Testimony

Statement by
Richard J. Hodes, M.D.
Director, National Institute on Aging

on
Alzheimer's Disease Research
The Senate Appropriations Subcommittee on Labor, Health and Human Services, and Education

March 23, 2004

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 today 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. Approximately 4.5 million Americans are currently battling AD, with annual costs for the disease 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 to sharply 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 rise to some 13.2 million, an almost three-fold increase.

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, to reverse the current trends. As a part of our Government and Performance Results Act, NIH has developed a long-term, high-risk goal of identifying at least one clinical intervention that will delay the progression, delay the onset, or prevent Alzheimer's disease.

Risk Factors

Many Americans wonder whether they or their loved ones are at risk of developing AD. Sadly, as they age, many of them will be. The risk of AD increases dramatically with age, with nearly half of all individuals over age 85 being diagnosed. Many older Americans struggle with mild cognitive impairment (MCI), a condition that is frequently a precursor to AD; in one recent population-based study of cognition in the elderly, 22 percent of participants over 75, and 29 percent of those over 85, were diagnosed with MCI. Determining who is at high risk of developing AD and who is not – and why -- will enable us to identify potential targets for preventive intervention, as well as those individuals who might benefit most from such interventions.

Through laboratory, clinical and population-based research, we have identified a number of risk factors for AD, including both genetic and lifestyle factors. We already know of three major genes for early-onset disease and have identified a major risk factor gene, ApoE4, for the more common late-onset disease. Recent findings are enabling us to close in on several others, thought to be on chromosomes 9, 10, and 12.

However, neuroscientists have become increasingly interested in a specific set of genes that may influence not whether, but when, a person might develop symptoms of neurodegenerative disease. Delaying the onset of AD symptoms by even five years could greatly reduce the numbers of people who will have the disease, as well as providing additional cognitively-healthy time to those who will eventually be diagnosed.

Recently, NIH-supported investigators found a gene on chromosome 10 that they believe influences the age of onset of both Alzheimer’s disease and Parkinson’s disease. Using a novel method to match the genes of people affected with these diseases with the age at which study participants started developing symptoms, the scientists found that one gene, GSTO1, was significantly associated with late onset of both Alzheimer’s and Parkinson’s. This important work gives us new clues to the role of genetics in the timing of late-life forms of these devastating neurodegenerative diseases.

Last year this Committee heard about the NIA’s AD Genetics Initiative, a program to accelerate the pace of AD genetics research by 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 additional 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 a national repository to qualified investigators.

This year, we have launched several well-integrated components of the Genetics Initiative. Mechanisms to efficiently identify and share large numbers of samples for AD genetic analysis have been developed through the recently-enlarged National Cell Repository for AD (NCRAD), and eighteen of the NIA’s Alzheimer’s Disease Centers (ADCs) have received supplemental funding to recruit new family members for participation. Uniform standards for sample collection have also been developed.

In order to publicize the initiative, the NIA Office of Communications and Public Liaison, together with its Alzheimer’s Disease Education and Referral Center, Columbia University, and NCRAD, partnered with the Alzheimer’s Association to conduct focus groups and develop materials to publicize the initiative and help recruiting efforts. These publicity materials, including a workbook, CD ROM, fact sheet, and brochure were distributed at a recent meeting of all Alzheimer’s centers and have been sent to ADCs and Alzheimer’s Association chapters to further recruitment efforts.

As of Late January, over 200 families, of the approximately 1000 needed, have been evaluated and are now enrolled in the study, and over 800 blood samples have been logged at NCRAD. Working groups have been established which are helping to determine the most useful phenotypic data to be included in the data bank along with the biological samples. A major goal is the long-term follow-up of individuals participating in the study.

