Progress Report on Alzheimer's Disease, 1996 Contents Introduction -- Alzheimer's Disease Prevalence and Costs of Alzheimer's Disease Research Directions National Institute on Aging Structure and Function of the Brain Changes in the Brain in Alzheimer's Disease Amyloid Plaques Neurofibrillary Tangles Advances in Identifying Risk Factors for Alzheimer's Disease Genetic Research in Alzheimer's Disease Role of Amyloid in Protein Binding Protein Structure in the Aging Nervous System Cognitive Ability in Young Adults and Alzheimer's Disease Risk Later in Life Learning and Memory in Aging Advances in Diagnosing Alzheimer's Disease Tau Levels: A New Tool for Diagnosing Alzheimer's Disease Joint Statement on Genetic Testing of Alzheimer's Disease Advances in Treating and Preventing Alzheimer's Disease Alzheimer's Disease Centers (ADC's) Consortium To Establish a Registry for Alzheimer's Disease (CERAD) Alzheimer's Disease Cooperative Study (ADCS) Innovative Programs for Caregivers Special Care Units Initiative Research Conducted by Other NIH Institutes National Heart, Lung, and Blood Institute National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Neurological Disorders and Stroke National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institute on Deafness and Other Communication Disorders National Institute of Mental Health National Center for Research Resources National Institute of Nursing Research National Eye Institute Outlook National Institute of Arthritis and Musculoskeletal and Skin Diseases The National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) leads the research effort to combat the many forms of arthritis. As part of this effort, NIAMS supports research on types of amyloidosis. In amyloidosis, longstanding joint disease is related to amyloid buildup in the kidneys, liver, and spleen. Similarly, AD shows amyloid buildup in the brain but is not associated with joint disease. NIAMS sponsors research on amyloid at its Multipurpose Arthritis and Musculoskeletal Diseases Center at Boston University in Massachusetts. Researchers there have studied protease expression in the central nervous system. This particular protease, found in the brains of AD patients, splits off the abnormal protein fragment that also is found in nerve cells of people with AD. This important finding relates to the buildup of these protein fragments in nerve cells, the major pathologic finding in AD. National Institute on Deafness and Other Communication Disorders The National Institute on Deafness and Other Communication Disorders (NIDCD) conducts and supports research on the normal and disordered processes of hearing, balance, smell, taste, voice, speech, and language. The NIDCD supports AD research in its chemosensory (relating to perception of chemical substances, such as detecting odors), voice and speech, and language studies. Some NIDCD studies suggest that people with mild AD may make certain spelling errors because their visual attention skills, rather than language skills, are impaired. In a NIDCD-funded study of spelling ability, people with mild AD had more spelling errors than did healthy volunteers. Tests for visual attention predicted the number of spelling errors better than did measures of language. People with AD performed worse when they copied words that they viewed and then had removed from their sight than when they copied the same words directly. People without AD showed no significant difference in their performance on delayed and direct copying tasks. Although word length somewhat affected the spelling performance of healthy people, those with AD had significantly worse performance when words were longer. Other NIDCD-supported researchers compared how 20 people with AD and mild dementia versus 20 people without AD spelled words that sound the same but have different meanings (homophones). Performance was measured at the start of the study and again 9 months to 1 year later. The researchers found two types of errors: homophone confusions (such as spelling the word "doe" given the context "bake the bread dough"); and other spelling errors. People with AD misspelled more homophones than did healthy volunteers; this trend increased during the period between the two tests. These results suggest that people confuse homophones because they cannot pull the meaning of a word in a certain context from their memories. In normal memory, a person can tap a mental list of correct spellings of words. Other errors may reflect problems that do not involve changes in the use of word meanings to spell homophones. Other NIDCD-supported researchers assessed in three experiments how AD patients process sentences. The results show that AD patients had difficulty with a grammatical feature of sentences. This impairment could not be explained by factors such as sentence length, dementia severity, or a short-term memory flaw; and was not affected by difficulty in figuring out word meanings. National Institute