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Article title: NIA's Progress Report on Alzheimer's Disease, 1998: NIA
Alzheimer's disease (AD) is an irreversible, progressive brain disorder that occurs gradually and results in memory loss, unusual behavior, 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; however, the disease can last for up to 20 years.
AD advances by stages, from early, mild forgetfulness to severe dementia. Dementia is the loss of mental function. 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 like washing their hands. Eventually, people with AD lose all reasoning abilities and become dependent on other people for their everyday care. Finally, the disease becomes so debilitating that patients are bedridden and likely to develop coexisting illnesses. Most commonly, people with AD die from pneumonia.
The risk of developing AD increases with age, but AD and dementia symptoms are not a part of normal aging. AD and other dementing disorders in old age are caused by diseases. In the absence of a disease, the human brain often can function well into the tenth decade of life and beyond.
AD is the most common cause of dementia among people age 65 and older. AD affects as many as 4 million Americans; slightly more than half of these people receive care at home, while the others are in many different health care institutions. Before long, ongoing population studies will give estimates of the number of people at different stages of the disease.
The prevalence of AD doubles every 5 years beyond age 65. Prevalence is the number of people in a population with a disease at a given time. In fact, some studies indicate that nearly half of all people age 85 and older have symptoms of AD.
Life expectancy has increased dramatically since the turn of the century. More than 34 million people--13 percent of the total population of the United States--are age 65 and older. According to the U.S. Bureau of the Census, this percentage will climb to 18 percent by the year 2025. In addition, the proportion of very old people (those aged 85 and older)--who often are most in need of care--will increase considerably. In most industrialized countries, the 85 and older age group is the fastest growing segment of the population over age 65. Now approximately 4 million, the number of Americans aged 85 and older is expected to total nearly 8.5 million by the year 2030, according to the Bureau of the Census. Some experts who study population trends suggest that number could be even greater. As more and more people live longer, the number of people affected by diseases of aging, including AD, grows.
A great many spouses, relatives, and friends take care of people with AD. These caregivers are the backbone of the Nation's informal system of long-term care for AD patients. Their numbers also can be expected to grow significantly as the population ages and as the number of people with AD increases.
During years of caregiving, families experience emotional, physical, and financial stresses. They watch their loved ones become more and more forgetful, frustrated, and confused. Many caregivers--most of them women--juggle child care and jobs with caring at home for relatives with AD who cannot function on their own. As the disease runs its course and the abilities of people with AD steadily decline, family members face difficult decisions about the long-term care of their loved ones.
AD puts a heavy economic burden on society as well. A recent study estimated that the cost of caring at home or in a nursing home for one AD patient with severe cognitive impairments, not including indirect losses in productivity or wages, is more than $47,000 a year. For a disease that can span from 2 to 20 years, the overall cost of AD to families and to society is staggering. The annual economic toll of AD in the United States in terms of health care expenses and lost wages of both patients and their caregivers is estimated at $80 to $100 billion.
AD is a major health problem and expense for the United States. Until researchers find a way to cure or prevent AD, a large and growing number of people, especially those who live to be very old (85'), will be at risk for AD. Providing and financing the care of this growing older population will increase the strain on our already burdened health care system.
AD research is divided into three broad, overlapping areas: causes/risk factors, diagnosis, and treatment/caregiving. Research into the basic biology of the aging nervous system is critical to understanding what goes wrong in the brain of a person with AD. Understanding how nerve cells lose their ability to communicate with each other and the reasons why some nerve cells die is at the heart of scientific efforts to discover what causes AD.
Many researchers are working to slow AD's progression, delay its onset, or eventually, prevent it altogether. In looking for better ways to diagnose AD, investigators strive to identify markers (indicators) of dementias, develop and improve ways to test patients, determine causes and assess risk factors, and improve case-finding and sampling methods for population studies. Scientists also seek better ways to treat AD, improve a patient's ability to function, and support caregivers of people with AD.
The National Institute on Aging (NIA) is part of the Federal Government's National Institutes of Health (NIH). One of NIA's main goals is to enhance the quality of life of older people by expanding knowledge about the aging brain and nervous system. NIA has primary responsibility for research aimed at finding ways to prevent, treat, and cure AD.
NIA's AD research has important implications for public policy. Changes in the way the brain works are associated with many age-related losses that lead to institutional care. Changes in the brain that significantly affect the senses, movement, and the ability to think influence the quality of life of older people. For people with AD, decline in these abilities limits independence, affects self-image, and influences the attitudes of others. Ultimately, these attitudes determine the nature and quality of health care services AD patients receive.
The goal of research on AD is to identify early treatments that will change the disease's course or reduce its severity. Although no cure exists yet for AD, there is reason to be optimistic. Recent advances in understanding the way this devastating illness affects the brain now are suggesting new strategies for treating AD.
This report highlights recent progress in AD research conducted or supported by NIA and other components of NIH, including the following:
Other smaller AD research efforts not summarized in this report are supported by the National Cancer Institute (NCI), National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Child Health and Human Development (NICHD), National Institute of Dental Research, National Institute of Environmental Health Sciences, and Fogarty International Center.
The brain does many things to ensure our survival. It integrates, regulates, initiates, and controls functions in the whole body, with the help of motor and sensory nerves outside of the brain and spinal cord. The brain governs thinking, personality, mood, and the senses. We can speak, move, and remember because of complex chemical processes that take place in our brains. The brain also regulates body functions that happen without our knowledge or direction, such as digestion of food.
The human brain is made up of billions of nerve cells, called neurons, that share information with one another through a large array of biological and chemical signals. Each neuron has a cell body, an axon, and many dendrites. The nucleus, which contains genes composed of deoxyribonucleic acid (DNA), controls the cell's activities. The axon, which extends from the cell body, transmits messages to other neurons, sometimes for very long distances. Dendrites, which also branch out from the cell body, receive messages from axons of other nerve cells or from specialized sense organs. Axons and dendrites collectively are called neurites. Even more numerous are the glial cells (approximately 10 times the number of neurons in the central nervous system), which surround, support, and nourish neurons.
Neurons communicate with each other and with sense organs by producing and releasing chemicals. An electrical charge (nerve impulse) builds up within the sending neuron as it receives messages from surrounding cells. The charge travels down the nerve cell until it reaches the end of the axon. Here, the nerve impulse triggers the release of neurotransmitters. These chemicals carry messages from the axons across synapses (gaps between nerve cells) to the dendrites or the cell bodies of other neurons. Scientists estimate that the typical neuron has up to 15,000 synapses. Neurotransmitters carrying messages bind to specific receptor sites on the receiving end of dendrites of adjacent nerve cells. Receptors are proteins (molecules that determine the physical and chemical traits of cells and organisms) that recognize and bind to chemical messengers from other cells.
When the above receptors are activated, they open channels into the receiving nerve cell's interior or start other processes that determine what the receiving nerve cell will do. Some neurotransmitters inhibit nerve cell function; that is, they make a neuron less likely to act. Other neurotransmitters stimulate nerve cells; they prime the receiving cell to become active or send a message. In this way, signals travel back and forth across the brain in a fraction of a second. Millions of signals flash through the brain all the time.
Groups of neurons in the brain have specific jobs. For example, the brain's cerebral cortex is a large collection of neurons all over the surface of the brain. Some of these nerve cells are involved in thinking, learning, remembering, and planning.
The survival of nerve cells in the brain depends on the healthy functioning of several processes all working in harmony. These processes involve nerve cell activities related to intercellular communication, cellular metabolism, and cell and tissue repair. The first process, communication between nerve cells, is described in the preceding paragraphs. The loss or absence of any one of several chemical messengers or receptors disrupts cell-to-cell communication and interferes with normal brain function.
The second process is metabolism, the pathway(s) by which cells and molecules break down chemicals and nutrients to generate energy. Efficient metabolism in nerve cells requires adequate blood circulation to supply the cells with important nutrients, such as oxygen and glucose (a sugar). Glucose is the only source of energy available to the brain under normal circumstances. Depriving the brain of oxygen or glucose causes nerve cells to die within minutes.
The third process is the repair of injured nerve cells. Unlike most other body cells, neurons live a long time. Brain neurons have the capacity to last more than 100 years. In the adult, when neurons die (due to disease or injury), they are not replaced. To prevent their own death, living neurons constantly must maintain and remodel themselves. If cell cleanup and repair slow down or stop for any reason, the nerve cell cannot function properly. It is not clear when and why some neurons start to die and some synapses stop working.
Research shows that the damage seen in AD involves changes in all three of these processes: nerve cell communication, metabolism, and repair.
In AD, communication between some nerve cells breaks down. The destruction from AD ultimately causes these nerve cells to stop functioning, lose connections with other nerve cells, and die. Death of many neurons in key parts of the brain harms memory, thinking, and behavior.
AD destroys neurons in parts of the brain controlling memory, especially the hippocampus (a structure deep in the brain that helps code memories). As nerve cells in the hippocampus stop functioning properly, short-term memory fails, and often, the person's ability to do familiar tasks begins to decline. AD also attacks the cerebral cortex. The greatest damage occurs in areas of the cerebral cortex responsible for functions such as language and reasoning. Here, AD begins to take away language skills and change a person's judgment. Personality changes also occur; emotional outbursts and disturbing behavior, such as wandering and agitation, appear and can happen more and more often as the disease runs its course.
Two abnormal structures in the brain have long been known as hallmarks of AD: amyloid plaques and neurofibrillary tangles. Plaques are dense deposits of an amyloid protein (called beta-amyloid), other associated proteins, and non-nerve cells that gradually build up outside and around neurons. Amyloid is a generic name for protein fragments that aggregate (collect or mass together) in a specific way to form insoluble deposits. The fragments can arise from different mechanisms. Neurofibrillary tangles are insoluble twisted fibers that build up inside neurons. Much progress has been made in determining the makeup of amyloid plaques and neurofibrillary tangles and in proposing mechanisms that could account for their buildup in AD.
In AD, plaques develop first in areas of the brain used for memory and other cognitive functions. These plaques consist of beta-amyloid intermingled with neurites from neurons and with non-nerve cells. These non-nerve cells include glial cells and microglia (cells that surround and digest damaged cells or foreign substances, causing inflammation).
In plaques, beta-amyloid is a protein fragment snipped from a larger protein, called amyloid precursor protein (APP), during metabolism. Researchers do not know yet whether amyloid plaques themselves cause AD or whether they are a side effect of AD. APP is a member of a large family of proteins that is associated with cell membranes. The cell membrane encloses the cell and acts as a barrier that selects which substances can go in and out of the cell. During metabolism, APP becomes embedded in the membrane of the nerve cell, partly inside and partly outside of the cell, like a needle poking partway through a piece of fabric. While APP is embedded in the cell membrane, proteases cleave APP apart. Proteases are enzymes (substances that speed up or cause chemical reactions in the body) that snip proteins into smaller pieces. Beta-amyloid is produced only when two kinds of cleavages happen at particular sites in APP.
When protease(s) cuts APP apart to form beta-amyloid, a peptide (a string of 2 or more amino acids) may form that is 1 of 2 lengths: a string of 40 amino acids or 42 amino acids. Amino acids are organic compounds needed for forming proteins and pieces of proteins. The shorter beta-amyloid is more soluble and aggregates slowly. The longer, "sticky" beta-amyloid rapidly forms insoluble aggregates and appears to play a critical role in the initial buildup of plaque and in the onset of AD.
While beta-amyloid is being formed, scientists do not yet know exactly how it moves through or around nerve cells. In its final stages, the "sticky" beta-amyloid aggregates into long beta-amyloid filaments outside the cell and, along with fragments of dead and dying neurites, forms the dense, insoluble plaques that are a hallmark for identifying AD in brain tissue. Some researchers believe that the longer beta-amyloid sets off the AD process and/or is an early byproduct in the slow, many-step process that ultimately leads to nerve cell damage and death in the brain.
Many studies have centered on how enzymes break down APP to form beta-amyloid. Several researchers are working to identify enzymes that form beta-amyloid and find ways to change or block their action. Investigators also are looking at how beta-amyloid forms plaques, and they are seeking clues in beta-amyloid's environment. For example, normally, substances may bind to beta-amyloid and keep it in solution. But in AD, according to one theory, something causes beta-amyloid fragments to aggregate together. Beta-amyloid aggregates gradually build up to form dense, insoluble plaques that the body cannot dispose of or recycle.
Many scientists believe that beta-amyloid is toxic to neurons, perhaps by causing inflammation in the brain or by generating free radicals. Researchers at NIA's Laboratory of Neurosciences (LNS) in Bethesda, Maryland, and Texas Tech University in Amarillo (Allen et al., 1997) have found that beta-amyloid increased the transport of a molecule called choline across nerve cell membranes. If the beta-amyloid is depleting the intracellular stores of choline, this may explain why cholinergic neurons, which use choline to transmit messages, are especially vulnerable to dying off in AD.
There are several other pathways by which beta-amyloid could be toxic to neurons. Some studies indicate that beta-amyloid disrupts potassium channels, which in turn can affect calcium levels inside the cell. Potassium (an element or electrolyte) helps control the normal activity of nerves and muscles. Among other things, potassium channels (tunnel-like structures in cell membranes) help balance the amount of calcium that the cell takes in and removes. Calcium (another element or electrolyte) helps cells do many things, such as carry nerve signals. The correct amount of electrolytes, such as potassium and calcium, also helps the body use energy. However, too much calcium inside the cell leads to cell death.
More research is needed to determine the exact mechanism of selective nerve cell damage in the AD brain and the roles that beta-amyloid and APP play in this process.
Neurofibrillary tangles are abnormal collections of twisted threads found inside nerve cells. The chief component of tangles is one form of the protein, tau. In the central nervous system, tau proteins are best known for their ability to bind and help stabilize microtubules (the cell's internal support structure or skeleton).
In healthy neurons, microtubules form structures like train tracks, which guide nutrients and molecules from the bodies of the cells down to the ends of the axons. In cells affected by AD, these structures collapse. Tau normally forms the "railroad ties" or connector pieces of the microtubule tracks. However, in AD tau is changed chemically, and this altered tau can no longer hold the railroad ties together, causing the microtubule tracks to fall apart. This collapse of the transport system first may result in malfunctions in communication between nerve cells and later may lead to neuron death.