Type 2 diabetes, which, according to the American Diabetes Association, affects approximately 17 million Americans, is another potential risk factor for cognitive decline and AD. In a recent study, researchers found that compared to older non-diabetic women, older women with type 2 diabetes were about 30 percent more likely to score poorly on tests of cognitive function, and that the risk increased with the duration of their condition. However, the diabetic women in the study who took glucose-lowering pills had a risk similar to non-diabetic women. Recognizing the potential link between type 2 diabetes and cognitive decline, NIA researchers are currently participating in an offshoot of the National Heart, Lung, and Blood Institute’s Action to Control Cardiovascular Risk in Diabetics (ACCORD) study. ACCORD evaluates whether more intensive glucose, blood pressure and lipid management can reduce cardiovascular disease in people with diabetes; the aim of this sub-study, ACCORD-MIND, is to test whether the rate of cognitive decline and structural brain change in people with diabetes treated with standard care guidelines is different than in people with diabetes treated with intensive care guidelines. Recruitment for the ACCORD study began in January 2003, and we anticipate that 2800 people will participate in ACCORD-MIND.

Imaging

Powerful imaging techniques, including positron emission tomography (PET) and magnetic resonance imaging (MRI), are opening a window into the brain, allowing us to visualize not only anatomical structures but also functional processes and activities at the molecular level. The refinement of these techniques continues to have a profound effect on all areas of AD research.

For example, improvements in brain imaging, coupled with the development of more sensitive cognitive tests, are enabling us to diagnose AD in the research setting with greater precision than ever before, despite the fact that there remains no scientifically validated method to visualize AD’s characteristic amyloid plaques and neurofibrillary tangles in a living human. However, even this may be changing. Researchers have recently developed the first radiotracers, including a molecule called Pittsburgh Compound-B, that facilitate visualization of amyloid deposition in living AD patients using PET scans (Chart # 1). Although further research is needed, these molecules may eventually offer us a powerful and accurate diagnostic tool for the disease.

Visualization of brain structures and activities may also enable us to identify people at risk of developing the disease even decades before the onset of symptoms. In a recent study, investigators used positron emission tomography (PET) to examine the brains of asymptomatic young adults (ages 20-39) who were carriers of the APOE-e4 gene, a common susceptibility gene for late-onset AD. Middle-aged carriers of this gene are known to have abnormally low rates of metabolism in the same brain regions as patients with AD; in this study, the investigators found the same brain abnormalities in the younger carriers of the gene. The precise link between the APOE-e4 gene, the altered metabolism, and AD remains unknown, and more research is needed on this provocative finding, but it may offer important clues to AD’s etiology and perhaps even a target for future prevention efforts.

Advances in imaging also have the potential to speed our basic understanding of the disease -- for example, to determine which pathological features of AD (plaque and tangle development, cell death, loss of connections between neurons) best correlate with cognitive loss. Improved imaging techniques may further enable us to visualize the effects of therapeutic interventions more rapidly and accurately, with the potential for making AD clinical intervention trials smaller, faster and more affordable.

Last year, we told this Committee about our plans for a Neuroimaging Initiative, a longitudinal, prospective, natural history study of normal aging, mild cognitive impairment, and early AD to evaluate neuroimaging techniques such as MRI and PET, as well as other biological markers. This year, I am pleased to tell you that work on the Initiative is underway. We have issued a Request for Applications and have received submitted applications. In addition, we have secured the participation of several key industry participants. Awards will be made this summer, with work on the project to begin shortly thereafter. The study objectives are to:

  • Identify the best markers for early diagnosis of AD

  • Identify markers for following disease progression and monitoring treatment response

  • Develop surrogate endpoints for clinical trials

  • Decrease time and expense of drug development

  • Establish methods for the collection, processing, and distribution of neuroimaging data in conjunction with other biological, clinical, and neuropsychological data

The initiative is planned as a partnership among the NIA/NIH, academic investigators, the pharmaceutical and imaging equipment industries, the Food and Drug Administration, the Centers for Medicare and Medicaid Services, and the NIH Foundation, with participation from the Alzheimer’s Association and the Institute for the Study of Aging. The clinical, imaging, and biological data and samples will be made available, with appropriate safeguards to ensure participant privacy, to all scientific investigators in the academic and industrial research communities.

Prevention and Treatment

As imaging and laboratory studies tell us more about AD’s pathology, we are identifying a number of novel molecular characteristics that may prove to be targets for treating the disease or preventing it altogether. For example, enhancing the brain’s self-protective capacity by inducing production of naturally-occurring proteins that destroy beta amyloid shows promise in mice that have been genetically altered to produce amyloid plaques. In a recent study, boosting production of two proteins, insulin-degrading enzyme and neprilysin, in neurons of these mice reduced brain amyloid levels, slowed or even prevented amyloid plaque formation, and prevented their premature death (Chart # 2).

