Alzheimer's disease – The Committee encourages NIA to expand its investment in Alzheimer's disease research, including clinical trials for the rapid translation of laboratory findings to effective treatments and prevention, as well as new initiatives in imaging and genetics aimed at finding risk factors and surrogate markers. (p. 78)
Action taken or to be taken
In 1999, at the direction of Congress, the NIA, in conjunction with the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Mental Health (NIMH), and the National Institute of Nursing Research (NINR), embarked on the Alzheimer's Disease Prevention Initiative, which encompasses a number of interrelated efforts, including basic, epidemiological, behavioral, and clinical research.
To identify targets for prevention efforts, basic research on Alzheimer's disease (AD) illuminates the mechanisms underlying disease pathology and determines the stages at which intervention might slow progression of dementia, delay onset of symptoms, or eventually prevent the disease. Expanded investment in basic research is facilitating the identification of potential biomarkers (indicators of biological changes with age) that can aid in diagnosis and in understanding the progression of AD. New findings from basic research are also enabling analyses of disease progress and assessment of treatments in tissue culture and animal models. For example, the beta-amyloid peptide, which aggregates to form the plaques found in brains of Alzheimer's disease patients, is cut out from a large protein, the amyloid precursor protein (APP). Some non-steroidal anti-inflammatory drugs (NSAIDs), the use of which has been associated with reduced risk of Alzheimer's disease from epidemiological studies, have been shown to modify APP metabolism, resulting in lower amounts of the toxic form of beta-amyloid. Also, more information is becoming available about one of the enzymes, called gamma secretase, which produces the beta-amyloid peptide by cutting it out of APP. It turns out that this is really a gamma-secretase complex made up of a number of individual components, and understanding how they work will help to identify targets for development of new therapeutics. Another important new advance from basic research is the development of transgenic mouse models of the other pathological hallmark of Alzheimer's disease, tangles, which are comprised of abnormal forms of a protein called tau. These mouse models will help to better understand the role of tangles in Alzheimer's disease and to facilitate discovery of new therapeutics targeted at this pathology. Epidemiological research on populations suggests genetic and environmental protective and risk factors for the disease. For example, several new gene candidates have recently been reported which are likely to affect the risk and/or age of onset of late-onset Alzheimer's disease. In addition, results from epidemiological studies have identified associations between intake of certain dietary components and the risk of Alzheimer's disease; saturated fats and low intake of certain B vitamins and folic acid may increase risk and foods high in the antioxidant vitamin E and in omega-3 fatty acids (e.g., certain fish and nuts) may reduce risk. These types of studies and others showing associations between intake of certain drugs and risk of Alzheimer's disease have led to new trials of anti-inflammatory drugs, statins, B vitamins and folic acid, antioxidant vitamins, and fish oil to treat or prevent AD. Recently funded epidemiological studies also include genetic analyses and neuroimaging components.
Expanding clinical trials, and in particular prevention trials, is another critical objective of the Alzheimer's Disease Prevention Initiative. Until recently, clinical trials have only studied persons who already have clinically detectable mild to moderate AD. While NIA is continuing to evaluate treatments for the cognitive and behavioral symptoms of AD, it is also going beyond treatment to initiate studies on prevention strategies. Under the auspices of the Alzheimer's Disease Prevention Initiative, a number of agents such as NSAIDs, estrogen, anti-inflammatory vitamins, and ginkgo biloba are now being tested to determine their potential efficacy in delaying the onset of or preventing cognitive decline and Alzheimer's disease. To rapidly translate laboratory findings into effective treatments and prevention, the NIA supports a resource contract which provides access for investigators who are developing promising new compounds to the toxicological screening needed to receive an Investigational New Drug (IND) designation from the Food and Drug Administration (FDA) in order to take the compounds into human clinical trials. The NIA also supports a program for pilot human clinical trials, the purpose of which is to allow investigators to obtain preliminary data and conduct studies to support the rationale for subsequent full-scale clinical trials of interventions to slow, halt, or reverse the progressive decline in cognitive function and/or to modify the cognitive and behavioral symptoms in Alzheimer's disease victims as well as to delay the onset of or prevent Alzheimer's disease and age-associated cognitive decline.
