autopsied individuals, as compared to intermittently treated or untreated people of the same age and background. In older people who were treated, the CA3 neurons of the hippocampus of the brain, usually highly affected in AD, were well preserved. In addition, while the intellectual ravages of AD were not apparent in the treated group, they did occur in several untreated individuals (Chui et al. 1994). In accord with the original suggestion that an inflammatory cascade may be involved in the development of AD, the microglial response also was suppressed. It therefore is wise to provide support for further studies of these potentially beneficial drugs. A renewed and more detailed examination of mediators of inflammation in various dementias also is pertinent, as it may suggest even more effective combined therapies, especially at early stages of disease.
Source: Advisory Panel on Alzheimer’s Disease
Published in August 1995
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