In AD, chemically altered tau twists into paired helical filaments (two threads wound around each other). These filaments are the major substance found in neurofibrillary tangles. NIA-funded researchers at the New York State Institute for Basic Research in Developmental Disabilities on Staten Island and New York University Medical Center in New York City (Bobinski et al., 1997) found neurofibrillary changes in less than 6 percent of the neurons in a particular part of the hippocampus in normal brains, in more than 43 percent of these neurons in people who died having mild AD, and in 71 percent of these neurons in people who died having 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 over the course of AD.
Every healthy person has 46 chromosomes in 23 pairs. Usually, people receive one chromosome in each pair from each parent. Chromosomes are rod-like structures in the cell nucleus. In each chromosome, DNA forms two long, intertwined, thread-like strands that carry inherited information in the form of genes.
In humans, one of the above chromosome pairs carries genes that transmit sexual traits. These two separate sex chromosomes, called X and Y, determine the sex of offspring. Females have one pair of X chromosomes, and males have one X chromosome and one Y chromosome. The Y chromosome causes male traits to develop. Having two X chromosomes means that female traits will develop. The X chromosome, which is present in both males and females, carries many genes linked to important disorders.
Genes are basic units of heredity that direct almost every aspect of the construction, operation, and repair of living organisms. Each gene is a set of chemical instructions that tells a cell how to make one of the many unique proteins in the body. Every human cell has from 50,000 to 100,000 genes arranged on the chromosomes like beads on a string.
Genes are made up of four chemicals (bases) arranged in various patterns along the strands of DNA. In each gene, the bases are lined up in a different order, and each sequence of bases directs the production of a different protein. Even slight changes in a gene's DNA code can make a faulty protein, and a faulty protein can lead to cell malfunction and possibly disease.
Two types of AD exist: familial AD (FAD), which is found in families where AD follows a certain inheritance pattern; and sporadic (seemingly random) AD, where no obvious inheritance pattern is seen. Because of differences in age at onset, AD is further described as either early-onset (younger than 65 years old) or late-onset (65 years and older). Early-onset AD is rare and generally affects people aged 30 to 60. Early-onset AD progresses faster than the more common, late-onset forms of AD.
Almost all FAD known so far has an early onset, and many cases involve defects in three genes located on three different chromosomes (chromosomes 1, 14, and 21). For example, if a person inherits one of these mutated genes from his or her father or mother, then that person is almost 100 percent certain to develop AD at an early age. Until recently, AD genetic research was dominated by the discovery that an unidentified defective gene on a particular region of chromosome 21 was the cause of AD in a few early-onset families. This finding was followed by the identification of gene mutations in the APP gene on chromosome 21 as the cause of AD in these families. (In affected people, the gene on chromosome 21 carries the code for an abnormal form of APP.) Very few cases of FAD are caused by defects in this latter gene.
This emphasis shifted in 1992, when researchers at the University of Washington Alzheimer's Disease Center (ADC) in Seattle--supported by NIA and the National Institute of Neurological Disorders and Stroke (NINDS)--discovered a link between other FAD cases and genes in a particular region of chromosome 14. They subsequently identified the defective gene and named it presenilin 1. Many cases of FAD are caused by presenilin 1.
More recently, these same scientists also found a link between FAD in families descended from a group of Germans (called Volga Germans) living in the Volga Valley of the former Soviet Union and a gene in a particular region of chromosome 1. These families have a higher than average occurrence of AD and show no link to AD through genes on either chromosome 21 or 14. These investigators and others funded by NIA and NINDS at the Massachusetts ADC in Boston and in Toronto, Canada, identified the defective gene on chromosome 1 and called it presenilin 2. Only a very small fraction of early-onset FAD is caused by mutations in the presenilin 2 gene.
Together, these mutations (APP and presenilins 1 and 2) account for approximately 50 percent of early-onset FAD. The other genes have yet to be identified. (For additional information about presenilin genes, see The Role of Presenilins.)
Pursuing another avenue, researchers at NIA are looking at Down's syndrome because it shares some traits with AD. Down's syndrome is caused by a birth defect in which the person has three, rather than the normal two, copies of chromosome 21. Down's syndrome is associated with mental retardation and the development of AD pathology. Because the gene for APP has been mapped to chromosome 21, some researchers believe that Down's syndrome is related to the "overexpression" of APP.
Some gene forms occur more often in AD patients than among people in general. Unlike the mutated presenilin and APP genes that cause AD for certain, inheriting the AD-related form of these other genes will only increase a person's risk of developing the disease. In 1992, researchers at the Duke University ADC 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 epsilon4) allele on chromosome 19. An allele is one of two or more alternate forms of the same gene, in this case, APOE. This finding helped scientists explain variations in age at onset based on whether people had zero, one, or two copies of APOE epsilon4.
APOE is a protein that sits on the surface of the cholesterol molecule and helps carry blood cholesterol throughout the body. APOE is found in glial cells and neurons of healthy brains, but also is associated with the plaques and neurofibrillary tangles found in AD brains.
Every person has two APOE genes, one inherited from each parent. AD researchers are interested in three common alleles of APOE: epsilon2, epsilon3, and epsilon4. They are studying people who inherit different forms of this gene to learn more about risk factors for AD. A simple blood test can be used to determine which alleles a person has inherited.
The relatively rare APOE epsilon2 may protect some people against the disease; it seems to be associated with a lower risk for AD and later age of onset. APOE epsilon2 also appears to protect people with Down's syndrome from developing AD-like pathology. APOE epsilon3 is the most common version found in the general population and may play a neutral role in AD.
AD scientists are most interested in APOE epsilon4 because it is linked to an increased risk of the disease. The APOE epsilon4 form in AD patients is not limited to those with a family history of AD. In addition, people who carry two copies of APOE epsilon4 are more likely to get AD than those with one copy of APOE epsilon4. How APOE epsilon4 increases a person's susceptibility to AD (likelihood of developing AD) is not yet known. APOE epsilon4 may contribute to beta-amyloid buildup. APOE epsilon4 also appears to lower the age of onset of AD, perhaps because APOE epsilon4 speeds up the AD process in some unknown way. Researchers believe that AD risk related to APOE epsilon4 may increase because the age of onset decreases.
A flurry of activity has followed the APOE findings to discover the molecular mechanisms that underlie the effects of the different forms of APOE on the development of AD. Scientists are looking at how the different forms of APOE interact with both beta-amyloid and tau. Researchers also are studying how forms of APOE affect the way that cells remodel themselves and grow after being damaged.
Whatever its role in AD, the mere inheritance of an APOE epsilon4 gene does not predict AD with certainty; that is, APOE epsilon4 is a risk factor gene. A person can have an APOE epsilon4 gene and not get the disease, and a person with AD may not have any APOE epsilon4 genes. As of now, no predictive test for AD exists. Even with the current knowledge about APOE, scientists cannot predict whether or when any person might develop AD, no more than a doctor can predict whether a person with high cholesterol will have a stroke. However, many researchers believe that inheriting an APOE epsilon4 gene, in association with lower memory performance in older people that gradually worsens with time, may be a predictor for who is going to develop AD.
Genetic analysis someday could help scientists find people with probable early AD to include in clinical trials of promising treatments. Clinical trials are carefully controlled studies designed to test how certain drugs work to treat symptoms in people and at which dosages the drugs are safe and effective. Because of the increased risk associated with APOE epsilon4, people with clinical signs of memory problems who have this allele could become volunteers to be studied in clinical trials of experimental drugs for preventing the progression of AD.
Scientists are studying families to find more risk factor genes. Having multiple risk factor genes may further increase a person's likelihood of developing AD. With each new finding, researchers gain more clues about basic mechanisms in AD and move closer to understanding the disease and designing treatments that slow its progression, delay its onset, or even prevent it.
Last year, NIA-funded scientists made numerous important advances in understanding AD, including learning more about a new risk factor for AD in some minorities, many of the roles of presenilin proteins 1 and 2, and new sites on human chromosomes that sometimes may be involved in causing AD. Findings from these and other investigations eventually may lead to new treatments and strategies for prevention.
One important advance this year was the extensive use of new transgenic mouse models for AD, which are enabling scientists finally to untangle the roles of different genes in AD and to trace the progression of the disease, identifying points for potential therapeutic intervention.
Animals that exhibit the pathophysiology and symptoms of human disease provide a unique opportunity to investigate the causes and development of these diseases. And they can provide a safe way to test possible treatments. In 1996, a team of researchers at the University of Minnesota in Minneapolis supported by NIA and NINDS developed a new mouse model for AD by inserting human genes containing different mutations of APP into the mouse DNA. This genetically-engineered (transgenic) mouse is the first to develop learning and memory problems characteristic of AD as well as amyloid plaques like those found in the brain tissue of AD patients. Researchers continue to develop new transgenic mice carrying various combinations of human genes linked to AD.
These mice give scientists a powerful new tool for studying the relationship among the genetics, physical changes in the brain, and behavioral changes characteristic of AD. For example, researchers hope studies of these mice will help solve the longstanding question of whether amyloid plaques are a direct cause of neurodegeneration or simply a byproduct of the AD process.
So far, none of the transgenic mice has shown the loss of neurons that occurs in human AD. In a 1997 study led by NIA-funded researchers at Massachusetts General Hospital in Boston (Irizarry et al., 1997), 18-month-old mice carrying the human APP mutation had extensive amyloid plaques but their neurons were surviving. One theory is that because mice reach old age in only 2 years, there simply is not time for the disease to reach the level where neurons start dying. Another explanation could be that because mouse brains have different proteins from human brains, the cascade of events that ultimately lead to the death of brain cells in human AD is altered somehow in mice. More research is needed to understand the results of this important study and to develop an animal model for neuronal loss. The transgenic mouse model of AD was validated in another respect by a study (Johnson-Wood et al., 1997) showing that in these mice, as in humans, it is primarily the longer, "stickier" form of beta-amyloid that forms deposits in the brain.
The new transgenic mouse model for AD is already helping to unravel how AD can be triggered and modulated by a complex interplay of different genes. A team of NIA-funded researchers in Montana, Maryland, Florida, and Minnesota (Carlson et al., 1997) discovered that the effect of the APP mutations in transgenic mice varied tremendously depending on the strain of mouse that was used. The different genetic makeup of the different mouse strains made the difference between whether the mice died prematurely as a result of the APP mutations or survived. Analyzing the different mouse strains could lead to the identification of new genes involved in AD.
Transgenic mouse studies also are shedding light on the interplay of APP and the presenilins in AD. In two separate studies, NIA-funded researchers at the Mayo Clinic in Jacksonville, Florida, and the University of Minnesota in Minneapolis (Holcomb et al., 1998); and The Johns Hopkins University School of Medicine in Baltimore, Maryland (Borchelt et al., 1997), mated mice carrying human APP mutations with mice carrying a human presenilin 1 mutation. The crossbred offspring developed brain changes typical of AD far earlier than either of the parent strains, showing that the presenilin mutation accelerates the development of AD-type changes in mice with the APP mutations. In the former study, the researchers also were very interested to note that all of the mice with the APP mutation showed signs of behavioral problems before any plaque formation could be detected.
Transgenic mice with human APP mutations also are helping researchers to understand the role of inflammation in AD. In 1998, NIA-supported researchers at the University of California in Los Angeles (Frautschy et al., 1998) published a study on the concentration of cells involved in the inflammatory response, called activated microglia, in and around particular plaques in the brains of transgenic mice. Their study supports the theory that this inflammatory response may actually play a role in causing the neurodegeneration and symptoms of AD. Thus, this research suggests that the new transgenic mouse could be a good model for unraveling the role of microglia in AD and for testing anti-inflammatory drugs against AD.
Researchers also are using transgenic mice to illuminate the role of the APOE gene in AD. NIA-funded researchers at the Indiana School of Medicine and scientists from the Neuroscience Discovery Research Section of Lilly Research Laboratories, both in Indianapolis (Bales et al., 1997), mated transgenic mice that carried a mutant human APP gene with mice that lack the APOE gene. The offspring showed a dramatic reduction in beta-amyloid deposits in the brain, when compared to mice that carried the APOE gene. This result may begin to explain how the APOE gene can alter the risk for AD, through its effect on amyloid deposits.
Many researchers are now using transgenic mice to study the role of the presenilins in AD. One 1997 study helped to make an important link between presenilin gene mutations and increased production of the "sticky" type of beta-amyloid, called beta-amyloid 1-42. NIA-funded researchers at the Center for Neurologic Diseases at the Brigham and Women's Hospital and Harvard Medical School, both in Boston, Massachusetts (Citron et al., 1997), led a study in which transgenic mice carrying mutated presenilin 1 genes and human APP genes produced a highly significant increase in the amount of this "sticky" beta-amyloid. Eventually, research in this area could lead to new therapeutic strategies to block the production of beta-amyloid 1-42 in AD.
Seeking to understand the effect of mutations in the presenilin 1 gene, a team led by NIA-funded researchers at The Johns Hopkins University School of Medicine (Lee et al., 1997) studied transgenic mice bearing these presenilin 1 mutations. They found that at least some presenilin 1 mutations lead to an overaccumulation of pieces of presenilin 1 that had been clipped apart at the wrong locations. Researchers are now trying to determine whether this overaccumulation somehow affects the processing of APP into beta-amyloid 1-42.
There also was a significant research effort this year using transgenic mice to understand the role of APP itself in healthy brains and in AD. In a study by a team led by NIA-funded researchers at the Brigham and Women's Hospital (Perez et al., 1997), human APP produced in the brains of transgenic mice appeared to play an important role in the growth and survival of neurons. Neurons from mice lacking APP did not send out as many branches and did not survive as well in culture as those from mice with APP.
Sometimes, too much of a neurotransmitter can be bad. For example, brain cells can be damaged when levels of neurotransmitters that stimulate nerve cells, such as glutamate, get too high outside the cells (excitotoxicity). APP may play an additional role in the healthy human brain by protecting neurons from these toxins, according to another study. A collaboration led by NIA-funded researchers at the University of California at San Diego; Boston University, Massachusetts; and the Gladstone Institute of Neurological Disease in San Francisco, California (Masliah et al., 1997), exposed the brains of seven different types of transgenic mice to two types of toxins, one causing acute damage and the other causing chronic damage. These mice carried seven different forms of human APP expressed at low levels. The researchers found that particular forms and amounts of human APP could protect neurons against both chronic and acute toxicity. They speculate that APP, in specific forms and amounts, could even be used to treat brain disorders.
In a followup study, these researchers along with scientists at the University of Kentucky, Lexington (Masliah et al., 1998), found that APP may play a role in protecting the brain against excitotoxic damage, perhaps by facilitating removal of extracellular glutamate.