With respect to new initiatives in imaging, the NIA is developing an Alzheimer's Disease Neuroimaging Initiative to facilitate the scientific evaluation of neuroimaging (magnetic resonance imaging [MRI], positron emission tomography [PET]) and other biomarkers for the onset and progression of mild cognitive impairment (MCI) and AD. A primary goal is to identify the biomarkers of disease progression that are most promising for use as surrogate endpoints in phase 2 and 3 clinical trials for the prevention and treatment of AD. A number of studies in AD and MCI have demonstrated that imaging parameters are more sensitive and consistent measures of disease progression than cognitive assessment. Some studies have shown that imaging measures correlate with cognitive test performance in MCI and AD—an initial step in the validation of markers that accurately predict the course of disease and that could be used as surrogate endpoints to establish claims for disease-modifying treatment. In phase 2 trials, imaging and other markers can help to rapidly identify appropriate doses, assess safety, and compare drugs in early development. Identification of biomarkers may decrease the time and cost of clinical trials, increasing the safety and efficiency of drug development. The initiative is being planned as a partnership among the NIA/NIH, academic investigators, the pharmaceutical and imaging equipment industries, the Food and Drug Administration (FDA), and the NIH Foundation, with participation from the Alzheimer's Association and the Institute for the Study of Aging. An important aspect of this initiative is that the clinical, imaging, and biological data and samples will be made available to all qualified scientific investigators. The RFA for the initiative, a U01 cooperative agreement, was released Oct. 2, 2003, and funding is anticipated to begin September 2004.
Regarding new initiatives in genetics, the NIA is accelerating the pace of Alzheimer's disease genetics research with a major new initiative to speed the process of creating a large repository of DNA and cell lines from families with multiple AD cases. The goal of this initiative is to develop strategies for identifying the remaining late-onset AD (LOAD) risk factor genes, associated environmental factors, and the interactions of genes and the environment. The NIA's AD Genetics Initiative will intensify sample collection and encourage data sharing by providing access to the repository to qualified investigators. The NIA is collaborating with the Alzheimer's Association and many of the NIA-funded Alzheimer's Disease Research Centers to identify suitable families for the study.
Bone diseases – The Committee encourages NIA to enhance research into the pathophysiology of osteoporosis and Paget's disease and the role of environmental and lifestyle factors associated with these diseases, particularly in men and women of diverse races and ethnicities. The Committee also encourages NIA to coordinate research with the National Institute on Arthritis, Musculoskeletal and Skin Diseases (NIAMS) into treatment for aging-related osteogenesis imperfecta complications. (p. 78)
Action taken or to be taken
NIA continues to support and promote basic and epidemiologic research to identify markers and risk factors (including genetic, lifestyle and environmental risk factors) that predict changes in bone mass, bone strength, and fracture susceptibility. NIA also fosters the testing of new strategies aimed at reducing bone loss and the risk of osteoporotic fractures through its clinical trials program.
In September 2003, at the Annual Meeting of the American Society for Bone and Mineral Research, NIA collaborated with the National Institute of Dental and Craniofacial Research (NIDCR) in convening the Ninth Working Group on Aging and the Human Skeleton on Age-Related Changes in Periosteal Bone . Objectives of the Working Group are to review current knowledge and address methodological issues integral to facilitating clinically relevant studies on the causes and consequences of bone loss and osteoporosis as it occurs at the cellular and tissue levels in adult and elderly humans.
NIA funds a number of studies on age-related skeletal changes in ethnically diverse populations, including the Study of Women's Health Across the Nation (SWAN), which evaluates bone mass changes during the menopause transition in a population of some 3,000 women (including African American, Caucasian, Chinese, and Japanese participants). Another NIA study follows changes in bone mass and risk factors for fractures in populations of Caucasian, African American and Hispanic middle-aged men. NIA collaborates with the National Institute on Musculoskeletal and Skin Diseases (NIAMS) in co-funding osteoporosis- and other bone-related research projects. The NIAMS and NIA continue to co-fund the Osteoporotic Fractures in Men (MR. OS) study. The primary goal of the MR.OS study is to determine the extent to which fracture risk in older men is related to bone mass, bone geometry, lifestyle factors, biochemical measures, fall propensity, and other variables. NIA also collaborates in the NIH Federal Working Group on Bone Diseases (FWGBD), which is convened quarterly by NIAMS to provide relevant Federal agencies a forum for sharing information and ideas, identifying collaborative projects and carrying out joint activities such as conferences and initiatives. In such collaborations with other NIH institutes and DHHS agencies, future opportunities for new studies in skeletal diseases related to aging, Paget's disease and osteogenesis imperfecta (OI) are explored.
