Alzheimer's Disease and Related Dementia
PET scans can show a pattern of relative abnormality of people who will develop memory loss on psychological tests within a few years, but who are not yet manifesting it.
Researchers and physicians at Mayo Clinic's sites in Florida, Minnesota, and Arizona are studying various aspects of Alzheimer's disease (AD). When combined, the elements provide a comprehensive approach to unraveling the mystery of the disease: from understanding why it develops to how it can be diagnosed early, treated effectively, and, ultimately, prevented.
Mayo Clinic neurologists studying AD have been at the forefront of the field with regard to the neuropathology of non-Alzheimer's disease dementias such as frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), and vascular dementia (VaD). Investigators are studying autopsy materials from individuals followed in the Alzheimer's disease Research Center to learn about the underlying pathologic causes of the disease. Since a great number of normal elderly subjects have also volunteered for the research projects, they are learning about the underlying foundation of normal aging changes in the brain. This is an important backdrop against which to compare the changes found in the brains of individuals with the various dementing diseases.
Investigators at all three Mayo clinic sites—Rochester, Jacksonville, and Arizona—are involved in basic research and numerous clinical trials for Alzheimer's disease. Some of these studies of potentially new therapeutics include anti-inflammatory agents, lipid lowering drugs, drugs that are designed to alter chemical systems in the brain, and the use of certain vitamins and supplements. These clinical trials give Mayo patients the opportunity to be involved in cutting-edge research in the therapeutics of AD. Some highlights from each site are listed below.
Mayo Clinic in Jacksonville
Since 1989, scientists at Mayo Clinic in Jacksonville have studied individuals with Alzheimer's disease, mild cognitive impairment, frontotemporal dememtia, dementia with Lewy bodies, and vascular dementia as part of the NIH-funded Alzheimer's Disease Research Center. In addition, Mayo Clinic in Jacksonville has a state-designated Memory Disorder Clinic. Such clinics are sponsored in part by Florida's Department of Elder Affairs and are the state's focal points for research, training, and services directed to residents with symptoms of Alzheimer's or related dementias. The services are available to all residents of Florida, regardless of their ability to pay. Mayo Clinic Jacksonville has recruited and is following a large number of black study participants, providing increased diversity to the study pool. The Mayo Jacksonville research group has a cohort of 200 to 300 African American normal elderly individuals and is following this group longitudinally (following patients over time) to determine predictors that might lead to Alzheimer's disease. These studies have identified factors involving these participants' genetics, blood proteins, and neuroimaging characteristics that may be useful in developing prediction models.
Basic science laboratories at Mayo Clinic in Jacksonville have been involved in research designed to understand and prevent Alzheimer's disease and frontotemporal dementia. Several laboratories are involved in studying the protein, amyloid—believed to be a major factor in the development of Alzheimer's disease. Mayo Jacksonville researchers are among the world's leaders in this research and have investigated characteristics of the amyloid protein and genetic factors that may predispose individuals to processing this protein in an aberrant way. Studies involving humans and mouse models of Alzheimer's disease have yielded exciting new prospects for diagnostic tests for Alzheimer's disease. A blood test that may shed light on an individual's risk for developing Alzheimer's disease is in development. If this were to be successful, this blood test could be used as either a diagnostic tool or, possibly, to monitor specific drugs developed to have an effect on the amyloid protein in the body. Recent studies have indicated that a certain genetically driven elevation of this protein may play a major role in the development of typical late-onset Alzheimer's disease.
Investigators are also trying to identify novel compounds that may lower the amyloid protein in the brain. By studying many compounds that are already FDA-approved and on the market, researchers may gain insight into new therapeutic options. Using this approach, investigators have already identified a subgroup of drugs with anti-inflammatory action that may have specific action on the amyloid protein. This work has been translated into clinical trials, now under way, to investigate the potential utility of this new therapeutic agent.
Research also is progressing on a better understanding of the genetics, pathological development, and, hopefully, treatment of individuals who have frontotemporal dementia. Mayo Clinic Jacksonville researchers were among the first to identify novel genetic mutations in some families that have frontotemporal dementia. This work has led to an animal model of the disorder and a better understanding of the causes of the disease. Work is continuing toward therapeutics for this form of dementia, and a new project focuses on a particular subtype of individuals with frontotemporal dementia who also have features of neurological diseases that affect motor functions.
