Part 4: Outlook for the Future

Research in AD continues to move forward rapidly, bringing us ever closer to a full understanding of the causes of this devastating disease and to effective prevention and treatment strategies. Findings from basic science are unlocking the secrets of the disease process at a molecular level, involving beta-amyloid, presenilins, tau, and mitochondria, to name just a few. Findings from other types of studies are providing insights about possible risk and protective factors and ways to help caregivers cope as the disease takes hold in a loved one. Knowledge from these studies is giving scientists and clinicians increasing hope about the potential for new therapeutic agents and strategies.

Realizing these hopes for the future, however, requires action on a number of complementary fronts. In the past several years, the NIA, along with other NIH Institutes and Centers, the Alzheimer’s Association, the Institute for the Study of Aging, and additional organizations, have launched several major initiatives to create and nurture the essential research infrastructure that will help NIH move from basic science to fully developed drugs and therapeutic approaches that can be tested in clinical trials and ultimatelyused to help people with AD.

Providing a Planning Framework
Two of these initiatives provide a critical framework for overall planning and support for AD and broader neurosciences research.

• NIA has partnered with NIMH, NINDS, and NINR in the AD Prevention Initiative, which is designed to invigorate discovery and testing of new treatments, identify risk and protective factors, enhance methods of early detection and diagnosis, and advance basic science to understand AD. The Initiative also endeavors to improve patient care strategies and alleviate caregiver burden.
• NIA is an active member of the newly-established multi-institute NIH Blueprint for Neurosciences Research. This effort provides a framework to enhance cooperative activities among 15 NIH Institutes and Centers to reduce the burden of nervous system disorders, including AD.

Supporting a Collaborative Research Infrastructure
Two other initiatives provide venues and mechanisms for interdisciplinary and collaborative research on AD development and progression.

• Many milestones in AD research in the U.S. since 1984 stem from resources provided by the Alzheimer’s Disease Centers. NIA currently funds 32 ADCs around the country. Imaging, pathology, and clinical studies conducted in the ADCs are allowing investigators to correlate changes in brain structure and function with clinical evidence of disease. In recent years, the Centers have placed increasing emphasis on evaluating cognitive function in healthy aging and the transition to MCI and early dementia as well as mixed dementias and overlapping dementia syndromes. Another growing focus for the ADCs is collaborative trans-Center projects and collaborations with investigators outside the Centers’ network.
• In 1999, NIA established the National Alzheimer’s Coordinating Center (NACC) to provide a mechanism whereby data on patients from all of the ADCs could be pooled and shared. Eleven collaborative multi-Center studies have been funded by NACC and seven other collaborative investigator-initiated grants have been funded and are linked to NACC. The NACC now has information on more than 73,000 ADC study participants enrolled since 1984 and neuropathological data on 9,400 brains from participants autopsied in the ADCs. The data are accessible to Center scientists through NACC’s website. NACC is now including more long-term data on ADC study participants and is working to define and standardize the clinical data elements that will be collected. This uniform data set became operational in September 2005. It is hoped that this effort will lead to better and more extensive research projects using standardized data collected from all Centers. New procedures have been adopted for widening access to the NACC database by non-Center scientists wishing to use the data.

Facilitating Innovation for the Future
An additional five efforts focus on particular aspects of AD or brain research, including neuroimaging, genetics, drug development and clinical trials, techniques for evaluating change over time in cognitive functioning, and healthy brain aging:

• NIA has launched a multi-year AD Neuroimaging Initiative, which will use serial MRI and PET scans to examine how brains change as amnestic MCI and AD progress. The scans and other data and biological samples from the Neuroimaging Initiative will be collected at about 60 clinical sites based in universities throughout the U.S. and Canada. The project will follow approximately 200 cognitively healthy individuals for 3 years, 400 people with amnestic MCI for 3 years, and 200 people with early AD for 2 years. Planning for the many interrelated facets of this initiative has been moving forward rapidly and enrollment has begun. By using MRI and PET scans at regularly scheduled intervals, investigators hope to learn when and where in the brain degeneration occurs as memory problems develop.

Scientists will correlate this imaging information with clinical and neuropsychological assessments, and biomarkers from blood, cerebrospinal fluid, and urine samples collected at intervals from individuals in the study. Potential markers include levels of beta-amyloid and tau, indicators of inflammation, and meas-ures of oxidative stress. NIA hopes the Neuroimaging Initiative will help create rigorous imaging and biomarker standards that will aid in early diagnosis and provide the yardstick by which the success of future treatments can be measured. This would substantially increase the pace and decrease the cost of developing new treatments.