Down syndrome – Research has shown that people with Down syndrome have an increased risk of developing Alzheimer's disease. Approximately fifty percent of individuals with Down syndrome over the age of 35 will develop the clinical signs and symptoms of Alzheimer's type dementia. All persons with Down syndrome will develop the neuropathology of Alzheimer's disease, even if they do not demonstrate dementia. Research into the process by which Alzheimer's disease evolves in persons with Down syndrome affords the opportunity to understand an important link between development and aging in all individuals. The Committee encourages NIA to enhance its research into the connection between Down syndrome and Alzheimer's disease. (p. 78)
Action taken or to be taken
NIA is aware that older individuals with Down syndrome have an increased incidence of dementia and evidence of Alzheimer's disease pathology in their brains and agrees that continued research focused on understanding the mechanisms and processes involved has relevance for brain aging and Alzheimer's disease in general. One of these brain mechanisms involves oxidative stress; thus, the Down syndrome population is an excellent candidate for testing potential antioxidant interventions for delaying cognitive and functional decline. There are currently two ongoing NIA-supported clinical trials in individuals with Down syndrome. One double-blind, placebo-controlled pilot clinical trial is currently testing a combination of two cellular antioxidants (vitamins E and C) and a mitochondrial antioxidant (alpha-lipoic acid) given for two years in Down syndrome individuals who have been diagnosed with Alzheimer's disease. The major aim of the study is to determine whether decline in cognitive and functional measures is slowed by antioxidant supplementation. The other trial is a multi-center, randomized, double blind, placebo-controlled international trial of vitamin E in individuals with Down syndrome 50 years of age or older, with or without a diagnosis of Alzheimer's disease. The purpose of this trial is to evaluate the safety and efficacy of vitamin E for three years in slowing the rate of cognitive/functional decline.
NIA is also supporting basic studies using a mouse model of Down syndrome which shows similar genetic changes to those found in human Down syndrome. A number of brain dysfunctions have been demonstrated using this model involving disruption of the processes by which nerve cells communicate, including loss of nerve growth factor signaling, which contributes to the degeneration of specific nerve cells, as well as abnormal phosphoinositide signaling, which is important for cellular communication. This latter dysfunction was also found in studies of young adult and older Down syndrome individuals using magnetic resonance spectroscopy. Altered lipid metabolism in brains of Down syndrome individuals has also been found. Researchers have directly compared brains from Alzheimer's disease patients to those from Down syndrome individuals and have found many similarities between the two in terms of inflammatory processes and other pathological indices. Thus, research supported by NIA's intramural and extramural programs is actively pursuing not only an understanding of the basic mechanisms that lead to dementia in individuals with Down syndrome, but also the translation of these mechanisms into interventions in human clinical trials that are attempting to slow the cognitive decline and dementia associated with Down syndrome in these older individuals.
End-of-life/palliative care – The Committee encourages NIA to expand research, implementation of insights in practice, and training programs, aiming to understand the mechanisms of disability and suffering in fatal chronic illness and to prevent and relieve that disability and suffering, particularly with respect to pain management. (p. 78)
Action taken or to be taken
NIA supports an active portfolio of grants on end-of-life research. Following an earlier NIA conference, NIA and the National Institute of Nursing Research (NINR) published an agenda- setting Special Issue of The Gerontologist (October 2002): “End-of-Life Research. Focus on Older Populations.” In addition, NIA is on the planning committee of a trans-NIH State of the Science Conference on end of life issues. Scheduled for October 2004, this public conference will help establish and disseminate the current state of knowledge and lead to fuller dissemination of research knowledge related to palliative care, pain management, and the well-being and health of family members caring for dying loved ones.