of Mental Health Research topics supported by the National Institute of Mental Health (NIMH) include the causes, development, clinical course, and treatment of AD; sources and types of caregiver stress; and services AD patients and their caregivers use. Genetic Studies The NIMH Genetics Initiative and the Diagnostic Centers for Psychiatric Linkage Studies of Alzheimer's Disease continue to develop a national resource of demographic, clinical, and genetic data from people with AD. The data from the three university-based diagnostic centers come from families with two or more living siblings/first-degree relatives with AD and certain siblings without AD. To increase the sample size, researchers include family members with varying lines of descent. Participants are tracked over time until autopsy to examine possible changes in diagnoses to avoid false positives--a major difficulty in genetic studies. An AD genetics catalog is available on the Internet, with gene status results to be added in the future. Molecular Genetics and Promising Approaches for Screening for AD While conducting brain chemistry analyses of AD, an NIMH-supported researcher at the Albert Einstein College of Medicine in New York City found a new protein called FAC in fetal brain tissue. The FAC gene was on chromosome 17, near the tau gene. Fetal brains contain high levels of FAC; in later stages of development, less FAC is found in the brain. However, FAC is higher than normal in AD brains and in the spinal fluid of people with Lou Gehrig's disease (amyotrophic lateral sclerosis). Researchers will explore this protein further to determine its role in AD. ApoE and PET Scans Although researchers disagree about the exact number, some NIMH-supported scientists believe that the apoE4 allele is present in just under one-third of adults unaffected by AD and in more than half of those with AD. While apoE gene status does not provide enough sensitivity or specificity to be used as a diagnostic test for AD, it has led researchers in promising new directions. NIMH and NIA grantees at the University of California at Los Angeles Medical School conducted the first study combining PET scans with apoE genetic testing. Other NIMH- and NIA-supported researchers have found significant differences in how apoE is distributed in the cerebrospinal fluid of people with AD versus healthy people. They found that while there are equal amounts of apoE3 and apoE4 in the cerebrospinal fluid of healthy people, there is less apoE3 in the cerebrospinal fluid of AD patients. NIMH Basic Neuroscience: How Does Aging Affect Genetic Risk for AD? Genetic studies may help us understand who will be at more or less risk for AD in later life. However, we also must learn why people with genetic risk for AD do not develop the disease until later in life. Researchers at McLean Hospital and the Massachusetts Institute of Technology's Clinical Research Center found that brain levels of the nutrient choline help nerve cells make the neurotransmitter acetylcholine and cells in general to make lecithin, a key constituent of all cell membranes. When choline is in short supply and cholinergic nerve cells are active, most available brain choline goes into making acetylcholine and almost none into making or maintaining cell membranes. Importantly, scientists also have shown that in older people, the brain takes in less blood choline. This work suggests one theory about why AD tends to be a disease of older people even though the genes that place people at risk are present from birth. Physiology of Beta-Amyloid Protein The physiologic role of naturally occurring beta-amyloid is a mystery; this limits understanding of the role of beta-amyloid in AD. Researchers in the NIMH intramural program have shown that low levels of beta-amyloid can increase tyrosine processing. Tyrosine is an amino acid, a constituent part of proteins. It is a precursor to thyroid hormones and other substances. Furthermore, beta-amyloid produces a rapid rise in calcium levels in certain cells treated with a substance that blocks the processing of tyrosine. Calcium may be involved in the toxic role of beta-amyloid in the brain. Understanding the Neurochemical and Cortical Metabolic Bases of Non-Cognitive, Psychiatric Symptoms Although memory and thinking problems often are considered the primary symptoms of AD, psychiatric symptoms (such as delusions, mood swings, indifference, irritability, agitation, loss of inhibitions, and aggression) also are important disease manifestations. These symptoms are critical because they have been associated with faster decline, higher caregiver distress, and earlier placement of patients in nursing homes. AD patients may have other disorders that can complicate AD, for example, psychiatric disorders (such as depression) and physical illnesses (such as diabetes or heart disease). NIMH-funded researchers are examining the biological bases of psychiatric symptoms in AD and coexisting