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. For example, investigators recently studied the effects of an enriched diet on age-related cognitive decline in dogs, a model that mimics the behavioral and brain pathological declines of older humans more closely than rodent models. Young and old dogs were given a series of baseline cognitive tests. Half of each age group then remained on a standard diet, while the other half of each age group was placed on a diet enriched with antioxidants and mitochondrial co-factors, which are thought to improve nerve cell energy and efficiency and decrease production of molecules that contribute to oxidative damage in the brain. Animals remained on their respective diets for six months and then were assessed again for cognitive performance on a variety of tasks. When tested, old dogs on the control diet learned more slowly than the young dogs and made significantly more errors; however, when compared to the old animals on the control diet, old animals on the enriched diet showed significantly better learning, although not to the level of the younger animals. The success of this simple, cost-effective intervention has significant implications for dietary interventions that might lessen or even prevent some of the cognitive decline seen with age and with disease; a pilot trial of similar antioxidants in older Down syndrome patients who have developed AD is currently under way.

In fact, NIA is currently supporting 25 AD clinical trials, including large-scale prevention trials, which are testing agents such as hormones, anti-inflammatory drugs, statins, homocysteine-lowering vitamins, 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.

Caregiving

Most of the over 4 million Americans with AD today are cared for outside the institutional setting by an adult child or in-law, a spouse, another relative, or a friend. Caregivers frequently experience significant emotional stress, physical strain, and financial burdens, yet they often do not receive adequate support for their remarkable efforts. Several recent studies have explored the problems faced by caregivers of AD patients, and have sought to design interventions to reduce their burdens. Although family caregiving has been extensively studied, there has been less research on the impact of end-of-patient-life on caregivers who are family members of persons with dementia or to the caregivers' responses to the death of the patient. As part of the NIA=s Resources for Enhancing Alzheimer=s Caregiver Health (REACH) study, a multisite randomized clinical intervention of 1222 caregiver and recipient dyads, investigators assessed the type and intensity of care provided by 217 family caregivers to persons with dementia during the year before the patient's death, as well as the caregivers' responses to the death. Additionally, this group was compared to the 180 caregivers who institutionalized their family member. The researchers found that the in-home caregivers reported tremendous levels of stress in the year leading up to the care recipient=s death, and that levels of caregiver depression Aspiked@ immediately following the care recipient death. However, the caregivers in this study demonstrated tremendous resilience: Within fifteen weeks of the recipient=s death, depression returned to pre-death levels, and within one year, depression was significantly lower than prior to the care recipients’ death. Importantly, caregiver depression for those placing their loved ones in an institution was slightly higher both pre- and post-death than for those caring for the patient at home. These findings suggest that interventions for caregiver support are particularly critical in the periods immediately prior to and immediately after the patient’s death.

The NIA’s REACH Project, a large, multi-site intervention study of 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 certain interventions alleviated caregiver burden, and that certain specific interventions, such as structured family therapy, 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 intervention and is ongoing.

Conclusion

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.

Data from the Alzheimer’s Association. See also Ernst, RL; Hay, JW. “The U.S. Economic and Social Costs of Alzheimer’s Disease Revisited.” American Journal of Public Health 1994; 84(8): 1261 – 1264. This study cites figures based on 1991 data, which were updated in the journal’s press release to 1994 figures.

Hebert, LE; Scherr, PA; Bienias, JL; Bennett, DA; Evans, DA. “Alzheimer Disease in the U.S. Population: Prevalence Estimates Using the 2000 Census.” Archives of Neurology August 2003; 60 (8): 1119 – 1122.

Data from the Alzheimer’s Association. See also Evans, DA; Funkenstein, HH; Albert, MS; et al. “Prevalence of Alzheimer’s Disease in a Community Population of Older Persons: Higher than Previously Reported.” JAMA 1989; 262(18): 2552 – 2556.

Lopez O, Jagust WJ, DeKosky ST, Becker JT, et al. “Prevalence and Classification of Mild Cognitive Impairment in the Cardiovascular Health Study Cognition Study.” Arch Neuro 60: 1385-1389, 2003.

Last Revised: March 24, 2004