Mayo Clinic Jacksonville researchers recently found that variations within the gene encoding Tau protein are associated with FTDP-17 dementia. This research has placed Tau dysfunction at the center of the pathogenic cascade in these diseases. They are now studying the effects of FTDP-17 tau missense mutations in both transfected cells and in transgenic mice to determine how these mutations cause neurodegeneration.
Mayo Clinic in Arizona
In Arizona, clinical and research work is being done in neurodegenerative disorders that cause cognitive impairment/dementia, neurogenetics. Two key research projects are described below:
Mild Cognitive Impairment (MCI) is currently thought to be the earliest symptomatic stage of Alzheimer's disease. Patients with MCI have memory trouble but function well enough to maintain their complete independence. Studies of healthy people with no memory loss, however, sometimes show a decline in their performance on neuropsychological tests, before any symptoms of memory loss are expressed. This stage, termed "Pre-MCI," suggests that people who exhibit such test decline are at increased risk for clinical symptoms of MCI to emerge within the following two to three years, especially if their test declines were on memory tests, and if they are among that two percent of the population who carry two copies of the APOE*e4 gene.
Dementia with Lewy Bodies
Dementia with Lewy bodies (DLB) is the second-most frequent cause after Alzheimer's disease as a cause of dementing illnesses. "Lewy bodies" are a microscopic abnormality detectable in certain brain cells of patients with this disease. Patients with Parkinson's disease also have signs of Lewy bodies, and patients with DLB frequently have symptoms of parkinsonism in addition to dementia. DLB patients also have an unusual sleep disorder called REM sleep behavior disorder (RBD), in which people act out their dreams. In a longitudinal study, Mayo researchers are surveying people's sleep patterns and identifying people with such dream enactment behavior. PET scans on a group of these individuals showed subtle abnormalities that resemble those seen in patients with DLB. In other words, it appears that completely healthy individuals, whose only symptom is that they act out their dreams when they sleep, have PET scans that show that they may be at risk for developing DLB.
Mayo Clinic in Rochester
The Rochester site holds a National Institute on Aging-funded registry on aging and dementia. This is a longitudinal project on clinical, epidemiological, genetic, biomarker, imaging, and neuropathological aspects of aging and very early cognitive impairment. Researchers are developing models for predicting a subsequent cognitive impairment in normal elderly persons. Much of their work has focused on mild cognitive impairment as an intermediate stage between normal aging and Alzheimer's disease. Recently, researchers in Rochester have begun a project funded by the Mayo Clinic investigating various aspects of successful cognitive aging in the community.
Current Projects in Alzheimer's Disease and Related Dementia
Genetics and epidemiology
Researchers are working to create and validate molecular targets for new drug development through genetic epidemiology studies. Investigators partner with industry to develop new drugs and to test the safety and efficacy of these drugs. To discover and validate the targeted therapies, researchers are working to uncover susceptibility genes, understand their complex interactions with each other and with the environment, and, finally, to uncover the allelic variations in these genes that predispose to disease and modify disease outcomes. This research aims to bring drugs to clinical trials, during which the study participants will be tracked over time and indications of the severity of the disease can be obtained.
Diet and Alzheimer's Disease
A Mayo Clinic research team led by neurologist David Knopman, M.D., will join a nationwide consortium of leading Alzheimer's disease researchers in a large-scale clinical trial evaluating the effectiveness of omega-3 fatty acids in slowing the progression of Alzheimer's disease. Nutritionists have long endorsed fish as part of a heart-healthy diet, and now some studies suggest that omega-3 fatty acids found in the oil of certain fish, algae, and human breast milk also may benefit the brain by lowering the risk of Alzheimer's disease. In order to test whether docosahexaenoic acid (DHA), an omega-3 fatty acid, can impact the progression of Alzheimer's disease, the consortium, supported by the National Institute on Aging (NIA), part of the National Institutes of Health (NIH), will evaluate DHA in a clinical trial.
Research advances in Alzheimer's Disease and related dementia
The diagnosis of mild cognitive impairment
Richard J. Caselli, M.D.; Dona E. C. Locke, Ph.D.; Michael L. Hutton, Ph.D.; Joseph G. Hentz, MS; Charlene Hoffman-Snyder, RN, CNP; Bryan K. Woodruff, M.D.; David Osborne, Ph.D.