psychiatric disorders. These studies are important because these symptoms and disorders can be treated more easily than the cognitive symptoms of AD. Further, their treatment can enhance the quality of life for both patients and family caregivers. Researchers at the University of California at Los Angeles Medical School used PET scans to examine the relationship between psychiatric symptoms of AD and patterns of metabolism in the cortex of the brain. They found that various psychiatric symptoms were associated with a low metabolic rate in specific regions of the brain. Agitation and loss of sexual inhibitions were associated with low metabolism in the frontal and temporal lobes of the brain. Psychosis was linked with the temporal lobe. Anxiety and depression were linked with the parietal lobe. These findings suggest that psychiatric symptoms result from things that go wrong in the cortex in AD. Scientists at the University of Pittsburgh have studied brain tissue of patients with and without psychosis for whom AD was confirmed at autopsy. Compared to AD patients without psychosis, those with psychosis had more amyloid plaques and neurofibrillary tangles, and more norepinephrine in a certain brain region (the substantia nigra). This pattern is unique for AD patients with psychosis. AD patients who have major depression do not show these same brain chemistry signs. However, both AD patients with psychosis and AD patients with major depression have reduced serotonin in the hippocampus. By examining changes in the brains of AD patients with and without depression, these researchers also found that affective (emotional) disorder in AD is distinct from AD, with a unique profile of brain chemistry changes. For example, depressed AD patients have a 10- to 20-fold drop in the amount of norepinephrine in the cortex. Costs and Benefits of Treating Psychiatric Symptoms in AD AD patients who have delusions and hallucinations and those who are agitated typically receive neuroleptic medications. In addition to determining the effectiveness of these medications, researchers seek information about the risk of tardive dyskinesia (involuntary muscle rigidness and tremors) when using neuroleptic drugs. Data are needed to determine doses and weigh the risks and benefits of this treatment over time. Scientists at the University of California at San Diego are studying older psychiatric patients, including AD patients. They are examining the patients' risk for tardive dyskinesia related to dosage and cumulative exposure to neuroleptic medication. The results suggest that cumulative exposure is the greatest risk factor for tardive dyskinesia, even using relatively low doses of neuroleptic medication: up to 60 percent of middle-aged to elderly patients experience tardive dyskinesia after 3 years of exposure to neuroleptics. Health Consequences of Caregiving In ongoing studies of spouses of AD patients, scientists at the Ohio State University have shown both the mental and physical health effects resulting from the stresses of caregiving for a relative with AD. Many researchers have found high rates of depression among family caregivers. These scientists have learned that spouses of AD patients perform worse on qualitative immunological assays and have more infectious disease episodes than do non-caregivers; have a lower antibody buildup in response to an influenza vaccination; and have slower wound healing compared to healthy volunteers. These findings suggest that family members caring for AD patients are at risk for physical illness due to caregiving stresses. Improving Dementia Care in Long-Term Care Settings The most common diagnosis among nursing home residents is dementia, and most of these residents are assumed to have AD. As a result, many nursing homes offer SCU's to meet the needs of people with dementia. Unfortunately, methods used in these SCU's rarely are designed based on controlled treatment trials that treat AD patients' psychiatric symptoms, such as psychoses, depression, and agitation. To address the lack of efficacy data, researchers at the Jefferson Medical College of Philadelphia carried out what may be the first randomized trial of an intervention in this area of care. The intervention program was called AGE (for activities, guidelines for psychotropic medications, and educational rounds). The activity program consisted of a 4-hour regimen on weekdays intended to provide structure, increase mental and physical stimulation, and reinforce social skills. Guidelines for use of psychotropic drugs (drugs that affect mental state) included transferring the role of prescribing psychotropic medications from primary care physicians to a geriatric psychiatrist. During the educational rounds, the psychiatrist and activity program staff discussed the patients' behavioral, functional, and medical status and factors that may lead to problem behaviors. After 6 months of the intervention, 29 percent of the study-group