Researchers at NIA's Gerontology Research Center in Baltimore (Wallace et al., 1997) examined why APP is released in the brain in response to injury. In test tube studies, these scientists found that APP may play a role in making damaged neurons more responsive to repair mechanisms and help parts of nerve cells grow. In response to brain injury, APP may interact with nerve growth factor and other neurotrophins to help repair damaged nerve cells. Neurotrophins are natural proteins that protect nerve cells from damage and enhance the regrowth of damaged nerve tissue.
A detrimental effect of beta-amyloid may be that it makes the brain more susceptible to damage by ischemia (poor blood flow), according to a 1997 study led by NIA-funded researchers at the University of Minnesota, Minneapolis (Zhang et al., 1997). These researchers found that when mice had an artery to the brain blocked, the brain damage was greater in transgenic mice carrying a mutant human beta-amyloid gene linked with AD. One reason for this effect may be that beta-amyloid reduces the ability of some blood vessels in the brain to dilate and compensate for the diminished blood flow, thus damaging neurons. Another recent study (Crawford et al., 1997) also suggests that beta-amyloid encourages blood vessels to constrict, which may eventually cause oxidative stress which, in turn, damages neurons.
Finally, research in transgenic mice is helping scientists to understand how beta-amyloid deposits into particular kinds of plaques. NIA-funded researchers at the University of California at San Francisco and San Diego (Wyss-Coray et al., 1997) mated transgenic mice carrying genes for mutant human APP with transgenic mice carrying genes that caused them to overexpress a molecule known as transforming growth factor beta-1 (TGF-b1), which normally helps the brain respond to injury. They found that the combination of mutant human APP and TGF-b1 accelerated the deposition of beta-amyloid in the blood vessels of brains of old transgenic mice. Thus, they believe that TGF-b1 may be involved in initiating or promoting the formation of amyloid plaques, especially around damaged blood vessels. Now, more research is needed to determine whether people with too much TGF-b1 may be at greater risk for AD.
In other laboratory studies, researchers are focusing on how beta-amyloid itself, as opposed to amyloid plaques, may be toxic to neurons. NIA-funded scientists at Columbia University in New York City (Yan et al., 1997) found that beta-amyloid binds with a protein, amyloid beta-peptide binding alcohol dehydrogenase (ABAD), inside the cell. ABAD is thought to be a neuronal enzyme that is expressed in normal tissues, but is overexpressed in neurons affected in AD. Beta-amyloid was more toxic to cells that contained more ABAD, suggesting that ABAD could affect the AD process. The study also provides further evidence that in AD, beta-amyloid could cause damage inside cells as well as form extracellular plaques. Researchers now are working to determine the normal function of ABAD, which appears to be an enzyme encoded by a gene on the X chromosome.
Another area of fruitful research this year has been the study of how and why APP becomes beta-amyloid, and beta-amyloid in turn forms plaques. NIA-funded researchers at Cornell University and Rockefeller University in New York City and The Johns Hopkins University (Xu et al., 1997) found that in cells carrying mutant APP, the APP was cleaved to form beta-amyloid inside a part of the cell called the trans-Golgi network. They were intrigued to find that the beta-amyloid formed even when the Golgi apparatus could not form vesicle buds. Usually, proteins in the Golgi apparatus are cleaved and transported through vesicular budding. So it seems that the beta-amyloid may be formed in an unusual way. In another study on beta-amyloid formation, a team based at the Harvard Medical School (Cataldo et al., 1997) found that other organelles in the neuron, called early endosomes, were much larger in brains affected by the sporadic form of AD than were endosomes from healthy brains. This may indicate that APP processing and beta-amyloid production are occurring in these endosomes.
In AD, insoluble beta-amyloid aggregates into plaques. Therefore, one might expect that as the disease progresses, more and more plaques are formed, filling more of the brain. However, scientists have observed that this is not necessarily the case. In fact, the amount of beta-amyloid often seems to appear relatively constant as the disease progresses. To study this mystery, a team led by NIA-funded researchers at Boston University and Massachusetts General Hospital (Cruz et al., 1997) used a confocal scanning laser microscope, which enabled them to view the three-dimensional structure of plaques. The studies revealed that the plaques were not solid, but had minute holes. The team believes that this structure could be explained if beta-amyloid is aggregating and disaggregating at the same time, in a sort of equilibrium. It is possible that the microglia cells that surround the plaques, cells that are part of the immune-inflammatory response, may be able to digest some of the beta-amyloid. This observation raises the hope that it may be possible to design a therapeutic strategy to break down the plaques after they have formed.
In another study on the formation of amyloid, NIA-funded researchers at the Massachusetts Institute of Technology in Cambridge and Harvard University (Harper et al., 1997) used an atomic force microscope to study beta-amyloid in the process of forming the fibrils (thread-like structures) found at the core of amyloid plaques. They identified an early, unstable stage of amyloid aggregation called the protofibril. They found that the longer beta-amyloid linked to early-onset AD aggregated much more rapidly. And they proposed that it might be useful to search for a way to keep the protofibrils from changing into fibrils, and thus forming plaques. What is clear from the results of these and other experiments is the pressing need to find out which form of beta-amyloid is the most toxic.
Much more study is needed to understand how and why certain forms or amounts of APP could be beneficial to nerve cells, while high levels of mutated forms are linked to the harmful effects normally seen in AD. This startling contrast intrigues scientists. What is it about APP that may help nurture nerve cells, and alternately, what causes a piece of it to be harmful? How and why does the "sticky" form of beta-amyloid, which used to be a part of APP, play a role in the development of harmful plaques and adversely affect blood vessels in the brain? These are just a few of the questions many researchers are addressing.
As noted above, identifying the genes causing AD in some families pinpoints where the disease can start. To this end, scientists are looking at what the previously unknown presenilins do in the cell; what their role is, and how mutations in them can cause AD.
In 1992, investigators supported by NIA and NINDS first identified specific variants of a gene (now called presenilin 1) on chromosome 14 in people with AD in some inherited, early-onset AD families. Although researchers believe that mutations in the presenilin 1 gene account for close to 50 percent of all cases of FAD (the most aggressive form), they are just now beginning to understand the function of this gene. Scientists have found almost 30 mutations of presenilin 1 in approximately 50 early-onset AD families. These defects are scattered across the protein encoded by the mutated gene. Some of these mutations may lead to AD earlier than others. Rather than cause protein products to stop working, mutations may produce altered, harmful protein products.
Scientists now are working to reveal the normal function of presenilins and how mutations of these genes affect the onset of FAD. They do not yet know whether presenilins play any role in the more common, sporadic or non-familial form of late-onset AD.
Much evidence suggests that neurons are a major source of the beta-amyloid that forms plaques in AD. Thus, it is important to study how presenilins function in neurons. Researchers are looking at how presenilins 1 and 2 interact with APP processing (Mehta et al., 1998), beta-amyloid, plaques, and tangles. It appears that the presenilin mutations may contribute to the degeneration of neurons in at least two ways: by modifying beta-amyloid production (Duff et al., 1996) or by triggering the death of cells more directly (Wolozin et al., 1996). Researchers have discovered that 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 of AD. This finding suggests that mutations in the presenilins can in some way drive the production of this form of amyloid in AD. A recent study in mice (De Strooper et al., 1998) gives weight to this theory, in that presenilin 1 appears to facilitate the cleavage of APP. It may even be possible to develop drugs to mimic the normal function of the presenilins, and thus, decrease the formation of amyloid in AD.
Scientists also are following other clues about how the presenilins might alter beta-amyloid production. NINDS-funded researchers at the University of California at San Diego (Dewji and Singer, 1997 [Cell...]) determined that parts of the presenilins are in fact on the surface of neurons (see the NINDS section). So it is possible, as these researchers have theorized, that the presenilins could interact directly with APP on the surface of a neighboring cell to produce beta-amyloid.
A more complex role for the presenilins in altering the production of beta-amyloid was proposed by NIA-funded researchers at the Harvard Medical School (Li et al., 1997). They found that a fraction of the presenilins is located in cells on the nuclear membrane, but that they also are associated with cell structures called the centrosomes and kinetochores, both of which are crucial for segregating the chromosomes into two groups in the nucleus prior to cell division. It appears from this study that the presenilins could act normally to bind the chromosomes to the nuclear membrane while the chromosomes divide up in preparation for nuclear division. The researchers theorize that mutant presenilins might not bind with chromosomes and then let them go at the appropriate time, causing the wrong number of chromosomes to end up in the newly-divided cells. Some cells might end up with three copies of chromosome 21, which contains the gene for APP. People who have three copies of chromosome 21 in all of their cells have Down's syndrome, produce too much APP, and inevitably develop AD-like pathology. According to this theory of presenilin function, mutations in the presenilins would cause some cells to get three copies of the APP gene, triggering AD pathology, but at a later age than in people with Down's syndrome.
In the past year, many researchers have focused on other possible roles of presenilins in AD and in the healthy brain. NIA-funded scientists at the Harvard Medical School (Kim et al., 1997) described how both presenilins 1 and 2 are involved in apoptosis, the natural process in which cells are programmed to die. This programmed cell death is an important and necessary process during embryonic development. The researchers found that in cells with one mutation in presenilin 2 that causes FAD, the presenilin 2 protein was being cleaved more frequently at an alternative place, creating fragments of a different size, which seemed to correlate with cell death. It is possible that drugs that could prevent the presenilin proteins from being clipped apart at these alternative sites could be beneficial in delaying the progression of AD.
Already, researchers have identified at least one way to protect cells from some of the effects of mutant presenilin 1. NIA-funded researchers at the University of Kentucky (Mattson et al., 1997) found that estrogen could protect brain cells from undergoing cell death triggered by mutant presenilin 1. They exposed cells with the mutant presenilin 1 gene to beta-amyloid and to other substances that trigger programmed cell death. But when they also added estrogen, the amount of cell death was significantly reduced. The estrogen also seemed to suppress oxidation and protect mitochondria from dysfunction caused by the beta-amyloid and the presenilin 1. Epidemiology studies continue to suggest that estrogen reduces the risk of AD in postmenopausal women. As a result of this study, the authors suggest that estrogen therapy may delay the onset or slow the course of AD, particularly in people with the presenilin 1 mutation.
To understand the role of presenilin 1 in embryonic development, a team led by NIA-funded researchers at The Johns Hopkins University in Baltimore, Maryland (Wong et al., 1997), developed a mouse deficient in presenilin 1. In their study, these researchers showed that the development of mouse embryos lacking the presenilin 1 protein was so disrupted that none of these mice lived beyond birth. The lack of presenilin 1 shortened and deformed the spinal column and ribs, and also weakened the blood vessels in the brain. Clearly, presenilin 1 is crucial to the developing embryo, though its role in adults is less clear.
Yet another proposed role for the presenilins was published in 1998, when NIA-funded researchers at the Washington University School of Medicine in St. Louis, Missouri (Zhang, W. et al., 1998), found that both presenilins 1 and 2 bind with two proteins that are part of the cytoskeleton, or structural support for cells. In cells transfected with a mutant form of presenilin 1, which leads to the overexpression of that protein, the distribution of the two cytoskeletal proteins that interact with presenilin 1 was altered. These changes may have contributed to the pathology in the neuron. In brain tissue from people with AD, these two cytoskeletal proteins were found in the neurites of some of the plaques and neurofibrillary tangles in neurons, as well as in blood vessels and astrocytes (a type of glia).
To summarize, researchers are learning more about how mutations in the presenilins affect FAD onset; and how presenilins 1 and 2 interact with APP processing, and beta-amyloid, plaque, and tangle production. Presenilin mutations may contribute to nerve cell degeneration by altering the way beta-amyloid is produced or by triggering cell death, perhaps by making nerve cells collapse. Once they know how the presenilins and other factors lead to AD, scientists then can look for drugs to delay AD progression and perhaps prevent it altogether. For example, estrogen has shown promise in protecting brain cells from undergoing cell death triggered by mutant presenilin 1.
Scientists continue to search for new genes that might be involved in AD. A number of studies have reported associations between specific forms of known genes and late-onset AD. Like APOE epsilon4, these genes would only increase the risk of developing AD; they would not be causal. Association studies such as these need to be confirmed in different populations before the gene can truly be identified as a risk factor in AD.
A study led by NIA-funded researchers at the Oregon Health Sciences University in Portland (Payami et al., 1997) suggests that one allele known as human leukocyte antigen-A2 (HLA-A2) of a gene, HLA-A, that regulates immune response is linked with AD onset approximately 3 years earlier than the average. But researchers still need to confirm that it is HLA-A2 that causes the delay, and not another gene that happens to be close. The idea that HLA-A2 may have some effect on the age of onset for AD is intriguing, because the HLA genes are involved in immune response and inflammation; and in epidemiological studies, the use of non-steroidal anti-inflammatory inhibitors is reported to delay the onset of AD. The genetic studies are preliminary and need to be repeated in other laboratories before their findings can be confirmed.
Another gene possibly linked with late-onset AD was described by a team of NIA-funded researchers at the University of Pittsburgh in Pennsylvania (Montoya et al., 1998). They were studying the gene that codes for bleomycin hydrolase, an enzyme that breaks down the cancer drug bleomycin. The gene has two alleles, called A and G. In a study of several hundred people with AD, those without the APOE epsilon4 allele but with two copies of the bleomycin hydrolase G were about 4 times more likely to have AD. While this result also needs to be confirmed, it is interesting because bleomycin hydrolase has properties expected of enzymes that would be involved in the cleavage of APP to yield the amyloid found in plaques in AD brains. A number of researchers are using different approaches to identify the elusive enzymes that cleave APP.
The APOE epsilon4 version, or allele, of the APOE gene is known to increase the risk for AD in people of European descent. Now researchers have discovered that a region of the chromosome that lies next to the APOE gene, and appears to be involved with how much APOE is produced (promoter region), also may alter AD risk. NIA-funded researchers at Washington University in St. Louis (Bullido et al., 1998) contributed to a study of hundreds of people in Spain and St. Louis. They found that there were two versions of this APOE promoter region and that people with one version had an increased risk for AD whether or not they had the APOE epsilon4 allele. They believe that people with this version of the promoter region may be producing more APOE and that the APOE itself may be toxic to brain cells, contributing to AD. This result also needs to be confirmed.
