Witness appearing before the Senate Committee on Appropriations,
Subcommittee on Labor, Health & Human Services, Education, and Related Agencies
Richard J. Hodes, M.D.
Director
National Institute on Aging
April 1, 2003
Senator Specter and Members of the Committee:
Thank you for inviting me to appear before you today to discuss Alzheimer’s disease (AD), an issue of interest and concern to us all. I am Dr. Richard Hodes, Director of the National Institute on Aging (NIA), the lead federal agency for Alzheimer’s disease research. I am delighted to be here this morning to tell you about the progress we are making toward understanding, treating, and preventing AD.
As you know, AD is a devastating condition with a profound impact on individuals, families, the health care system, and society as a whole. According to data from the Alzheimer’s Association, approximately 4 million Americans are currently battling AD, with annual costs estimated to exceed $100 billion. Moreover, the rapid aging of the American population threatens to increase this burden significantly in the coming decades: Demographic studies suggest that if current trends hold, the annual number of incident cases of AD will begin a sharp increase around the year 2030, when all the baby boomers (born between 1946 and 1964) will be over age 65. By the year 2050, the number of Americans with AD could double.1
But these numbers, however stark, do not tell the whole story. Although AD remains a major public health issue for the United States, we have made, and are continuing to make, dramatic gains in our ability to understand and diagnose AD that offer us the hope of preventing and treating the disease, reversing the current trends.
Fifteen years ago, we did not know any of the genes that cause AD, and we had only a limited understanding of the biological pathways that are involved in the development of brain pathology. Ten years ago, we could not model the disease in animals. Five years ago, we were not funding any prevention trials and had no way of identifying persons at high risk for the disease. And as recently as two years ago, we did not understand anything about how AD’s characteristic amyloid plaques and neurofibrillary tangles in the brain relate to each other.
Today, we have accomplished all of these things through a far-ranging and innovative program of scientific endeavor. And in the past year alone, we have made a number of important discoveries.
A crucial underpinning of our efforts to develop interventions that delay or even prevent clinical manifestation of AD is the understanding of the events leading up to the disease’s appearance, including risk factors. Through laboratory and population-based research, we have identified a number of risk factors for AD, including genetic and lifestyle factors. We already know three major genes for early-onset disease and have identified a major risk factor gene for late onset disease, ApoE4. Recent findings are enabling us to close in on several others, thought to be on chromosomes 9, 10, and 12.
In order to move the field of Alzheimer’s disease genetics forward more rapidly, the NIA has developed an Alzheimer’s Disease Genetics Initiative. A major component of this initiative is the collection of family-based, population-based, and case-control sample sets. To facilitate collection of the family-based sample set, administrative supplements were awarded last year to ten Alzheimer’s Centers to identify families with two or more affected members and to collect blood and information from them for archiving in the National Cell Repository for Alzheimer’s Disease (NCRAD). DNA and information on these individuals will be made available, with appropriate controls to ensure participant confidentiality, to the research community. The information gained through this initiative will be invaluable to the discovery of AD-related genes, which will in turn help us identify pathways affecting AD development or progression.
In addition to genetic and molecular risk factors, studies funded by a number of NIH Institutes are revealing the possible impact of diseases such as cardiovascular disease and diabetes on AD-related dementia in later life. Researchers in one study found that persons in a Latino population had a 7-8 fold increased risk of dementia if they had both type 2 diabetes and stroke compared to persons who had neither, suggesting that improved interventions to prevent diabetes and stroke may prevent dementia in substantial numbers of people. Results from the ongoing Cardiovascular Health Cognition Study demonstrated that measures of cognition, ApoE4 status, and certain results on magnetic resonance imaging (MRI) of the brain are together strongly predictive of both dementia and AD.