patients had behavior problems compared with 51 percent of those receiving care as usual (the control group). Control patients were more than twice as likely to receive anti-psychotic medications and to be restrained. Patients in the study group were much more likely to take part in activities. These findings suggest that nursing home care of AD patients can be improved when their psychiatric symptoms are treated with appropriate behavioral and medical strategies. National Center for Research Resources Software Used To Identify AD Genes Genetic researchers at a resource center supported by the National Center for Research Resources (NCRR) are using Statistical Analysis for Genetic Epidemiology software to study the existence of genes to explain the segregation of AD in a group of people in Vancouver, British Columbia. The data consist of 402 people with AD and 2,245 relatives from their immediate families. Preliminary data support Mendelian models of genetic inheritance and suggest that this study group may be used to identify individual genes involved in AD. Visualization of Paired Helical Filaments in AD NCRR-supported researchers at the Albert Einstein College of Medicine used a scanning transmission electron microscope (STEM) to study paired helical filaments taken from the brain tissue of AD patients. Two types of paired helical filaments were identified: one that was derived from the tangles; and one new, less-aggregated type that differed in shape and makeup. Because of the small number of these new paired helical filament molecules, STEM analysis was needed to describe them. STEM analysis enables scientists to distinguish between and identify very small molecules. The data indicate that these new fractions of paired helical filaments were larger, wider, and shorter, and contained more highly processed regions than paired helical filaments derived from tangles. The differences suggest that paired helical filaments undergo digestion by chemicals. This process forms a more aggregated type of paired helical filament, leading to neurofibrillary tangles. STEM studies of the role of protein processing in forming tangles continue so that a model for understanding this aspect of AD may be developed. Cerebrospinal Fluid Levels of Amyloid-Protein in AD: Inverse Correlation with Severity of Dementia and Effect of ApoE Gene Status Investigators at the Massachusetts General Hospital General Clinical Research Center in Boston explored the relationship between this gene, the levels of total protein in spinal fluid, and the mental decline commonly seen in AD patients. They discovered that levels of total protein in the spinal fluid decrease as mental abilities worsen. However, the researchers found no relationship between the levels of total protein in the spinal fluid and the apoE allele. Theoretical Analysis of Learning and Memory in Age-Related Diseases NCRR-supported researchers at the Massachusetts Institute of Technology General Clinical Research Center are exploring the effects of AD, Parkinson's disease, and Huntington's disease on learning. They are identifying the types of tasks that people with these diseases can and cannot learn. These researchers currently are studying memory problems in patients with damage that disrupts the connections between limbic structures (parts of the brain concerned especially with emotion and motivation) and the cortex (in global amnesia), between the striatum and cortex (in Parkinson's disease and Huntington's disease), and within the cortex (in AD). Neuropathology and ApoE Profile of Old Chimpanzees NCRR researchers at the Yerkes Regional Primate Research Center of Emory University searched for evidence of AD in the brains of three old chimpanzees and four old rhesus monkeys. They found amyloid plaques but no neurofibrillary tangles. None of the animals showed evidence of AD-related cognitive impairment. Also of great interest was the genetic evidence of apoE4 in chimpanzees. The presence of apoE4 and amyloid plaques in the primates suggests that the ways amyloid is processed and builds up in these animals and in people may be similar. The finding that the chimpanzees lacked apoE3 does not support the theory that the absence of this gene puts an organism at risk for developing neurofibrillary tangles. Gene Therapy for Neurodegenerative Disease in the Non-Human Primate Model The California Regional Primate Research Center, the Salk Institute, and the University of California at San Diego are collaborating on gene therapy studies. These studies use nerve cell damage in the non-human primate as a model for studying degenerative diseases of the human brain. Fibroblasts (cells that are part of the tissue that binds together and supports various body structures) taken from the monkeys' skin are given the human NGF gene and transplanted into the monkeys' brain tissue. This procedure incites cells from the monkeys' bodies to make the desired factor that aids in cell