In another attempt to find more genes associated with late-onset AD, a team led by NIA-funded researchers at Duke University Medical Center in Durham, North Carolina (Pericak-Vance et al., 1997), screened the entire human genome in people from a group of families in which more than one member had late-onset AD. Using statistical analyses, the researchers identified four regions that might contain genes that put these families at higher risk for AD. The strongest and most consistent pattern for these families seemed to indicate a possible gene for susceptibility to AD on chromosome 12. Scientists are searching within the chromosomal regions identified in this study to try to find specific genes that play a role in AD.
According to one new theory about the causes for sporadic AD, as neurons age, they may begin to make errors in translating the information contained in the gene's sequence of bases into the correct protein for beta-amyloid, causing a buildup of abnormal proteins in the neuron (van Leeuwen et al., 1998).
In another study, NIA- and National Center for Research Resources (NCRR)-supported investigators at the Columbia University College of Physicians and Surgeons General Clinical Research Center (GCRC) in New York City (Stern, Brandt et al., 1997) studied the relationship between APOE genotype and rate of disease progression and survival in 99 patients with probable AD for up to 6 years. The rate of progression in symptoms associated with AD (for example, decline in mental ability and development of myoclonus and extrapyramidal signs) was decreased in patients with APOE epsilon4 alleles compared with those patients with other genotypes, indicating that APOE epsilon4 is associated with a less aggressive form of AD.
To recap AD genetics, almost all FAD is early-onset, and many cases involve defects in three genes located on chromosomes 1, 14, and 21, respectively. The defective gene on chromosome 14 is presenilin 1, and that on chromosome 1 is presenilin 2. If a person inherits even one of these defective genes, he or she is almost 100 percent certain to develop AD at an early age. Inheritance of the APOE epsilon4 allele on chromosome 19 is linked to an increased risk for late-onset AD. Several new candidates for additional risk factor genes have been identified, but none has yet been confirmed in other study populations.
Perhaps most exciting is the recent, successful development of a mouse model for AD, because it opens up new avenues of research. Using transgenic mice, scientists now are able to study the effect of different mutations of APP in mouse DNA; the interplay of APP and presenilins; the role of inflammation, presenilins, and APOE; and how beta-amyloid deposits into plaques in AD.
Building on our improved understanding of AD genetics, scientists continue to look for clues as to what mechanisms cause AD and what the sequence of events is. Once they understand these, they then can look for interventions.
Researchers now understand that AD is caused by a complex cascade of events that takes place inside the brain. As a result, they believe that there is no single cause of AD, but that the disease can be triggered by any number of small changes in this cascade, and that these different causative factors interact differently in different people. Most clearly, the older you are, the more likely you are to develop AD. In most cases, genetic risk factors alone, as previously noted for APOE epsilon4, are not enough to trigger AD. Other risk factors may combine with your genetic makeup to increase your chances of developing AD.
Researchers looking at the frequency of AD and related dementias in people over age 65 seek to identify additional risk factors for AD and to show how and why AD develops. By studying various ethnic, racial, and social groups of people, scientists may discover new risk factors for AD. These risk factors, in turn, may suggest new theories about mechanisms involved in setting up and/or triggering the disease process.
In an important new development, NIA-funded researchers at Columbia University (Tang et al., 1998) announced that some unknown genetic or environmental factors are increasing the risk for AD among African-Americans and at least some Hispanics. The researchers followed more than a thousand older New Yorkers for between 1 and 5 years to see if they developed AD. Approximately 17 percent identified themselves as African-American, 22 percent as Caucasian, and 61 percent as Hispanic. The researchers found that having the APOE epsilon4 allele did not have the effect of increasing AD risk in the minority groups, the way it does in the Caucasian population. On the other hand, in people without the APOE epsilon4 allele, African-Americans had a cumulative risk of getting AD before age 90 that was 4 times higher than in Caucasians. Among Hispanics in the study, who were mostly from the Dominican Republic and other parts of the Caribbean, the risk was 2 times higher than for Caucasians, in the absence of the APOE epsilon4 allele. Determining what is elevating the risk of AD in the African-American and Hispanic populations could lead to new insights into understanding AD and ultimately to new treatment or prevention strategies. Identifying this new risk factor or factors is especially important since AD could increase disproportionately in some minorities as the population ages.
One longstanding theory of aging suggests that the buildup of damage from oxidative processes in neurons causes a loss of function. Scientists believe that free radicals produced through oxidative mechanisms play a role in several diseases, including cancer and AD.
A free radical is a molecule with one unpaired (leftover) electron in its outer shell. Healthy metabolism can produce free radicals of oxygen with unpaired electrons. The body produces free radicals to help cells in certain ways, such as in fighting infections. However, too many free radicals can injure cells. Free radicals are highly reactive. They readily modify other molecules available nearby, such as part of the cell membrane or a piece of DNA. The resulting, newly combined molecule then can set off a chain reaction, releasing additional radicals that can further damage neurons.
Free radicals may be involved in the development of AD by several means. They attach to molecules of fat in nerve cell membranes and thus may upset the delicate membrane machinery that regulates substances (for example, calcium) that go into and out of a cell. As mentioned before, too much calcium can kill cells. Further, oxidation due to free radicals may alter proteins; these new forms of proteins may be associated with the development of AD. Some of these oxidative changes are found in amyloid plaques in AD, where beta-amyloid causes the release of free radicals. Reactions like these also produce several free radicals of oxygen that may target the internal support structures of nerve cells.
Researchers are working to determine which oxidants are involved in AD and what role these oxidants play in the disease. NIA-funded researchers at Case Western Reserve University in Cleveland, Ohio, and the University of Alabama in Birmingham (Smith et al., 1997) found evidence in brain tissue affected by AD that a powerful oxidant called peroxynitrite was damaging neurons, including neurons that contained neurofibrillary tangles. There was no evidence of peroxynitrite damage in brain tissue from people without AD.
NIA- and NINDS-supported investigators at the University of Virginia Health Sciences Center in Charlottesville (Swerdlow et al., 1997) showed that a defect involving mitochondrial DNA (mtDNA) seen in some AD patients causes a rise in the production of oxygen free radicals. These scientists developed a cellular AD model by placing mtDNA from AD patients into a cell line from which all other mtDNA had been depleted. This created a "hybrid" cell that expressed the AD patients' mtDNA. A similar hybrid was prepared using mtDNA from healthy participants, enabling the researchers to identify the functional consequences of mtDNA in both populations. When they compared the two cell lines, they found greater oxygen free radical production in the AD hybrid.
NIA-funded researchers at the University of Kentucky's Sanders-Brown Research Center on Aging in Lexington (Snowdon et al., 1997) studied the relationship between brain infarction and clinical signs of AD in a group of nuns from the School Sisters of Notre Dame who took part in a long-term study of aging and AD. A brain infarction is an area of injury in brain tissue that occurs, usually when the blood supply to that area is interrupted.
The researchers found that nuns who had had the infarctions in certain brain regions had more clinical symptoms of dementia than could be explained by the number of plaques and tangles in the cerebral cortex. These findings suggest that at least some brain infarcts, which do not themselves cause dementia, may play an important role in increasing the severity of the clinical signs of AD. In addition, other signs of disease related to the brain's blood vessels or blood supply, such as atherosclerosis, may be involved in the development of AD. Further research is needed to understand whether preventing these types of blood vessel diseases in the brain can help reduce the clinical signs of AD.
Researchers are beginning to understand important parallels between AD and other neurological diseases including prion diseases, Huntington's disease, and Parkinson's disease. Most notably, all of these diseases can involve abnormal protein deposition in the brain. The common aspects shared by these diseases should accelerate the understanding of AD and the development of possible treatments.
In 1997, scientist Dr. Stanley Prusiner won the Nobel Prize in Physiology or Medicine for his discovery of prions, a novel and controversial infectious type of protein. Diseases that are believed to be caused by prions, such as Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy (so-called "mad cow disease"), can involve formation of a different kind of amyloid. Both prion diseases and AD cause dementia and death, and both are associated with cell-surface proteins (the prion protein and APP, respectively). Using electron microscopy and electron spin resonance, NIA-funded researchers at the University of California at Santa Cruz and San Francisco (Lundberg et al., 1997) studied amyloid formation in prion diseases and detected an important stage just before the formation of fibrils. Their technique may be useful in studying amyloid formation in AD.
Parkinson's disease is the second most common neurodegenerative disorder, after AD, in the United States. In 1997, researchers discovered the first gene linked to Parkinson's disease, which codes for a protein called synuclein. Synuclein also is found in the amyloid plaques in the brains of people with AD, an intriguing connection. And an abnormal structure called a Lewy body, formed of aggregated synuclein, found in the subcortical regions of the brain in Parkinson's disease, also sometimes appears in the brains of people with AD.
New research also shows that in Huntington's disease, another progressive neurodegenerative disorder causing dementia, genetic defects cause a long protein to form into insoluble fibrils very reminiscent of the beta-amyloid fibrils of AD, or the protein fibrils of prion disease. Thus, research into each of these neurological disorders may yield unexpected benefits in understanding and treating the other diseases of the brain.
Currently, AD can be diagnosed conclusively only by autopsy examination of the brain. To confirm AD, pathologists look for the presence of characteristic plaques and tangles in brain tissue during an autopsy. The features of AD during life may be caused by other conditions such as stroke or other diseases. One reason it is very important to diagnose AD accurately as early as possible is that when new drugs are developed they can be tested in patients before the disease has progressed too far.
Through the work of many researchers, the diagnosis of AD in living people has become more and more accurate. In specialized research facilities, clinicians now can diagnose AD with up to 90 percent accuracy, as confirmed later at autopsy. The diagnosis includes taking a personal history from patients and their families, doing a physical exam and tests, and administering memory and psychological tests to patients. A team of NIA-funded researchers based at the Harvard University ADC (Solomon et al., 1998) proposed a preliminary 7-minute screening test that might be used to distinguish between people who might have AD and those experiencing normal memory loss. The utility of this screening test has yet to be thoroughly evaluated.
Now, tests of mental status are needed that can pinpoint the gradual loss of cognitive ability in AD patients and identify people who are at a very early stage in the course of the disease. The search continues for reliable biological markers for diagnosing AD in both the early and later stages. The sooner an accurate diagnosis of AD is made, the greater the gain in managing symptoms, determining the natural history of AD, and defining subtypes of patients. An early, accurate diagnosis of AD is especially important to patients and their families because it helps them plan for the future and pursue care options, while the patient still can take part in making decisions.
One 1997 study found that family members often fail to recognize that someone with dementia is having significant problems with memory. Even when they recognize that there is a problem, they often do not take the person with dementia in for a medical evaluation. As part of the Honolulu-Asia Aging Study, a long-term study funded by NIA of dementia in older Japanese-American men living on the island of Oahu, Hawaii, researchers (Ross, G. et al., 1997) interviewed family members of 191 men with dementia who were living at home. Of the men who were found to have dementia, 21 percent were accompanied by family members who had failed to recognize that there was a memory problem. Among participants with very mild dementia, 52 percent of their family members failed to recognize a significant memory problem, compared with 13 percent of family members among participants with more severe dementia. And of family members who did recognize that there was a problem, 53 percent had not brought their loved one with dementia in for a medical evaluation of the condition. More research is needed to develop strategies to encourage families to identify and evaluate memory problems in their relatives as early as possible.
NIA supports research aimed at developing and testing reliable, valid diagnostic tools for AD and other dementias in older people. For example, a consensus statement by NIA and the Alzheimer's Association published this year (Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the National Institute on Aging Working Group, 1998) states that for cases of suspected early-onset FAD, it is appropriate to search for mutations in the presenilin and APP genes to confirm a diagnosis. In late-onset AD, detecting an APOE epsilon4 allele can add confidence to the clinical diagnosis, but should not be a primary method of diagnosis (see below). According to the statement, of the other methods under investigation, analyzing cerebrospinal fluid for low levels of beta-amyloid of a particular length (the "sticky" beta-amyloid) and high levels of the tau protein is the biochemical test that comes closest to being useful (Proceedings..., Neurobiology of Aging, 19(1 Suppl), 1998).
Another possible new way of diagnosing AD was described last year by a scientific team led by researchers at the Harvard Medical School (de la Monte et al., 1997). They discovered a protein that is overexpressed in the brains of people with AD. It appears that the overexpression of this protein can be detected in cerebrospinal fluid taken from AD patients.
One major advance in late-onset AD was the discovery of the genetic risk factor APOE epsilon4 by NIA-funded researchers at the Duke University ADC in 1992. Before 1992, scientists made a determination of probable or possible AD based on clinical diagnosis alone. Since the discovery of APOE epsilon4, researchers have been trying to determine whether APOE can be used to aid in diagnosing AD. In 1997, an analysis was published pooling data from hundreds of AD researchers on thousands of probable or definite AD patients. The NIA-funded analysis (Farrer et al., 1997) found that the risk of AD was significantly increased for Caucasians carrying one or both APOE epsilon4 alleles, and that the risk was decreased for those carrying one or both APOE epsilon2 alleles, with no APOE epsilon4 alleles. These associations were even stronger among Japanese. However, they found that the picture became much less clear when considering the risks for African-Americans and Hispanics.
Then in 1998, NIA-led researchers (Mayeux et al., 1998) at the 27 ADCs across the country reviewed the cases of more than 2,000 patients referred for evaluation of dementia, all of whom had AD confirmed or ruled out in autopsies. They concluded that APOE could not be used alone to diagnose AD. However, they did suggest that APOE testing might be used after clinical diagnosis, to refine the diagnosis and help to reduce the small number of people who might be falsely diagnosed with AD.
Ultimately, researchers hope to be able to diagnose AD before the patient has any behavioral symptoms, so that once drugs are available to stop or slow the process of degeneration, they can be used at the earliest possible opportunity. One possible step toward pre-symptomatic diagnosis was found in a new study led by NIA researchers at the LNS (Pietrini et al., 1997). They studied a group of older patients with Down's syndrome, who often develop AD-like dementia. These patients were not yet showing any signs of dementia. Yet, using positron emission tomography (PET scans), the researchers found that they could detect changes in the way glucose was metabolized in parts of the brain most affected by AD, when the patients watched a movie to stimulate these parts of the brain.
Another possible method for detecting AD before symptoms develop is being studied by a team of NIA-funded researchers at the Brigham and Women's Hospital (Johnson et al., 1998). They used a different imaging method known as single photon emission computed tomography (SPECT) to study a large group of people with memory problems. Using SPECT, they were able to identify correctly 80 percent of the people who would go on to develop clinically-diagnosed AD. They believe that SPECT, when combined with genetic and psychological testing, could improve our ability to predict which people with memory problems will eventually develop AD.