Family caregiver – Since the burdens and challenges of family caregiving are already substantial and are expected to become overwhelming as the ratio of elderly persons to children gets larger, the Committee urges NIA to intensify its research activities to support rapid improvements in understanding human resources, service delivery arrangements, technology, and financing that would be most useful in ensuring comfort and dignity for individuals with fatal chronic illness, and in relieving the burdens borne by family and professional caregivers. (p. 79)
Action taken or to be taken
NIA's large, multi-site, ongoing randomized intervention trial, REACH (Resources for Enhancing Alzheimer's Caregiver Health), is intended to determine stress-reduction methods for caregivers to maintain their health and well-being. REACH interventions will be made available to family caregivers throughout the U.S. NIA also sponsors research on caregiving in institutional settings. NIA sponsored a two-day public symposium dealing with technology to help family caregivers and sponsors the National Long-Term Care Surveys Panel that will be adding a family caregiving component. Finally, NIA sponsors research on caregiving related to grandparenting, adult children with developmental disabilities, and the impact of changes in marriage patterns upon caregiving and disability for aging family members in the future.
Alzheimer's Disease – The Committee expects the NIA to expand its investment in Alzheimer's disease research, including clinical trials for the rapid translation of laboratory findings to effective treatments and prevention, as well as new initiatives in imaging and genetics aimed at finding risk factors and surrogate markers. (p. 137)
Action taken or to be taken
Please refer to page NIA-31 of this document for NIA's response to this significant item regarding Alzheimer's Disease.
Bone Diseases – The Committee recognizes that little is known about the pathophysiology of osteoporosis and Paget's disease and the role of environmental and lifestyle factors associated with these diseases, particularly in men and women of diverse races and ethnicities. Tools to assess risk have inadequate sensitivity and specificity and have not been widely tested, resulting in limited clinical effectiveness. The Committee urges NIA to expand research in all these areas. The Committee also encourages NIA to coordinate research with NIAMS into treatment for aging-related osteogenesis imperfecta complications. (p.138)
Action taken or to be taken
Please refer to page NIA-33 of this document for NIA's response to this significant item regarding Bone Diseases.
Claude D. Pepper Older American Independence Centers – The Committee continues to strongly support these successful centers, which focus on developing innovative and cost-effective ways to enhance the independence of older Americans. The centers also play the critical role of developing top-level experts in geriatrics. The Committee again urges NIA to make all possible efforts to expand these centers to include a school of nursing. (p. 138)
Action taken or to be taken
The Claude D. Pepper Older American Independence Centers (OAIC) program was established in 1994 by the National Institute on Aging to increase scientific knowledge leading to the development of innovative and cost-effective ways to maintain and restore independence in older persons. The OAIC awards not only foster aging research in specific areas of expertise of the individual centers but also support core activities focused on career development of junior faculty in geriatrics and geriatric subspecialties. The OAIC program stresses the importance of multidisciplinary “translational” research that develops and evaluates new tests or interventions based on findings from laboratory studies and other basic research and of studies to improve our understanding of clinical considerations in independent function.
Nursing expertise is an important part of the transdisciplinary approach to aging research, particularly in the areas of maintaining and restoring independent function. OAICs are strongly encouraged to integrate nursing program within their Center infrastructure and to support nursing research relevant to functional independence in the elderly. Applications for OAIC awards from nursing schools that meet the requirements of the current program are welcome and have been actively encouraged by NIA staff.
Cognitive Behavioral Research – The Committee commends the NIA for its research program to explore the research recommendations in the National Academy of Sciences report “The Aging Mind.” The Committee encourages the NIA to continue its own work, as well as cooperative efforts with other Institutes, to add to fundamental and applied knowledge of how the memory works and may be enhanced, and how age or behavior may affect memory. (p. 138)
Action taken or to be taken
Cognitive behavioral research in aging continues to be a priority at the NIA For example:
- Workshops planned for 2004 include ones on cognitive training, cognition and the aging worker, decision-making processes (e.g., health, financial) in old age, non-pharmacological interventions for age-related cognitive decline and Alzheimer's disease, and the design and incorporation of cognitive measures in clinical trials (a trans-NIH effort involving NINDS, NIMH and NIA).