In fact, the development and refinement of powerful imaging techniques that target anatomical, molecular, and functional processes in the brain is giving us an improved ability to identify people who are at very high risk for AD, as well as a greater understanding of the disease’s pathology. For example, in a recent mouse study, researchers found that changes in brain structure can be detected by magnetic resonance microscopy before amyloid plaques appear in the brain, suggesting that subtle pathologic changes are occurring long before signs and symptoms of the disease appear. Other investigators have found that metabolic changes in certain parts of the brain, as detected through positron emission tomography, show potential for predicting future decline in cognitively normal adults. Researchers are also working to improve our ability to image plaques and tangles in vivo, which will allow us to diagnose the disease with greater accuracy and more closely follow its progression and response to therapies.
These techniques, along with improved neuropsychological tests, are enabling us to diagnose AD early, while the patient can still take an active role in decision-making. This knowledge, in turn, may allow early intervention long before the disease affects the patient’s level of functioning.
An Alzheimer’s Disease (AD) Neuroimaging Initiative is under development as a study of normal aging, mild cognitive impairment (frequently a precursor of AD), and early AD, using serial magnetic resonance imaging and positron emission tomography scans, clinical and neuropsychological data, and collections of biological fluids and cells for other potential biomarkers. The Initiative is being planned with participation by NIA/NIH, the Food and Drug Administration, academic investigators, the pharmaceutical industry, the imaging equipment industry, the Alzheimer’s Association, and the Institute for the Study of Aging. It is anticipated that information gained from this initiative will help us identify potential uses of imaging and other surrogate markers for following progression of cognitive decline and dementia, and for assessing the effectiveness of interventions to prevent or treat AD.
As we learn more about AD’s pathology through imaging and laboratory studies, we are identifying a number of novel molecular characteristics that may prove to be targets for treating the disease or preventing it altogether. In this endeavor, animal models – particularly transgenic mice, but also worms, dogs, and even non-human primates – are invaluable research resources for studying age-related and disease-related changes in the brain and for testing promising interventions.
Two new research findings suggest that boosting normal, protective processes in the brain might help degrade or prevent the development of amyloid plaques. In one study, researchers found that gene transfer into mice of the enzyme neprilysin may help clear the protein that forms amyloid plaques in humans. In the other, researchers found that brain cells called astrocytes can degrade the beta amyloid peptide in cell cultures, suggesting that harnessing the protective function of these cells may be a strategy for AD prevention and treatment.
Another potential preventive strategy involves enhancing the function of chaperone proteins, which aid in proper protein folding. In various cellular models, researchers have noted an inverse relationship between levels of a heat shock protein (a chaperone) and neurofibrillary tangles in the brain, suggesting that up-regulation of molecular chaperones may suppress formation of neurofibrillary tangles. More research is needed to assess the clinical significance of these findings.
Researchers are also exploring immune approaches that target AD. In collaboration with the National Institute of Neurological Disorders and Stroke, NIA has issued a Request for Applications (RFA) and funded a number of studies to better understand the science underlying immunologic approaches. An encouraging outcome of this research is the observation that antibodies in the blood may draw soluble amyloid out of the brain, perhaps even reducing the size of plaques as well. The newest results suggest that other compounds that bind to amyloid may have the same effect. Whether these results in animal studies can be successfully applied to humans has not yet been evaluated.
Human stem cells, with their unique capacity to regenerate and give rise to many tissue types, are of particular interest in AD research because of their potential ability to generate new cells that could renew damaged brain tissue, replace dying neurons, or enhance the ability of the brain to respond to age-related impairments. Recent findings suggest that both human embryonic stem cells (hES), which can give rise to many cell types, and “adult” stem cells, which develop into specific cell types, show promise for the eventual treatment of AD and other neurodegenerative conditions. Researchers have recently developed a method for inducing hES cells to differentiate into neurons. These newly-derived cells exhibit the properties of cells ordinarily found in the brain and central nervous system, suggesting that hES cells could provide a source for neural progenitor cells and mature neurons for therapeutic use. Investigators have also found that in the adult hippocampus, neural stem cells can give rise to functional neurons that can integrate effectively into existing neural circuits.