Yet another technique for determining which people with memory problems may actually be in the earliest stages of AD is to measure the size of various structures in the brain, using magnetic resonance imaging (MRI). Many studies have shown AD causes some brain structures, particularly the hippocampus, to shrink. Now scientists are exploring exactly how early this shrinkage, or atrophy, can be detected. In another new study at NIA's LNS (Krasuski et al., 1998), researchers studied 13 people with mild cognitive impairment, using MRI to measure the volume of different structures in the brain's medial temporal lobe. They were able to correctly identify 94 percent of the people who would later be diagnosed with AD.
A team of NIA-funded scientists at the New York University Medical Center (Convit et al., 1997) found that measuring the volume of the hippocampus with MRI, they could discriminate between people with mild cognitive impairment and people with no memory or learning problems in 74 percent of the cases they studied. They also found that in a later stage of AD, another brain structure called the fusiform gyrus also atrophies. And in a larger study, a team of NIA-funded researchers at the Mayo Clinic in Rochester, Minnesota (Jack et al., 1997), found that by measuring the volume of the hippocampus with MRI they could discriminate between people without AD and people with even very mild AD.
NIA- and NCRR-supported investigators at the Columbia University College of Physicians and Surgeons GCRC (Stern, Tang et al., 1997) have made a promising first step toward providing specific prognoses to AD patients and their families. These scientists followed AD patients for up to 7 years in an effort to develop and validate an approach to estimate the length of time before an AD patient requires care equivalent to nursing home placement or dies. This group of researchers constructed algorithms using the predictor variables sex, duration of illness, age at onset, modified Mini-Mental State Examination score, and the presence of extrapyramidal signs or psychotic features.
In summary, an autopsy still is the only way for scientists to conclusively diagnose AD. However, this year, scientists made advances in diagnosing AD while patients are still alive. A consensus statement by NIA and the Alzheimer's Association now provides clinicians with more guidelines for diagnosing AD. And, laying the groundwork for the development of future tests, scientists are looking at ways to: distinguish between people with incipient AD and normal memory losses; analyze cerebrospinal fluid for low levels of the "sticky" beta-amyloid and high levels of tau; use PET scans to detect changes in the way glucose is metabolized in AD affected brain regions; and combine SPECT with genetic and psychological testing to predict which people with memory problems eventually will develop AD.
Perhaps most promising are the potential uses of MRI with regard to measuring the size of various brain structures to help researchers determine which people with memory problems are in the earliest stages of AD; to identify people who would later be diagnosed with AD; and to measure hippocampal volume to distinguish between people with mild cognitive impairment and those with no memory or learning problems, and between people without AD and people with even very mild AD. The current challenge is to confirm these and other findings through continued research. The aim is to find ways to diagnose AD at the earliest possible moment when treatments that slow or possibly prevent AD have a chance at being effective in maintaining good function and quality of life.
Immediate goals in treating and managing the dementia symptoms of AD are to slow, reduce, and/or reverse its mental and behavioral signs. The eventual goal is to prevent or stop the disease process altogether.
For those who are already suffering from the effects of AD, the most immediate need is for drugs to control their symptoms. Researchers, including those supported by NIA, are continually testing the effectiveness of a range of drugs on the mental and behavioral aspects of AD. Several clinical trials are testing a variety of compounds. Scientists are looking for treatments that work on many patients, stay effective for a long time, ease a broad range of symptoms, improve patients' activities of daily living and cognitive function, and have no serious side effects.
Treatments also are needed for managing problem behaviors, such as verbal and physical aggression, agitation, wandering, depression, sleep disturbances, and delusions that occur in AD. Preliminary studies suggest that these types of behaviors greatly influence families' decisions to move loved ones to care outside the home. Improving these behaviors could delay or even prevent placement in long-term care facilities, maintain patients' dignity, reduce caregiver stress, and lower overall costs to families and to society.
In 1996, the Food and Drug Administration (FDA) approved donepezil hydrochloride (Aricept) to help treat some mild to moderate symptoms in some AD patients and delay progression for from 6 to 12 months. Aricept (also known as epsilon2020) is the second drug approved by the FDA to treat AD. The first drug, tacrine (Cognex), has been marketed since 1993. AD is marked by the loss of neurons that produce acetylcholine, a key neurotransmitter in cognitive functioning. Both Aricept and Cognex act by inhibiting acetylcholinesterase, an enzyme that normally breaks down acetylcholine. However, neither drug stops nor reverses the progression of AD. Occasional side effects of Aricept include diarrhea and nausea. The drug also can cause an irregular heartbeat, especially in patients with heart conditions. Fainting spells have been reported in some patients. However, Aricept seems not to affect liver enzymes, an effect that prevented many patients from taking Cognex. Most researchers agree that neither Aricept nor Cognex works for all, or even most, AD patients so that the drugs' effects and duration of usefulness are limited.
However, scientists are now studying a new generation of cholinesterase inhibitors, which might have greater usefulness and fewer side effects. In studies on animals, scientists at NIA (Patel et al., 1998) have preliminary evidence suggesting that one such drug, called phenserine, may be useful in treating AD patients. In animal models of cognitive decline, phenserine was significantly more effective in enhancing performance and learning in a maze test than drugs currently marketed to treat AD. Phenserine is undergoing toxicology testing (studies to find safe doses and identify any potentially problematic side effects). And NIA scientists recently found that a drug called arecoline seems to improve cognitive function and the process whereby chemical messages are sent across synapses in animals. Arecoline artificially stimulates acetylcholine receptors. Researchers now are studying the effects of arecoline in people.
Another drug that inhibits acetylcholinesterase, called physostigmine, is helping researchers to understand how these drugs can improve brain functions such as working memory, the form of memory that enables people to hold information such as telephone numbers for a short period of time. NIA researchers (Furey et al., 1997) used PET scans to study the beneficial effect of physostigmine on working memory in humans. Because physostigmine has a shorter duration of action than the drugs that are already approved for AD treatment, researchers are developing a longer-acting form.
These drugs (Aricept, Cognex, and physostigmine) do not prevent AD from continuing to kill the nerve cells that normally produce acetylcholine. Therefore, researchers are looking for other drugs to help vital acetylcholine-producing cells survive longer and to slow or prevent AD.
The search for more effective ways to treat and prevent AD includes studying the use of estrogen, anti-inflammatory drugs, and other compounds in AD patients; determining which groups of people develop AD; and conducting several initiatives related to caregiving.
In looking for factors associated with earlier or later onset of AD, NIA and NCRR funded researchers at Columbia University. These investigators found that estrogen replacement therapy (ERT) was associated with a reduced incidence of AD in a group of older women. Incidence is the rate at which new cases of a disease occur. In this study, researchers found that women who took estrogen for longer than 1 year after menopause had a reduced risk of developing AD; their risk was reduced by about 80 percent compared to women who did not take estrogen.
Scientists at The Johns Hopkins Univer-sity reported similar results related to estrogen use among women in the Baltimore Longitudinal Study of Aging (BLSA). A long-term NIA study, the BLSA includes a physical and mental assessment of 2,283 men and women who were healthy at the start of the study. In a prospective study of one group of BLSA women, a history of ERT was associated with a reduction in AD risk by about half, also suggesting that estrogen helps protect women from AD. This beneficial effect is in addition to the lower incidence of heart disease and osteoporosis (a disorder in which normal bone tissue is lost) for women who take estrogen after menopause.
Estrogen is a hormone, a body chemical that initiates or regulates body functions. Some scientists believe that estrogen's role is in helping brain cells survive, which in turn delays the onset of AD. Other researchers think that estrogen aids the metabolism of APP, preventing it from forming beta-amyloid fibers. Still others propose that estrogen may work as an anti-oxidant to protect nerve cells. Additional laboratory research is needed to learn exactly how estrogen may protect women from AD. In turn, this research will help scientists develop new treatments for the disease.
While these findings are encouraging, they do not confirm that taking estrogen can prevent cognitive decline. To prove a cause and effect relationship, careful studies (clinical trials) are needed in which older participants are assigned randomly to take estrogen or not and then reexamined several times over a long period. Clinical trials will help determine whether estrogen therapy can delay or prevent the onset of AD as well as the safety, dose, and duration of estrogen treatment needed to produce these effects. One such clinical trial, the Alzheimer's Disease Cooperative Study (ADCS) trial of estrogen, is assessing the effect of ERT on the progression of AD in postmenopausal women who have the disease. If such studies confirm a positive effect on patients with AD symptoms, a next step would be an NIA-funded trial of whether estrogen could actually help to prevent AD in women.
A growing body of evidence suggests a link between inflammation and some changes that occur in the brains of AD patients. However, scientists do not know yet whether inflammation is a cause or an effect of the disease.
Researchers in NIA's 40-year BLSA believe they have found a link between anti-inflammatory drugs and a lowered risk of AD. Scientists surveyed 1,417 men and 648 women enrolled in the BLSA between 1955 and 1994 about their use of medications. A total of 110 participants eventually were diagnosed with AD. Those who regularly used non-steroidal anti-inflammatory drugs (NSAIDs) other than aspirin had a lower risk of developing AD than those who took acetaminophen (Tylenol) or no painkillers at all. For men and women in the BLSA study who took NSAIDs regularly for as little as 2 years, researchers found a lower risk of AD by as much as 60 percent. NSAIDs include ibuprofen (Advil, Motrin), naproxen sodium (Aleve), indomethacin (Indocin), and many other painkillers. Tylenol has no anti-inflammatory properties. Aspirin users had a slightly decreased risk of AD, but this drop was not statistically significant in this particular study.
Researchers previously had noted that AD is less common in arthritis patients. Now it appears that this finding may be associated with the high rate of NSAID use by arthritis patients. The way NSAIDs might reduce the risk of cognitive decline is unclear. However, some scientists think that NSAIDs may help prevent the inflammation found in the brains of people with AD.
Scientists advise against taking NSAIDs to prevent AD based on these results alone. The BLSA survey identified only an association of NSAID use with a decreased prevalence of AD, and did not establish any causal relationship or protective effect of these drugs. NSAIDs have potentially serious side effects, including stomach irritation and ulcers. Further research is needed to determine whether NSAIDs decrease a person's risk of developing AD. As with estrogen, the only way to prove a cause and effect relationship is through clinical trials. Until such clinical trials are performed and the results carefully evaluated, taking NSAIDs to preserve cognitive function is not advised.
Oxidative changes are seen in the brains of AD patients. Studies of compounds that fight oxidation are part of the effort to understand processes that damage cells and find ways to treat and possibly prevent AD. The NIA-supported ADCS trial of selegiline (l-deprenyl or Eldepryl) and alpha-tocopherol (vitamin E) is one such study. Both selegiline and vitamin E act as anti-oxidants. Selegiline, which has been used to treat patients with Parkinson's disease, works by inhibiting an enzyme in the brain that impairs certain neurotransmitter systems.
For 2 years, researchers at the Columbia University College of Physicians and Surgeons (Sano et al., 1997) studied 341 moderately impaired patients with probable AD who were recruited from 23 centers taking part in the ADCS. Participants were divided into four groups that received different treatments: selegiline, vitamin E, both selegiline and vitamin E, or a placebo (an inactive substance). Scientists compared the amount of time it took patients in each group to reach one of the following outcomes: death, institutionalization, loss of the ability to do activities of daily living (such as handling money, bathing, dressing, and eating), and severe dementia. They looked at the signs of AD that can worsen over time.
The results suggest that compared to those who took a placebo, the estimated average time to reach any one of the four outcomes increased by 230 days for participants who took vitamin E, 215 days for those who took selegiline, and 145 days for those who took both selegiline and vitamin E combined. Also compared to those who took a placebo, members of the treatment groups showed some improvements related to their level of independence and behavioral symptoms. No effect was found on cognitive measures.
Overall, this study shows that treatment with selegiline or vitamin E reduced moderately impaired AD patients' risk of reaching one of the four primary outcomes, with an estimated average delay of 6.5 months. In addition, these findings support the idea that damage due to oxidation plays a role in AD.
Scientists caution that further research is needed to confirm these preliminary findings. Researchers need to find out if these types of drugs actually can delay the development of symptoms much earlier in the course of the disease and learn how these drugs might affect patients at different stages of AD. An NIA- and industry-funded trial to see if vitamin E or Aricept will delay the onset of AD in people with mild cognitive impairment will begin in the ADCS in 1998. It also will be important to determine if the positive effects observed in the anti-oxidant trial were because these substances improved other aspects of the patients' health, such as heart-related effects, rather than specifically fighting oxidation in the brain.
Investigators further warn that selegiline may have potential side effects and interactions with other drugs. In addition, the dosage of vitamin E used in this study was much higher than that typically found in daily supplements. At these doses, vitamin E may be associated with an increased risk of bleeding in some people. AD patients and their families should consult their doctors to see whether these drugs or others approved by the FDA may be appropriate for a particular AD patient.
There is growing interest in the use of ginkgo biloba extract for the treatment of AD. Ginkgo biloba extract is a traditional Chinese medicine made from the leaves of the ginkgo tree. It apparently has anti-oxidant, anti-inflammatory, and anti-coagulant properties. In the first American trial of ginkgo against AD, the authors (Le Bars et al., 1997) found a "fairly modest" positive effect. However, there have been several reports linking ginkgo to hemorrhages, and other possible side effects are as yet unknown. NIA is funding some investigations into the use of ginkgo in treating AD.
The ADCS was established in 1991 to build the organizational structure needed for numerous centers to cooperate in testing promising drugs in AD and to develop and improve tests for evaluating AD patients in clinical trials. Many of the participating centers are carried out through the clinical cores of the ADCs (see below).
The following six studies began in the first 5-year grant period (some were completed by June 1996 and others still are ongoing): safety and effectiveness of selegiline and vitamin E (Sano et al., 1997); tests in English that measure treatment efficacy (A Multicenter..., Alzheimer's Disease and Associated Disorders: An International Journal, 11(Suppl 2), 1997); tests in Spanish that measure treatment efficacy (results in analysis); use of haloperidol, trazodone, and behavioral management techniques in patients with disruptive agitated behavior (results in analysis); use of ERT in women with mild to moderate AD (results in 1999); and use of the anti-inflammatory drug prednisone (results in analysis).