- During 2004, NIA will form a working group to review the utility of current measurement tools for assessment of executive function (ability to plan, schedule, and sequence) in older adults.
- The NIA is involved in an ongoing trans-NIH (NIA, NIMH, NINDS) initiative, the Cognitive and Emotional Health Project, to identify and, if needed, stimulate research on the factors for gaining and/or maintaining cognitive and emotional health in the older adult.
- The ACTIVE clinical trial, a training intervention to improve cognitive abilities in older adults, is drawing to a close; the next phase will be to explore the transfer of training from the laboratory to the real world. The cognitive training workshop planned for early 2004 will address these issues.
- In relation to the cognitive training workshop and others planned for the coming year, opinion papers from experts in the field have been commissioned on financial decision making, defining functional ability in the work place, and technology interaction costs and benefits in older individuals.
- During the past year, an ancillary component for neuropsychological assessment was added to the ongoing Health and Retirement Study (a longitudinal, multidisciplinary survey of more than 22,000 Americans over the age of 50) to allow dementia diagnosis and identification of mild cognitive impairment. This component should help inform us about national prevalence estimates as well as to the social and economic consequences of various levels of cognitive impairments.
- NIA funds several pharmacological trials for prevention of Alzheimer's disease that include examination of the drug effects on age-related cognitive decline.
- NIA supports a growing number of studies on the molecular and cellular mechanisms of cognitive decline with age, studies which may lead to development of effective treatments.
- Recent studies capitalizing on state-of-the-art gene chip technology have suggested that changes in the brain in early adulthood might initiate cellular or biological changes that could lead to functional changes in later life.
Demographic and Economic Research - The Committee once again commends the NIA for its demography and economic research, with special recognition of the research undertaken at NIA's 11 demographic research centers. The Committee also strongly recommends that NIA provide increased funding for these Centers to sustain their productivity and efficiency. The Committee is impressed by the findings from NIA's Health and Retirement Study [HRS] which provide important policy information necessary to evaluate the costs of alternative options. The Committee supports funding for a diverse body of analytic research on HRS findings so that as a Nation, we might better understand the timing of retirement, the transition from full-time work, and the social, as well as the economic consequences of retirement. Tracking research on the decline in disability continues to be a high priority for the Committee. (p. 138)
Action taken or to be taken
Development, collection, and analysis of longitudinal data on demographics, health, work, retirement, and savings are NIA priorities. The NIA currently supports 11 “Demography and Economics of Aging" centers that are vital sources of information on the changing demographic, social, economic, and health characteristics of the older population. Research embraces topics such as trends in the age-structure of populations, changes in levels of disease and disability, economic costs of disability, cost-effectiveness of interventions, migration and geographic concentrations of the elderly, decision-making about retirement, pensions and savings, the relationship between health and economic status, and health disparities by gender and race. Researchers at the Demography Centers conduct analyses of several large, publicly available datasets sponsored by the NIA and other government agencies, including the Health and Retirement Study (HRS), National Long-Term Care Study (NLTCS), Longitudinal Study of Aging (LSOA), National Survey of Families and Households (NSFH), Panel Study of Income Dynamics (PSID), and Current Population Study (CPS). The current round of funding for the Demography Centers ends in June, 2004 so the program is currently being recompeted. A funding decision for the continuation of the program will be made in the summer, 2004. At this time, the budget for the continuation of the Demography Centers is not expected to increase over last year.
The HRS is intended to provide data for researchers, policy analysts, and program planners who are making major policy decisions that affect retirement, health insurance, saving and economic well-being. The 2002 wave is nearly completed; in mid to late 2004, a new cohort (born 1948-53) will be added. NIA continues to encourage analyses of these data and expects to release a Program Announcement specifically calling for analysis of the HRS and PSID data.