This landmark Initiative is a public-private partnership among government, industry, foundations, voluntary organizations, and academia. An important aspect of this Initiative is that the clinical, imaging, and biological data collected will be made available to qualified scientific investigators for further analysis. This emphasis on sharing data and resources across research institutions will have an important beneficial impact on future research because it means that larger databases of information and samples of participants will be available. This expanded data will help increase the statistical power of studies and allow for analyses of small subpopulations and infrequent outcomes that wouldn’t be possible otherwise.

• Through the Alzheimer’s Disease Cooperative Study—the Federal government’s major mechanism for funding AD clinical trials—another NIA initiative is focused on a critical “nuts and bolts” aspect of prevention clinical trials. The Prevention Instrument Project is developing sensitive and more effective methods for evaluating change over time in cognitively healthy elderly. Investigators involved in this project are focused on designing, developing, and testing new questionnaires and other instruments that can be used to test individuals in a number of areas, such as overall cognitive functioning, memory, ability to carry out activities of daily life, and quality of life. This study is comparing the results of evaluation instruments filled out by participants at home versus those done in the clinic to determine whether the home evaluations are equivalent to the clinic evaluations. If this proves to be the case, this innovation could go far to reduce clinic visits and burden on participants and families, simplify and reduce the cost of clinical trials, and make recruitment and retention easier.
• As AD genetics research has intensified, it has become increasingly clear that scientists need many more samples of genetic material if they are to continue making progress. NIA’s Genetics Initiative is aiming to identify at least 1,000 families with members who have late-onset AD as well as unaffected family members, and is encouraging these individuals to provide blood samples and clinical data. The blood samples will allow investigators to create and maintain “immortalized” cell lines—cells that are continuously regenerated in the laboratory. These cell lines are crucial for the exhaustive DNA analysis studies needed to identify additional risk factor genes. The National Cell Repository for AD (NCRAD), located at Indiana University, serves as the centralized DNA and cell line repository for the Initiative.

Many families already have been recruited but more are needed. NIA has provided funding to the ADCs to help recruit additional study participants, and the ADEAR Center is collaborating with the Alzheimer’s Association to develop media and community outreach programs to foster participation in this Initiative. Results will allow scientists to find new pathways affected in AD and help clinicians accurately identify and counsel people at high risk of developing the disease. Results also will help investigators recruit susceptible individuals into clinical trials, which will reduce the number of participants necessary and the cost and complexity of trials. Shorter trials with fewer participants will allow investigators to be more effective in identifying and testing promising treatments emerging from basic science and translational studies. It also will contribute to future prevention strategies.

• NIA’s new Translational and Drug Testing Initiative aims to encourage researchers to move from purely basic research on AD and associated disorders into translational research and drug testing in clinical trials. This program is intended to expand the potential range of therapies that can be tested against AD and other aging-related diseases and age-related cognitive decline. The initiative provides small grants for research early in the drug development process and larger cooperative grants to move drugs through development up to approval by the FDA for clinical testing. Another component of the Translational Initiative is the longstanding Investigational New Drug Toxicology program, which provides toxicology services to academic and small business investigators who believe they have promising compounds to treat or prevent AD but lack the resources to perform the required toxicology studies. This initiative also funds pilot clinical trials as well as the ADCS and other clinical trials.
• NIA, NINDS, and NIMH have joined efforts to launch the Cognitive and Emotional Health Project: The Healthy Brain, a new trans-NIH initiative. A large number of people are at substantial risk for cognitive impairment from many causes as they age. The same is true for emotional disorders. Although research into biological mechanisms and environmental and social effects are yielding promising results in animal and human studies, much remains to be discovered. Advances in understanding the positive and negative changes in cognition and emotion in adulthood, and what can be done to preserve and enhance positive outcomes, is central to the missions of the participating Institutes. The goal of the Healthy Brain Project is to assess the state of longitudinal and epidemiologic research on demographic, social, and biologic determinants of cognitive and emotional health in aging adults, and to accelerate identification of ways to maintain cognitive and emotional health. The Project also is examining the pathways by which cognitive and emotional health may influence each other.
• As this report has shown, our knowledge about the many dimensions of AD is advancing rapidly, and the results of the initiatives described here will certainly accelerate new scientific discoveries. As we celebrate our scientific successes, however, we do not forget that AD remains an urgent problem for our Nation. Our challenge is to continue building upon the events and experiences of the past and present to create a brighter future in which the potential for successfully managing AD or even preventing it can become a reality for our older loved ones.

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