Apart from the vitamin E or Aricept prevention trial, five more proposed studies have been approved for the next 5-year grant period: development of improved measures of treatment efficacy; an anti-inflammatory study; AIT-082 in AD (in a Phase I study, which means the drug is being given to a small number of volunteers to determine toxic levels and safe doses); melatonin and sleep disorders in AD; and divalproex sodium (Depakote), an anti-seizure drug, as therapy for agitation and dementia in nursing home residents.
ADCS investigations of estrogen, anti-inflammatory agents, and AIT-082 are only three examples of a number of efforts to test promising new treatments for AD. As explained for estrogen and anti-inflammatory agents, each of these efforts was initiated based on molecular and epidemiological research. In the case of AIT-082, preliminary data suggest that this compound stimulates the production of neurotrophins. AIT-082 also stimulates cognitive function and memory in aged animals. As with other promising agents, the effectiveness of AIT-082 will only become known after several lengthy clinical trials.
NIA funds 27 ADCs across the United States. Each ADC supports four common functions: clinical diagnosis and followup, neuropathology, education and information transfer, and administration. Some ADCs also receive funding to perform specific research studies on AD. ADCs also support other functions, such as neuroimaging. The primary goals of the ADC Program are to promote research, training and education, technology transfer, and multicenter and interdisciplinary cooperative studies in the etiology, diagnosis, and treatment of AD.
Much of the success in AD research in this country since 1985 can be attributed to resources provided by NIA to the ADCs. Recent advances include linking genes on chromosomes 1, 14, and 21 to FAD and identifying inherited risk factors related to APOE. In addition, researchers at the ADCs helped lay the groundwork for studying how proteins associated with amyloid plaques and neurofibrillary tangles are processed.
Other programs funded by NIA depend on research activities at the ADCs, including the Consortium to Establish a Registry for Alzheimer's Disease (CERAD); and the ADCS. Along with conducting research and pilot research projects, the ADCs contribute resources such as patient data, brain and other tissue samples, and molecular probes to other scientific programs. The ADCs serve as a resource for many types of studies testing new AD treatments, in addition to their role in the ADCS trials.
It has become increasingly clear that AD research will benefit from the analysis of combined data collected systematically from multiple sources, including all of the ADCs and, eventually, from other sources where longitudinal data are collected. An interim Alzheimer's Disease Data Coordinating Center (ADDCC) has been established, and a permanent ADDCC is scheduled to be funded on July 1, 1999. The ADDCC will make it possible to address important and novel research issues that are not feasible with the resources available in any one Center. Many of these issues revolve around distinguishing among the subtypes of AD and the interface between normal age-related cognitive decline, AD, and other dementias.
In 1990, NIA began a program to link satellite diagnostic and treatment clinics to the ADCs. The satellite clinics offer diagnostic and treatment services to minority, rural, and other underserved people; and help increase diversity among research volunteers, so that answers to research questions apply to a wider group of people. This program makes it easier for diverse populations to take part in research studies and clinical drug trials through the parent ADC.
Twenty-seven satellite clinics serve communities with broad ethnic and cultural diversity, including African-Americans, Asian-Americans, Hispanic-Americans, and Native-Americans. Eleven clinics serve rural areas, 12 serve urban areas, and 4 serve a combination of urban and rural areas.
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. The idea behind SCUs is that people with dementia might benefit from specially designed programs or environments different from those provided in a traditional nursing home. However, because there has been no standard definition of what constitutes an SCU, there is large variability in the care provided in units identifying themselves as SCUs. Thus, the rapid proliferation of SCUs has raised some concerns, underscoring the need for research into these units. In 1991, NIA began 5 years of funding for the SCU Initiative, a collaborative effort designed to study the effectiveness of SCUs and address these concerns.
The SCU Initiative was conducted at 10 sites, with the participation of researchers at some ADCs, to evaluate the effectiveness and costs of special care for AD patients at nursing homes. Many of the results from the SCU Initiative were published over the past 2 years.
Study designs at the sites ranged from case studies to multi-State evaluations to a national assessment. Most of these collaborative investigations used large data sets to compare care and outcomes in SCUs with those in traditional nursing home care units. Researchers also sought to standardize a definition of units that provide special care.
NIA-funded scientists compared national survey data on nursing homes for 1991 and 1995. Compared to 1,497 SCUs in 1991, there were more than 3,746 SCUs in 1995. In 1995, among the Nation's 16,827 nursing facilities, more than 22 percent offered specialized care in some form for people with dementia, and the total SCU capacity was 122,479 patients.
The recent results of the SCU Initiative have shown that, on average, SCUs have more desirable staffing, programming, and environments than do non-SCUs. In 1 study in 123 Minnesota nursing homes, researchers found that SCUs provided more separate activities and physical space for residents, and more stable assignments of staff to residents. They also were less noisy and less complex, and had more tailored activities. The SCU staff had a higher tolerance for problem behaviors. And the presence of an SCU was associated with less staff turnover throughout the nursing home.
Also, facilities with an SCU offer more training in coping with dementia than do non-SCU facilities (Grant et al., 1998). However, a study of SCUs and non-SCUs in New York State (Teresi et al., 1998) found that there is a disturbing lack of staff training and support in both types of settings, leading to high levels of staff burnout. In another study (Maas et al., 1998), researchers found that the overall costs of caring for people with AD in SCUs were greater, thus justifying the fact that these residents paid a higher rate for their care. However, this presumes SCUs do in fact provide more and better staffing, a presumption that may not have a basis since there are not consistent standards for staffing in SCUs.
In 1995, the NIH established a major initiative to develop and test new ways for families and friends to manage the daily activities and stresses of caregiving for people with AD. Called REACH--Resources for Enhancing Alzheimer's Caregiver Health--the studies are sponsored by NIA and the National Institute of Nursing Research (NINR). This 5-year effort is a critical part of NIA's support for research on AD patients receiving care at home.
Participating researchers are from the Center for Aging at the University of Alabama; Veterans Affairs Medical Center and the University of Tennessee at Memphis; the Center on Adult Development and Aging at the University of Miami, Florida; Veterans Affairs Palo Alto Health Care System and Stanford University, California; the Center for Collaborative Research at Thomas Jefferson University in Philadelphia, Pennsylvania; the Medical Information Systems Unit at the Boston University Medical Center, Massachusetts; and the University Center for Social and Urban Research at the University of Pittsburgh. They are studying the effects of educational support groups, behavioral skills training, family-based interventions, environmental redesign, and computer-based information services for African-American, Caucasian, and Hispanic-American families.
REACH is designed to stimulate research on home- and community-based interventions to help families provide care for loved ones with mild and moderate dementia. For example, NIA-supported researchers at the Center for Collaborative Research at Thomas Jefferson University are looking at the role of adjustments in the home environment (design changes and ways of managing tasks) in supporting family caregivers and increasing their well-being. Both types of adjustments reflect adaptive strategies that caregivers may use to simplify the environment, make tasks easier, and increase patient safety.
NINR-funded REACH investigators at the University of South Florida in Tampa (Haley, 1997) have recently reviewed what is known about the caregiving role and its importance as well as the role of health care providers in identifying and responding to caregiving issues effectively. Factors such as the presence of patient behavioral problems and caregiver social supports and coping responses can be used to predict caregiver distress. These scientists have identified instruments that assess the level of distress. They are reviewing the effectiveness of interventions, including psychosocial strategies, support groups and respite care, and written materials.
As part of research into the caregiving experience, NIA also is funding studies on the risk for drug, alcohol, and sleep problems among caregivers; the effect of skills training for caregivers on their levels of stress, depression, and efficacy; and the benefits for caregivers of using adult day care.
NIA supports research at nine collaborating Exploratory Centers on the Demography of Aging. Demography refers to the study of certain health factors--in this case, aging--in human populations. The goal of these centers is to provide innovative and public policy-relevant research on health, long-term care, and the economic aspects of aging. Each center brings experts from different backgrounds together to conduct research in several areas of interest.
In the second year of this program, four new pilot projects are under way studying aspects of AD along with other demographic factors. As part of two of these, researchers at Duke University are studying the development of AD and the effects of different APOE gene alleles on AD. In other areas, the Duke University team is trying to forecast the life expectancy of older people and health service needs, studying how life expectancy can be extended, and measuring the rate of disease and disability in the U.S. population. Researchers in one of these studies are examining the costs and benefits of different medical treatments for older people.
In another exploratory center study, scientists at the University of Chicago, Illinois, are investigating the well-being of spouses of institutionalized AD patients. University of Chicago researchers also are studying the economics of aging from a historical perspective, retirement prospects and minority issues for Hispanic-Americans, and differences in family care and social supports between African-Americans and Caucasians.
Researchers at the University of Pennsylvania in Philadelphia are studying AD and life in nursing homes. These scientists are working to develop new measures of AD progression for use in projecting population and disability rates. They also are examining relationships between members of different generations, measuring death rates for African-Americans from 1930 to the present, comparing English and Spanish versions of the Dementia Severity Measure, and looking for ways to encourage minority researchers.
By collecting and analyzing data about health and economic trends in the older population, exploratory centers foster a better understanding of aging and its effects on both individuals and society.
Many investigators from a wide variety of scientific disciplines are working on the AD puzzle. The National Heart, Lung, and Blood Institute (NHLBI) is funding AD research, including the role of amyloid fibril formation and a new model for studying APP processing. Cerebral amyloid angiopathy is a disease that is common in AD patients and is associated with the deposition of the beta-amyloid peptide in the blood vessels of the brain. In one form of the disease called hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), the pathology tends to be more severe, and patients frequently bleed in the brain at a younger age. People with HCHWA-D have an amino acid substitution (epsilon22Q) in the beta-amyloid peptide due to a gene mutation.
NHLBI-funded researchers at the State University of New York, Stony Brook (Van Nostrand et al., 1998), reported that the beta-amyloid peptide with the substitution epsilon22Q, but not the control, induced degeneration and other severe pathological changes in cultured human cerebrovascular smooth muscle cells. The peptide with the HCHWA-D mutation selectively bound to these cells and assembled into fibrils on the surface of the cells. An interesting observation was that binding of the peptides caused a significant increase in the level of the APP from which the peptide is derived. Fibril formation was not observed at similar concentrations of the peptide in solution. This assembly could be blocked by the dye Congo red, which also prevented the pathologic action of the peptides on the cells. These data indicate that fibril assembly is essential for the pathologic actions of the amyloid peptides and that the cell surface plays a critical role in the formation of fibrils in this system.
The beta-amyloid precursor protein is present in significant amounts in the alpha granules of blood platelets. When platelets are activated by physiologic stimuli, this protein may be secreted to the outside medium and may regulate the clotting of blood by inhibiting coagulation factors IXa and XIa. An NHLBI grantee at Scripps Research Institute in California has been studying the processing of the precursor protein in megakaryocytes (MEG-01) that produce platelets. Early findings indicate that MEG-01 cells store a portion of their endogenously synthesized APP protein in a rapidly releasable form and raise the possibility that the MEG-01 cell line may be a useful model for studying the processing of APP into the regulated secretory pathway (Chuang and Schleef, submitted).
The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) conducts and supports research on molecular and biochemical mechanisms of cell signaling, including the role of neurotransmitters and ion channels; and mechanisms involved in abnormal metabolic processes.
This year, scientists at the NIDDK (Kawahara et al., 1997) reported progress in understanding how beta-amyloid affects ion channels in cells. Investigators found that beta-amyloid, when added to artificial membranes, spontaneously formed pores or ion channels. To understand how these pores for amyloid are formed, researchers performed a molecular modeling study and developed three basic types of channel models. Two of these models showed how adding a certain substance to the channel pore complex can affect whether the channel reacts to atoms that have positive or negative charges. These models then were used to design experiments to test the binding of zinc, a metal ion that some scientists think may play a role in the formation of amyloid plaques in AD. Researchers found that addition of zinc to the pore complex had a strong effect on how the channel worked, essentially blocking pore activity.
To determine whether beta-amyloid could form ion channels in natural membranes, investigators studied the buildup of beta-amyloid in a nerve cell line. Once again, they found that exposing the membrane to beta-amyloid causes pores to form, and that addition of zinc blocked channel activity. These results support the idea that beta-amyloid damages nerve cells by forming these channels.
Other NIDDK-funded investigators continue to study proteins that help carry glucose across cell membranes. Two such proteins have been located in the brain. One moves glucose across the blood-brain barrier, the protective membrane that controls the passage of substances between the blood and the central nervous system. The other protein carries glucose into nerve cells in the brain. Researchers (Vannucci et al., 1997) measured levels of these proteins in the brains, obtained at autopsy, of patients with and without AD. The results show lower levels of both transporter proteins in the brain tissue of patients with AD, arguing that the ability to transfer glucose in the brain and into neurons is reduced in AD patients. Researchers also counted the number of synapses to see if loss of neurons and synapses was responsible for the drop in transporter proteins. The measurements suggest that the decrease in protein level is not explained simply by the loss of nerve cells; thus, it represents a decrease in the expression of the transporter protein. Therefore, strategies aimed at increasing the expression of transporter proteins and determining the effects on increased circulating glucose on thinking abilities are being studied.
In type 2 diabetes (non-insulin-dependent), islet amyloid polypeptide (IAPP) forms amyloid deposits in pancreatic beta cells and has been implicated in disease development. NIDDK-funded researchers at the University of Washington, Seattle (Verchere et al., 1997), are using a transgenic mouse model to study mechanisms responsible for islet amyloidogenesis (the development of amyloid). It has been thought that excessive IAPP synthesis could lead to amyloidogenesis. Findings from the present study suggest that even excessive synthesis and secretion of IAPP by the beta cell for prolonged periods is insufficient for islet amyloid deposition. They propose that islet amyloid formation in these mice requires a change in beta cell function, such as can be induced by high doses of certain hormones or growth factors. Information gained studying IAPP will contribute to the overall understanding of the mechanisms underlying amyloid and associated protein accumulation, and to the design of treatments to reduce the effects of tissue damage, to an increase in the rate of recovery from tissue damage, and ultimately, to the prevention of disease.
Scientists supported by NINDS are conducting a variety of studies aimed at increasing our knowledge of the causes of, and finding new and better interventions for, AD. Some seek to elucidate the cellular, molecular, and chemical pathophysiology that differentiates AD from normal aging using sophisticated imaging methods, innovative genetic techniques, and novel animal models. Others are developing methods by which to diagnose the disease in its earliest stages. Yet others search for potential drug treatments.