repair. During the past year, these experiments have shown a strong protective effect for damaged nerve cells: 90 percent protection was achieved in animals receiving gene therapy, as compared to only 30 percent in control animals. More importantly, researchers have found evidence of gene expression lasting for at least 8 months, the longest period measured yet. These results suggest the potential of gene therapy for the long-term delivery of drugs in degenerative diseases of the brain and offer the potential of developing effective treatments. National Institute of Nursing Research The National Institute of Nursing Research (NINR) supports research on the biological and behavioral aspects of AD and related dementias. The main focus has been on dealing with the cognitive and behavioral symptoms that are so disruptive to patients' and their families' quality of life and frequently result in patients being placed in nursing homes. NINR-supported researchers have developed a program for cognitive stimulation that shows promise for dealing with these symptoms. Scientists taught the program to AD patients and their home caregivers during 12 weekly sessions. Caregivers then provided 1-hour daily sessions for their patients for 6 days each week. The program included memory, problem solving, and conversation activities. In the treatment group, behavioral problems decreased, and overall cognitive functioning, word fluency, and memory recall improved for 9 months before symptoms returned to baseline. A followup study is being done to test this program in other home- and community-based programs and to determine the effects of gender and ethnic background on the program's effectiveness. National Eye Institute The National Eye Institute continues to support research on human binocular vision and motion perception. Binocular vision is the merging of images from both eyes into a single image perceived by the visual cortex of the brain. Motion perception is the ability to perceive clearly the direction and speed of a moving object. This research focuses on interactions among the neurological mechanisms underlying these aspects of vision and stereopsis. Stereopsis is the ability to combine the images of two pictures of an object seen from slightly different viewpoints. It refers to how people see something as both a solid and three-dimensional object. These study areas may provide important clues about the perceptual consequences of neurologic dysfunctions in AD. Specific areas under study are: the coexistence of stereopsis and binocular competition the regions in the brain associated with binocular suppression (relative to the analysis of motion information) and visual attention interactions between stereopsis and depth perception in specifying structure from motion motion perception and stereopsis in AD patients Outlook In 1996, followup research will continue on genes already identified and other genes yet to be linked to AD and cloned. The relationships of the presenilin mutations to the development of amyloid in AD currently is unclear. One challenge, therefore, will be to determine whether defects in the APP gene on chromosome 21 and those in the presenilin genes cause AD by the same pathway or whether AD is the common final manifestation of several disease processes with unrelated causes. Another important step for researchers will be to find the level at which brain changes, that can be seen and measured on a PET scan, predict the likelihood of AD in later life. A long-term study is planned, which should provide more precise measures of brain activity in people who are at risk for AD because of their gene status, but show no signs of the disease. Other planned programs include further studies of attention problems in aging, AD and multi-infarct dementia versus other age-related memory problems, and failures in learning and memory as people grow older. Despite excellent beginnings, more rigorously controlled research is needed on how various interventions in SCU's and community settings and with families affect patients. More work also is required to enhance study methods used to evaluate program effectiveness. In addition, it will be important to recognize those areas where SCU's are not effective and determine whether SCU care can be cost effective. Promising directions for future research related to special care for people with dementia follow three themes: identifying individual elements of SCU's that make a difference, finding interventions that work, and expanding care settings. Finally, many researchers conducting clinical trials to test potential treatments for AD look at the disease as a chain of related events. They study therapies designed to stop or prevent the disease at different parts of the chain. By focusing broadly, scientists hope to find the best intervention points in the disease, and also to realize the cumulative benefits of weakening several links in the chain. Published in October 1996