The NIA concurs with the high priority given to continued investigation of the decline in disability. Both the extramural and intramural research programs have ongoing interests in methodological issues surrounding the assessment of disability and functional limitations and in surveys to track and analyze disability trends. In FY 2003 NIA funded the 6th wave of the NLTCS, which will be fielded in the Summer or Fall of 2004. The NLTCS samples the entire aged population and is designed to measure changes in chronic disability (and institutionalization) over time. NIA is strongly encouraging the dissemination of the NLTCS data to the research community. In addition, recent research has shown that various demographic characteristics may influence the way in which older persons answer questions on disability, so understanding disability declines across various subgroups of the U.S. population and making comparisons across countries remains a challenge. The use of objective performance measures of functional status may offer opportunities to further understand these issues. A new approach that uses standard vignettes that depict different levels of disability and allow for adjustments for group differences in reporting the same objective level of disability is also showing promise.
Down Syndrome – Research has shown that people with Down syndrome have an increased risk of developing Alzheimer's disease. Approximately 50 percent of individuals with Down syndrome over the age of 35 will develop the clinical signs and symptoms of Alzheimer's type dementia. All persons with Down syndrome will develop the neuropathology of Alzheimer's disease, even if they do not demonstrate dementia. Research into the process by which Alzheimer's disease evolves in persons with Down syndrome affords the opportunity to understand an important link between development and aging in all individuals. The Committee urges NIA to expand its research into the connection between Down syndrome and Alzheimer's disease. (p. 139)
Action taken or to be taken
Please refer to page NIA-34 of this document for NIA's response to this significant item regarding Down Syndrome.
Health and Behavior – The Committee commends the NIA for its continuing focus on behaviors that may enhance healthy aging, especially research on physical activity among sedentary or frail elderly. The Committee encourages the NIA to continue efforts, through the Roybal Centers for Applied Gerontology and other means, to move innovative behavioral interventions into health care and other settings where they may be applied. (p. 139)
Action taken or to be taken
NIA maintains a growing research portfolio on health behaviors. NIA recently funded two grants on mechanisms for long-term exercise program maintenance and also supports several grants on the impact of exercise on cognitive performance with age. NIA supports several research
projects focused on engagement in mental or leisure activities and reduction in risk for Alzheimer's disease. Funding of the Roybal Centers will continue translation research on health behaviors.
The NIA is also involved in an ongoing trans-NIH (NIA, NIMH, NINDS) initiative, the Cognitive and Emotional Health Project, to identify and, if needed, stimulate research on the factors for gaining and/or maintaining cognitive and emotional health in the older adult. This past year, NIA supported a workshop on the psychological foundations of public policy interventions that, in part, looked at how new theories of behavioral economics can be used to induce improvements in health behaviors, as well as a workshop on dietary supplement use in the elderly, who uses them, what supplements are most commonly used, and the impact on the health of the individual. NIA currently is supporting an NAS panel on Social Psychology that is examining some of the psychological foundations of successful behavioral interventions.
NIA is planning a workshop to provide the research direction for the area of health behavior to assure that NIA supported research is at the forefront of the discipline. Several relevant workshops are planned for the coming year including one that will focus on multilevel interventions for induction of change at both the individual and organizational level and another that will focus on non-pharmacological interventions for age-related cognitive decline and Alzheimer's disease.
Hematology – The Committee encourages NIA to develop new initiatives to study the basic biology of blood disorders that affect the elderly population, such as myelodysplastic syndromes and anemias, and the adverse quality-of-life consequences for the elderly who suffer from these disorders. (p. 139)
Action taken or to be taken
Blood disorders, particularly anemia, are common clinical findings among the elderly. Approximately 10 percent of men and women in the United States ages 65 years and older are anemic according to World Health Organization (WHO) criteria, and this number increases to above 20 percent among those 85 years of age and older. About one third of these anemias are due to nutritional deficiencies, approximately one quarter are associated with other chronic diseases, and about one third have no clearly identifiable cause (“idiopathic anemia of the elderly”). Because anemia can cause symptoms of weakness and fatigue and can worsen other medical problems such as heart failure in older patients, it is important to understand the changes in blood cell production that occur with aging and to develop ways to treat and prevent the diseases associated with these changes.
The National Institute on Aging is collaborating with the American Society of Hematology to summarize and evaluate current knowledge of anemia in the elderly and to identify areas in which research could improve our understanding of anemia and foster new approaches its treatment. For example, the recent identification of growth factors that boost blood cell production and their successful use in treating anemia due to cancer therapy may guide studies addressing the causes and management of anemia in the elderly.