NINDS-supported investigators at the University of California at San Diego (Dewji and Singer, 1997 [The Seven-...]) last year uncovered a critical clue to the puzzle of how presenilin proteins may interact with the body's cellular systems. (Two of the three genes known to account for FAD encode for presenilins.) Using a technique called immunofluorescence and antibodies to each presenilin, the scientists were able to demonstrate that presenilin proteins can be expressed on the surface of cells. This expression would enable the presenilins to interact with other proteins such as beta-amyloid. The investigators believe this interaction to be a crucial step in the molecular and cellular mechanisms that cause AD.
Researchers at Stanford University (McIntosh et al., 1997), with support from NINDS, NIA, and the National Institute of Environmental Health Sciences, have conducted studies of an effect of oxygen free radical molecules called lipid peroxidation. Cell membranes that undergo lipid peroxidation become leaky and may even rupture. The investigators studied the temporal cortex and cerebellum of brains from people who were found at autopsy to have AD, as well as brains from people who died of other causes. Using chemiluminescence, a laboratory technique that measures byproducts formed during lipid peroxidation, the scientists found that the temporal cortexes of the AD patients had significantly higher levels of those byproducts that indicate increased oxidative damage than the non-AD group. Interestingly, the temporal cortex of one AD patient who was known to have taken an anti-oxidant supplement (vitamin E) daily for the 4 years prior to his death showed a very slow initiation of oxidation. This suggests that the anti-oxidant in the brain tissue was scavenging the oxygen free radicals that cause lipid peroxidation.
For years, scientists have been debating what role, if any, aluminum and other metals may play in the development of AD. With support from NINDS and NICHD, investigators at the University of Kansas Medical Center in Kansas City (LeVine, 1997) reported that iron may contribute to AD by promoting the formation of oxygen free radicals and lipid peroxidation. The investigators studied the brains of people who died with AD using a newly developed stain that can reveal areas in the brain where iron is deposited; conventional staining methods are unable to detect such areas. They found iron deposits in some plaques and also in nerve cell bodies and parts of the cortex. Further study is needed to determine the composition of the stained deposits in nerve cells, but the researchers hypothesize that they may be made up of mitochondria, amyloid deposits, or other structures. If scientists can confirm and demonstrate a role for iron in the evolution of AD, they may be able to develop means to intervene in that process before brain cells are damaged.
Many investigators are working to develop animal models of AD. Such models aid investigators' efforts to understand the pathology of the disease and assist in the identification and screening of potential treatments. There have been a number of mouse models developed that express various fragments of genes related to APP. Last year, with support from NINDS, NIA, and NICHD, scientists at Case Western Reserve University and The Johns Hopkins University School of Medicine (Lamb et al., 1997) reported success in introducing the entire human APP gene from a subset of patients with autosomal dominant FAD into transgenic mice. This new animal model is being used to study the mechanisms by which the FAD mutations affect APP processing and beta-amyloid production.
The investigators used yeast artificial chromosomes to place the APP gene into the embryonic stem cells of the mice. Some mice received one mutation; some another; some more than one. By studying the various results, the scientists were able to determine the effect of each mutation on the production and accumulation of amyloid deposits and their associated lesions. They also will be able to study the effects of FAD mutations on APP processing in different cell types and alterations in the physiological function of these cell types. This model will enable the investigators to study other mutations and determine what, if any, interactions exist among the various FAD mutations. While some investigators pursue better animal models of AD, others have developed a cellular model using mitochondria, the body's energy-generating cells. Mitochondrial mutations have been implicated in a number of neurodegenerative diseases.
This new model system will enable scientists to study mitochondrial mutations at the cellular level. In addition, it may prove useful in the identification and evaluation of drugs. For instance, one study suggests that compounds that scavenge oxygen free radicals directly, or induce the body to do so, might be beneficial. This and other studies showing the protective effects of free radical scavengers in the test tube form the basis for the NIA-supported ADCS trial of the anti-oxidants selegiline and vitamin E (see Oxidative Damage and Alzheimer's Disease).
Scientists and doctors have been using radiopharmaceutical peptides (radioactive agents that interact with various body chemicals and enable researchers to "see" those chemicals with the help of scanning machines) for years. But these peptides have not been useful for most brain disorders because they are not able to pass through the blood-brain barrier. Last year, NINDS-supported scientists at the University of California at the Los Angeles School of Medicine (Wu et al., 1997) reported a new method of brain imaging that allows radiopharmaceuticals to enter the brain, a technique that may someday prove useful in diagnosing AD.
The investigators took a peptide that has been used to identify amyloid in brain tissue during autopsies and joined it to monoclonal antibodies (identical, laboratory-produced antibodies that are highly specific for a single target) to the human insulin receptor, which readily crosses the blood-brain barrier. The monoclonal antibody was tagged with streptavidin, a binding protein. When this formulation was injected into rhesus monkeys, whose insulin receptors are genetically similar to those of humans, it was able to cross the blood-brain barrier, enabling the scientists to image amyloid in the brain. Furthermore, the radioactivity was 90 percent cleared 48 hours after injection. Depending on the peptides used, this approach to brain drug delivery could be tailored to enable investigators to image a variety of brain functions or properties, and ultimately may be used to help diagnose AD and other brain diseases.
Some pharmacological agents already are being tested in human patients. NINDS's Experimental Therapeutics Branch is participating in a multicenter trial of HWA285 (propentofylline). HWA285 is believed to have anti-inflammatory and neuroprotective properties, and it is hoped that it will slow the rate of intellectual decline in patients with dementia. The results of this trial currently are being analyzed. The Branch also is testing Ampalex (CX516, AMPAKINE), a new drug that may improve thinking and memory, in patients with mildly to moderately advanced AD. Ampalex has been shown in preclinical trials to be highly promising in improving cognitive function, and has been relatively free of serious side effects. AMPAKINEs enhance the functioning of a receptor, called the AMPA receptor, which plays a key role in memory formation and communication within and between different regions of the brain.
The National Institute of Mental Health (NIMH) supports research on the causes, clinical course, and treatment of and services for AD patients as well as the stress, interventions, and outcomes of stress that caregivers face. This report discusses 1997 findings, not all of which are published at this time, on the development of AD, memory processes, comorbid disorders, and caregiver stress.
Amyloid deposits, insufficient blood flow, inflammation, and certain toxic agents are some factors that stress nerve cells and set off a chain of events that impair cellular function. Using molecular cloning techniques, NIMH-funded researchers at the University of Southern California in Los Angeles (Zhang, Y. et al., 1998) identified a brain protein, c-Jun N-terminal kinase that is activated by these stress factors. In turn, they have identified other proteins activated by this kinase, such as DENN/MADD, which may participate in an early step in the cell death process. These proteins are strongly expressed in nerve cells vulnerable to AD. Understanding molecular interactions of these proteins may lead to therapeutic strategies that block, when still reversible, the progression to cell death.
Early diagnosis of AD would be enhanced significantly if chemicals could be developed that enter the brains of living patients and stick tightly to the beta-amyloid peptide. Modern neuroimaging techniques then could be used to visualize the probes in the brains of living patients. Doctors would be able to make a diagnosis as definitive as that given at autopsy; and since beta-amyloid deposits may begin as early as 10 years before memory loss occurs, there would be time for active intervention. Development of these selective chemical compounds also would provide knowledge about the neural course of the disease since the probes could be used to study patients over time. To the extent that drugs reduce the number of beta-amyloid proteins, the probe could be used to assess the effectiveness of drugs currently being developed to prevent beta-amyloid deposition.
NIMH-supported scientists at the University of Pittsburgh have been searching for compounds that will bind tightly to beta-amyloid, are sufficiently fat-soluble to enter the brain, and are suitable for radioactive labeling. They have developed a general method that now is being tested in rats using a class of compounds that have nearly 10 times the fat solubility of the best previous probe, bind more tightly to beta-amyloid, and incorporate sufficient radioactivity to make them visible with neuroimaging.
During research conducted over the past 12 years in rat brains, NIMH-supported researchers at Cornell University Medical College have examined nerve cells in the front portion of the brain, which contain acetylcholine. These cholinergic nerve cells directly contact a specific population of nerve cells that contain another neurotransmitter, neuropeptide Y, in the hippocampus. The team has found that selective destruction of these cholinergic nerve cells leads to the death of the hippocampal neuropeptide Y nerve cells. The data were obtained using anatomical techniques that enable scientists to localize specific chemicals with antibodies that bind to them, in preparation for analysis with light and electron microscopes. These observations support the assertion that the selective destruction of the cholinergic nerve cells mimics some of the pathological changes seen in the autopsied brains of AD patients. However, the data also suggest that AD affects other groups of nerve cells in addition to cholinergic nerve cells.
Corticotropin-releasing factor (CRF) is a 41 amino acid peptide that integrates mammalian endocrine, autonomic, immunologic, and behavioral responses to stress; and it is decreased in the cortex of AD patients. A CRF-binding protein also exists in brain tissue, and it binds to CRF and decreases the availability of CRF within the brain. NIMH-funded scientists at Emory University in Atlanta, Georgia (Behan et al., 1997), have hypothesized that if the CRF that is bound to the CRF-binding protein could be liberated it may produce beneficial effects on cognition. They measured the concentration of CRF, CRF-binding protein, and the CRF/CRF-binding protein complex in 10 brain regions from AD patients and controls and found that CRF-binding protein concentrations were 10 times higher than CRF itself. This also was manifested by the fact that most CRF in the brain was in the CRF/CRF-binding protein complex form. CRF-binding protein concentrations were similar between AD patients and controls. However, CRF and the CRF/CRF-binding protein complex concentrations were decreased in many, but not all, brain regions studied in the AD patients. These data suggest that: (1) most CRF in the human brain is attached to the CRF-binding protein; (2) reductions in CRF alone do not necessarily predict reductions in CRF availability for brain signaling; and (3) total CRF and CRF-binding protein levels appear to be the main factors determining the amount of CRF available in the brain.
The NIMH also is involved in the search for AD genes. In 1990, scientists at the Massachusetts General Hospital, The Johns Hopkins Medical School, and the University of Alabama were funded to collect a large sample of affected relative pairs with AD that would serve as a national resource for the study of AD genetics. Approximately 500 sibling pairs and other small families have been collected, with cell lines maintained in a cell repository and a wealth of clinical data maintained in a central data management center. Followup of the study sample continues to collect autopsies on affected subjects and assess unaffected subjects for new disease onsets. The first findings from genotyping efforts were published in 1997 (Blacker et al., 1997), confirming the association between APOE epsilon4 and AD and showing that this AD risk factor acts more strongly in the sixties than later in life. Because APOE epsilon4 is the only identified genetic risk factor for late-onset AD and because numerous lines of evidence indicate that other genetic factors are involved in its etiology, this finding underscores the need to continue the search for late-onset AD genes. To that end, the Center for Inherited Disease Research (CIDR) has recently agreed to perform a complete genome scan on the NIMH Genetics Initiative sample.
In looking at memory, NIMH scientists have found that specific objects that an AD patient cannot name still manage to cue the patient's responses to words that either match or do not match a pictured object. Interestingly, pictures of objects that AD patients could not name elicited a frontal electroencephalograph response similar to that seen in young people presented with a picture of an imaginary object. To confirm this, researchers at Stanford University showed AD patients pictures of objects (for example, a zebra) for 1 second, followed in 0.5 second by words that either match (ZEBRA) or do not match (FOX) the picture. They presented each picture four times, twice with and twice without a matching word. There was a 1.5-sec interval between when the picture and word were presented, giving participants time to anticipate what the word might be. The findings suggest that patients had some semantic knowledge of specific objects, even though they could not name them correctly. Data about whether this semantic deficit relates more to information access or information retrieval than to knowledge loss might help clinicians and caregivers develop strategies to manage AD patient behavior.
Patients with dementia and AD suffer from multiple comorbid medical illnesses, typical of older people. AD patients are much more vulnerable to the effects of co-morbid medical illness than older people without dementia. For example, when ill with a mild urinary tract infection, a typical AD patient might develop rapid decline in memory and oppositional or aggressive behaviors and be less able to participate in daily living activities. AD patients have longer hospital stays, take longer to recover from surgery, and develop adverse reactions to medication more often than older people without dementia. This comorbidity leads to additional impairments in quality of life, greatly burdens caregivers, and is associated with increased use of health care services and frequent hospitalizations.
It might be possible through early diagnosis of AD and through special attention to medical comorbidities to reduce these additional burdens. However, little research has been done in this area in part because of the absence of an easy-to-administer, reliable, and valid measure of medical comorbidity for AD patients. Such a measure would not only improve the status of research into medical comorbidities but also would provide a means of measuring comorbidity in other clinical studies of AD. Researchers could then account for the concurrent effect of comorbidity on other outcomes.
As part of the NIMH-funded Depression in Alzheimer's Disease Study, scientists at The Johns Hopkins University have developed the General Medical Health Rating (GMHR) whose purpose is the rapid bedside quantification of medical comorbidity of dementia patients by a physician or a nurse. Taking into account type, severity, acuity, and treatment of comorbid medical conditions, GMHR ratings of "excellent," "good," "fair," and "poor" are possible. Papers reporting on the development of the GMHR are in various stages of the publication process. Although only about 2 to 3 percent of healthy older individuals suffer from major depression, the rate among those with moderately severe AD is in the range of 10 to 20 percent. Randomized clinical trials have demonstrated drug placebo differences for one or more anti-depressants for the treatment of depression in AD and in medical disorders as diverse as ischemic heart disease, cancer, Parkinsonism, stroke, diabetes, and arthritis. However, there are still questions about whether our knowledge about the treatment of depression is applicable to very old and very disabled patients, such as those in nursing homes.
NIMH-supported scientists at the University of Pennsylvania (Streim et al., 1997) recently conducted a double-blind study of regular versus low-dose nortriptyline, an anti-depressant with anti-cholinergic activity. The response to nortriptyline in cognitively intact patients was found to increase with blood levels of the drug within the therapeutic range established in younger and healthier patients. However, patients with AD were less likely to respond and showed no significant relationship between plasma levels and clinical response. These findings suggest that the neuropharmacological processes underlying depression and the responses to anti-depressant medications in cognitively intact older patients are similar to those that are operative in younger and healthier individuals. However, in patients with AD they are quite different. Meeting the mental health needs of patients with AD requires specific knowledge that must be derived from research conducted on this special population.