In addition to interventions at the molecular level, scientists are increasingly enthusiastic about the role of behavioral variables, such as mentally stimulating activities throughout life, as a factor capable of maintaining cognitive health or even reducing the risk of cognitive decline or AD. Through its Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study, NIA explored whether three specific interventions (on memory, reasoning, and speed of processing) could maintain or improve functioning in unimpaired, community-dwelling older adults. The investigators found that the interventions helped the participants to perform better on multiple measures of the specific cognitive ability for which they were trained, and that these improvements persisted for two years after training. Additional follow-up of participants is planned.
Research has also suggested that the use of several common, over-the-counter compounds may be associated with reduced risk of AD and dementia. For example, epidemiologic studies show a correlation between long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and a reduced risk of developing AD, and recent findings in animal models suggest the possibility that some newer anti-inflammatories may reduce inflammation as well as directly reduce the formation of amyloid. Likewise, researchers are developing and testing new antioxidant drugs that ameliorate or prevent brain cell damage or death caused by oxidative stress, a form of cell damage caused by molecules generated during normal energy metabolism. Chronic oxidative stress may be a contributing factor in neurodegenerative disorders, including AD. In studies of dogs and rats, diets rich in antioxidants resulted in a significant improvement in the ability of older animals to acquire progressively more difficult learning tasks. These results suggest that oxidative damage impairs cognitive function and that antioxidant treatment can result in significant improvements.
NIA is currently supporting 18 AD clinical trials, seven of which are large-scale prevention trials. These trials are testing agents such as estrogen, anti-inflammatory drugs, and anti-oxidants for their effects on slowing progress of the disease, delaying AD’s onset, or preventing the disease altogether. Other intervention trials are assessing the effects of various compounds on the behavioral symptoms (agitation, aggression, and sleep disorders) of people with AD. The design and implementation of all of these clinical trials will be carried out in the context of the NIH Roadmap initiative to enhance clinical research infrastructure and methodology.
Another very important area of research involves easing the burden on caregivers of AD patients. Most Americans with AD are cared for at home by an adult child or in-law, a spouse, another relative, or a friend. For this reason, the AD “patient” is, in a sense, not only the person with the disease, but the entire family unit. The NIA’s REACH Project (Resources for Enhancing Alzheimer’s Caregiver Health), a large, multi-site intervention study aimed at family caregivers of AD patients, was designed to characterize and test promising interventions for enhancing family caregiving. Nine different social and behavioral interventions were tested, and investigators found that the combined effect of interventions alleviated caregiver burden, and that interventions that enhanced caregiver behavioral skills reduced depression. The second phase of the study, REACH II, combines elements of the diverse interventions tested in REACH into a single multi-component psychosocial behavioral intervention and is ongoing.
The goal of AD research is ultimately to identify the most effective strategies for preventing and treating AD in diverse populations. Recent research findings have provided an unprecedented base of knowledge upon which to design these strategies. Research on AD genetics, on the basic cellular biology of AD-related pathways, the changes taking place in the brains of persons with mild cognitive impairment and early AD, animal models, and hints of possible risk and protective factors from epidemiology studies, have all contributed to identification of new clinical opportunities. These diverse and productive research approaches will continue to drive the design of innovative pilot studies and full scale clinical trials that are most likely to yield effective strategies for preventing and treating AD.
It is difficult to predict the pace of science or to know with certainty what the future will bring. However, the progress we have already made will help us speed the pace of discovery, unravel the mysteries of AD’s pathology, and develop safe, effective preventions and treatments, to the benefit of older Americans.
Thank you for giving me this opportunity to share with you our progress on Alzheimer’s disease. I would be happy to answer any questions you may have.
- Hebert LE, Beckett LA, Scherr PA, and Evans DA. Annual Incidence of Alzheimer Disease in the United States Projected to the Years 2000 Through 2050. Alzheimer Dis. Assoc. Disord. 15: 169-173, 2001.