Mayo researchers, along with colleagues Eric M. Reiman, M.D. and Gene E. Alexander, Ph.D., found that memory declines more rapidly with age in apolipoprotein E (APOE) _4 carriers than in APOE _4 noncarriers, and APOE _4 homozygotes' cognitive performances correlate with stressors. These changes could represent presymptomatic disease in some, despite their youth. They studied 43 APOE _4 homozygotes, 59 APOE _4 heterozygotes, and 112 APOE _4 noncarriers aged 50 to 69 years. They were cognitively healthy and matched at entry according to age, educational level, and sex, and took a neuropsychological battery of tests every two years.
APOE _4 homozygotes in their 60s have higher rates of cognitive domain decline than APOE _4 heterozygotes or noncarriers before the diagnosis of MCI and AD, thus confirming and characterizing the existence of a pre-MCI state in this genetic subset.
The Mayo Olmsted Study of Aging
The Mayo Olmsted Study of Aging began in January 2004 with a goal of recruiting 1,200 people ages 70-89, living in Olmsted County, who were cognitively normal (no diagnosis of dementia). In September 2004, the Mayo Clinic Research Center was awarded additional funding from the National Institute on Aging to increase the sample size to 2,300. The overall theme of the Mayo Olmsted Study of Aging is to explore cognitive (thinking) function in individuals as they age. Through this study, Mayo researchers ultimately hope to be able to develop prediction models that will help differentiate those people who are aging well from those who are experiencing a cognitive decline. In normal aging, there may be some changes with mental ability such as a slower speed of processing, difficulty retrieving information rapidly, and a reduced ability to focus on multiple tasks. These changes are expected and do not greatly affect a person's day-to-day life. However, some people may have symptoms of forgetfulness beyond what we would expect for normal aging, but not to the degree to meet criteria for a diagnosis of dementia, known as as Mild Cognitive Impairment (MCI). Previous research indicates that persons with MCI are at an increased risk of progressing to dementia or AD at an accelerated rate. Consequently, one of the primary objectives of the Study of Aging is to identify MCI in a random sample of people from Olmsted County. In total, Mayo physicians have evaluated a total of 2,300 persons: 74.1% were found to be normal, 11.9% had MCI, 4.2% had non-amnestic MCI, which means they are cognitively impaired but do not have significant memory impairment, and 9.8% were found to be demented.
Mayo researchers and colleagues from across the world discovered that variations in a gene known as SORL1 may be a factor in the development of late onset Alzheimer's disease. The genetic clue, which could lead to a better understanding of one cause of Alzheimer's, is reported in Nature Genetics online (Jan. 14, 2007) and was supported in part by the National Institutes of Health (NIH). The researchers suggest that faulty versions of the SORL1 gene contribute to formation of amyloid plaques, a hallmark sign of Alzheimer's in the brains of people with the disease. They identified 29 variants that mark relatively short segments of DNA where disease-causing changes could lie. The study did not, however, identify specifi c genetic changes that result in Alzheimer's. The study involved 14 collaborating institutions in North America, Europe, and Asia, and 6,000 individuals who donated blood for genetic typing. The work was funded by NIH's National Institute on Aging (NIA) and National Human Genome Research Institute (NHGRI), as well as by 18 other international public and private organizations.
New genetic clue to cause of Alzheimer's Disease
Scientists have previously identified three genes, variants of which can cause early onset Alzheimer's, and one that increases risk for the late onset form. This discovery provides a completely new genetic clue about the late onset forms of AD. The researchers combed two large data sets of genetic information from families in which more than one person has Alzheimer's disease. They were soon able to see that many of the families with Alzheimer's had variations in the SORL1 gene but not consistently in any of the other six genes. They then expanded their search to genetic data sets from families of Northern European, Caribbean Hispanic, Caucasian, African American, and Israeli Arab heritage for changes in the SORL1 gene. Again, they found the same association between SORL1 variations and Alzheimer's disease. Searching additional data sets provided by Steven Younkin, M.D., Ph.D., at Mayo Clinic further confirmed the association of SORL1 variations and Alzheimer's. Researchers also found less than half the level of SORL1 protein in people with Alzheimer's compared to people without the disease. In laboratory experiments, they found that altering the levels of SORL1 changed the way APP was moved around in cells, with low levels of SORL1 resulting in increased production of amyloid beta fragments while high levels decreased production.