NIMH-funded scientists at the University of California in Los Angeles are focusing on predictors of treatment outcome in patients with late-life mental disorders. They use quantitative electroencephalography (QEEG) to determine if, prior to treatment, patients can be identified who are most likely to benefit from use of cholinesterase inhibitors (medications such as Aricept or Cognex). They are using a QEEG-based medical test invented with NIMH grant support to examine patients before and during treatment with these medications. Preliminary data suggest that this test can identify those patients who are most likely to benefit from treatment with a cholinesterase inhibitor. Subjects who are likely to have a clinical response have a distinctly different pattern on the test from those who will not benefit and/or develop drug toxicity. This non-invasive test could be used to help maximize the therapeutic potential of the cholinesterase inhibitors. These initial findings are being pursued with controlled treatment studies.
Research that links the development of AD, comorbidity, and the potential for help for caregivers comes from a team of NIMH-supported researchers at Stanford University. These scientists are seeking to establish a link between disturbed sleep in AD patients and disruptive behavior during the day. Disturbed sleep and daytime disruptive behaviors may be an important element in maintaining patients at home and thereby reducing cost. It is well known that disturbed behavior in AD patients may lead to institutionalization that is costly in emotional and financial terms for many families. Using the actigraph, a portable motion sensing unit, the Stanford University researchers have documented patterns of disturbed nocturnal sleep and circadian rhythm in patients. They plan to follow up on this finding through treatment initiatives to determine if normalization of sleep and circadian rhythm in AD patients also results in a normalization of daytime disruptive behavior. If this treatment works, it will help avoid the need for drugs that can have harmful side effects. Scientists also may be able to use bright-light stimuli to reset the patient's circadian rhythm to a more normal cycle.
Dementia caregiving clearly is associated with adverse mental health consequences; differences in immune responses to latent herpes viruses add weight to the contention that the chronic stress of caregiving can have adverse consequences for older adults' physical health as well. It also is well known that there is some loss of control over latent herpes viruses in older people; the best example of this phenomenon is the increased incidence of shingles associated with aging, caused by a herpes virus called varicella zoster, the same virus that causes chicken pox in children. NIMH-funded scientists at Ohio State University in Columbus (Glaser and Kiecolt-Glaser, 1997) have been studying the effect of stress and aging on other latent herpes viruses. They compared 71 family caregivers of dementia sufferers and 58 control subjects on 3 different immune measures relevant to latent herpes simplex virus type 1 (HSV-1) infection. Caregivers demonstrated poorer immune response than controls; these data document further alterations in a virus-specific immune response associated with caregiving and provide additional evidence that psychological stress is associated with poorer control of latent herpes viruses beyond that already found with aging.
Both symptoms of psychiatric disorders and symptoms of physical ailments can vary with the level of the demands of caregiving. Moreover, use of the medical care system is associated with the scope and intensity of caregiving demands. The demands and stresses create problems in areas of life outside of caregiving, such as family finances. The stress of caregiving brings into question the ability of family caregivers to sustain the care they provide to their impaired family member.
NIMH-supported researchers at the University of Maryland, College Park, have interviewed 200 spousal caregivers who were providing assistance to their husbands and wives at home. Although the sample is socially and economically diverse, its representativeness cannot be determined because the characteristics of the population of caregivers in these localities are unknown. These interviews, which were the first of a multiwave study, were completed in recent months, and the analysis of the data will continue for the next year.
Until effective methods to prevent or cure AD are in operation, the family will continue to be the front line of care. The significance of these findings is that they point to the psychological and physical costs of caregiving, costs that the entire society eventually bears. These personal and social costs are further increased by the early placement of relatives in institutional facilities. To delay or eliminate institutionalization, it is in the public interest to develop policies that relieve the stresses that family caregivers frequently experience.
The National Human Genome Research Institute (NHGRI) funds a project to address ethical and policy issues regarding current genetic susceptibility testing for late-onset AD. It also addresses ethical aspects of ongoing gene testing in families with early-onset AD.
The project's Community Advisory Board and National Study Group will take up the following tasks: examine current testing developments in AD genetics, their pre-symptomatic applicability, and clinical usefulness; consider costs of testing, potential testing pool, and fairness in access to testing; address the potential impact of susceptibility testing on the private long-term care insurance industry; develop ethics guidelines for the use of susceptibility tests that detect a form of the APOE gene; develop ethics guidelines for the use of tests that detect an alteration in the APP gene; and develop recommendations for the Alzheimer's Association in ensuring public understanding of test developments (Winblad et al., 1997; Post, Beerman et al., 1997; Post, 1997 [Slowing...]; Post, 1997 [Physician-...]; Post, 1997 [Resource...]; Post, Whitehouse et al., 1997; Post et al., 1997 [Tough...]; Post et al., 1997 [Ethics...]). In addition, a pilot questionnaire study of population attitudes toward APOE susceptibility testing, to be implemented in Chicago, is included. This project is conducted in collaboration with the national Alzheimer's Association.
The NHGRI also funds efforts to create the tools and infrastructure to locate genes contributing to human diseases, particularly those, such as AD, in which more than one gene is likely to play a role. The CIDR, located on the Bayview campus of The Johns Hopkins University, supports complex disease research by providing high-throughput genotyping services, study design advice, and sophisticated database assistance to research efforts attempting to identify genetic loci and allelic variants. CIDR is a joint effort by eight NIH institutes: NCI, NICHD, National Institute on Deafness and Other Communication Disorders, National Institute on Drug Abuse, National Institute of Environmental Health Sciences, NIMH, NINDS, and NHGRI, serving as the lead.
NCRR develops and supports critical research technologies and shared resources that underpin research to maintain and improve the health of the Nation's citizens. NCRR supports the development and use of sophisticated instrumentation and technology, animal models for studies of human disease, and clinical research environments, as well as the enhancement of research capacity for under-represented groups.
Investigators at the Bio-Organic Biomedical Mass Spectrometry Resource at the University of California at San Francisco (Kaneko et al., 1997) are studying complexes of recombinant forms of the prion peptides with "wild type" prions of the scrapie form (PrPSc). These complexes may provide insights into how the non-pathogenic protein normally found in the cell, PrPc, interacts with the pathogenic isoform, PrPSc, during formation of the nascent molecule and into the process by which PrPc is converted to PrPSc. Further research may lead to an understanding of the biological mechanisms underlying other types of dementia-related diseases such as AD, as well as new drug development medical treatment strategies.
Nuclear magnetic resonance spectroscopy in low and medium magnetic fields yields well-resolved spectra from small volumes of brain in vivo in minutes. With this tool, neurochemical research has advanced through the identification and non-invasive assay of specific neuronal markers, osmolytes, and neurotransmitters. Investigators at the Center for Magnetic Resonance Research at the University of Minnesota, Twin Cities (Ross, B. et al., 1997), are using this technique to non-invasively image neuronal metabolites in AD patients. Alterations in brain metabolite concentrations may prove to be a newly identified diagnostic marker for AD.
The APOE epsilon4 allele is a major risk factor for the common forms of late-onset AD, but does not account for all the genetic variation. The D2 dopamine receptor (DRD2) A1 allele is associated with abnormal brain function, and decreased DRD2s are found in the hippocampus and amygdala of AD patients. Investigators at the University of California at Los Angeles GCRC (Small et al., 1997) examined the APOE and DRD2 genotypes in patients with AD and control subjects. They found no association between DRD2 alleles and the APOE allele, and the presence of the A1 allele did not increase the risk for AD. There also was no evidence of linkage between DRD2 and AD. In both patients and controls, there was a decrease in A1 allele frequency with age. The investigators conclude that the A1 allele does not contribute to AD risk, alone or in combination with the APOE epsilon4 allele.
The National Institute of Nursing Research (NINR) supports research on the biobehavioral aspects of AD and related dementias. The primary focus is on dealing with behavioral, physical, and functional problems, such as wandering, agitation and sleep disturbances.
NINR-supported researchers at the University of Arkansas for Medical Sciences in Little Rock (Beck et al., 1997) have developed and tested a behavioral intervention to improve dressing behavior in cognitively impaired nursing home residents. The researchers achieved a significant decrease in assistance residents needed in getting dressed without a concomitant increase in the care provider's time. Although much of the cognitive impairment experienced by the residents will increase over time, it is an important goal of nursing to maintain or improve cognitive skills to maintain independence for as long as possible. The Strategies to Promote Independence in Dressing intervention consisted of a specific list of prescribed activities designed for each resident based on his or her cognitive and physical abilities. Trained nursing assistants were provided with the assessment of each resident and a list of specific step-by-step commands to guide the resident in the various dressing behaviors.
In another study at Florida Atlantic University in Boca Raton (Tappen et al., 1997), researchers used data on physical performance measures with nursing home residents with dementia. Although it is becoming increasingly clear that exercise has significant benefits for older people, individuals with AD have been excluded from these studies because of problems measuring their physical performance. Therefore, researchers examined three established measures to determine their reliability for use in patients with moderate or severe dementia. The data suggest that a 6-minute walking test can be modified and used successfully to allow researchers to study the effects of exercise and activity in this population. This is an important methodological step in being able to determine if exercise in this population has beneficial effects.
The Division of Clinical and Biological Research in the National Institute on Alcohol Abuse and Alcoholism conducts research on AD. The two research projects are Determinants of Cognitive Dysfunctions in Neuropsychiatric Disorders, and Drug Effects on Memory and Related Cognitive Functions.
The research on AD that currently is under way--with collaborators at NIH and other national and international scientists--involve the following themes:
Although amphetamine has been shown to ease cognitive impairments associated with some forms of deficit states (for example, fatigue and sleepiness), it does not alter the cognitive impairment expressed in AD (Martinez et al., 1997). This perhaps is not surprising since the determinants of cognitive dysfunctions associated with AD are qualitatively different from those of other conditions.
Researchers continue to discover new pieces of the AD jigsaw puzzle. And they are beginning to see how some of these pieces fit together, as they discover connections such as those between presenilins and cell death, between beta-amyloid and oxidation, and between APP and APOE.
Identification of new AD genes provides opportunities to study the proteins for which they code and the roles of these proteins, and thus to identify and study the cascade of events that cause dementia in AD. One important new challenge will be to identify the genetic or environmental factors that appear to be increasing the risk of AD in some minority groups. Another goal is to identify the genetic mutations that account for the other half of the cases of early-onset AD. And researchers will continue to hunt down genetic risk factors for late-onset AD.
In the meantime, armed with the AD genes already discovered, researchers continue to breed and study new transgenic mice to answer some of the outstanding questions about the causes of dementia in AD. Is the brain damaged by amyloid plaques, beta-amyloid fibrils, beta-amyloid in solution, paired helical filaments, or some other substance? Is the increase in the longer form of beta-amyloid the key pathogenic event in AD, or not? What causes the cognitive decline?
Other researchers are focusing on the "oxidative stress" and "programmed cell death" parts of the puzzle. It is becoming clear that oxidative stress occurs in AD, but it is not yet clear whether oxidation actually causes the neurodegeneration, or is simply another side effect of AD. Some scientists believe that oxidative stress is a relatively early event in the disease process. They argue that the aging brain is less able to defend itself against oxidative stress, and that this helps to explain why AD is a disease that primarily strikes older people. Researchers are working now to understand whether beta-amyloid initiates the oxidative damage in AD. Vitamin E and some of the other drugs that show promise against AD may have anti-oxidant properties.
Other AD puzzle pieces under investigation include TGF and tumor necrosis factor, which, along with APP, increase production in response to brain injury. If these factors protect the brain from injury, then strategies to activate the brain's own protective mechanisms could lead to new treatments for AD. Similarly, inflammation is an important portion of the AD puzzle, and scientists are investigating the possibility that reducing inflammation in the brain may slow the disease's progression.
With each piece of the AD puzzle that is put into place, potential new treatment strategies arise. For instance, if the longer form of beta-amyloid accelerates plaque production and if plaques have a role in dementia, drugs could be found to block this process. A drug that stimulates cleavage of APP to produce more of the shorter form and less of the longer form of beta-amyloid might decrease plaque formation. As another example, if APOE is binding to beta-amyloid and influencing the formation of fibrils, then drugs that interfere with this interaction might alter the progression of the disease.
Scientists also will continue to study other disorders, such as strokes, to see if they affect the development or symptoms of AD. And research into other neurological diseases such as Huntington's disease, Parkinson's disease, and prion diseases, as well as the study of Down's syndrome, also will continue to yield insights into AD.
As the AD puzzle comes together, early and accurate diagnosis will become ever more important. The earlier the disease is recognized, the sooner it can be slowed, halted, or even reversed by future treatments. In the clinic, scientists working to improve the diagnosis of AD have multiple goals, including to establish if differences in disease patterns in AD reflect genetic- and gender-based factors, determine how age affects clinical and pathological criteria, find tests to determine which people with mild cognitive impairment will progress to clinical AD, develop biochemical and molecular methods for quickly diagnosing AD, and determine the nature and significance of white matter pathological changes in AD.
One upcoming clinical trial for ADCS scientists is to test the effectiveness of vitamin E or Aricept in people with mild cognitive impairment to determine whether either can reduce the number of people who would otherwise progress to more advanced stages of AD. This will be the first study to identify people at risk and bring them into a clinical trial. Eventually, the goal is to identify people at risk before they develop any signs of the disease and treat them with a drug (or a combination of drugs) that will slow or halt development of clinical AD.
As the population ages and the AD problem grows, researchers continue to seek new ways to help people who currently have AD and their caregivers. The ADCS plans additional studies of drugs used to treat the behavioral symptoms of AD. Members of the consortium currently are analyzing data from a clinical trial of the effectiveness of trazodone, haloperidol, and behavioral management in preventing or reducing agitation.
Research will continue into improving the quality of life for people with AD, living in or out of nursing homes. In the nursing home setting, research will focus on how different staffing, programming, and environments affect residents with AD. And some of these same variables will be analyzed in more home-like settings as well.
Research also will continue into caring for special populations to understand factors that influence minority and ethnic families, rural caregivers, employed caregivers, and male caregivers. In addition, scientists will study changing care structures; the interplay among older people, their families, and care settings; and the effects of these factors on an older person's ability to stay mentally and physically healthy.
The pieces of the AD puzzle are beginning to come together, as researchers discover AD's causes and effects at the molecular, biochemical, and neurological levels. Already, recent findings hold promise that we will be able to delay the progression of symptoms and bring us close to the day when we will be able to prevent and even cure AD.
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NIH Publication No. 99-3616
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