Research on Alzheimer's disease is at a critical juncture – a time when important insights about potential treatments from basic, animal, and epidemiological studies are ready to be tested in human clinical trials. But primary prevention trials in Alzheimer's are challenging and expensive to conduct, involving large numbers of healthy, elderly participants studied over long periods of time. Usually, participants have to come in to the clinic for baseline testing or investigators must visit homebound patients. Follow up testing usually occurs every six or 12 months. Frail, older participants are often more prone than younger patients to drop out of a study or stop taking the medicine. They also may pass away during the study.
"The high costs and complex logistics of these trials are major obstacles that must be overcome," said William Thies, Ph.D., vice president for Medical & Scientific Affairs at the Alzheimer's Association. "The National Institute on Aging, in partnership with the Alzheimer's Association, is making exciting progress in expediting prevention trials for Alzheimer's disease."
One current trial of ginkgo biloba for prevention of Alzheimer's sponsored by the National Institutes of Health (the National Center for Complementary and Alternative Medicine (NCCAM), with additional support from the National Institute on Aging (NIA)) involves studying more than 3,000 participants aged 75 and older for at least six years, and will cost more than $24 million.
Steven T. DeKosky, M.D., director of the Alzheimer's Disease Research Center at the University of Pittsburgh and Alzheimer's Association Board member, leads the ginkgo investigation, termed the Ginkgo in Evaluation of Memory (GEM) study.
"The GEM study shows us that we can successfully recruit large numbers of dedicated older citizens who are 'doing this for their children and grandchildren,'" said DeKosky. "While we will learn whether there is a role for ginkgo biloba in prevention of Alzheimer's, we are also gaining invaluable information about the course of cognitive changes in late life, and that will help us design future studies more efficiently and complete them more quickly."
The Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT), another large prevention study, has enrolled 2,500 of an intended 4,000 or more participants at a cost so far of about $25 million. This study, of naproxen and celecoxib, two non-steroidal anti-inflammatory drugs (NSAIDS), will test whether these medications can help prevent Alzheimer's in cognitively normal people with a family history of the disease.
The study's leader, John Breitner, M.D., of VA Puget Sound Health Care System and the University of Washington, notes, "ADAPT provides a compelling example of the difficulties and potential rewards of primary prevention trials in Alzheimer's using traditional methods. The preliminary data that NSAIDs can prevent Alzheimer's is very encouraging, but the treatments have known side effects and there are real difficulties with administration of these or other biologically active compounds to seniors in trials over several years."
"Clinical trials are the only way we can find out what works for patients and what doesn't," says Marcelle Morrison-Bogorad, Ph.D., Associate Director of the NIA for the Neuroscience and Neuropsychology of Aging Program. "We need to reduce the time it takes to do these studies, cut the costs involved, and find ways to conduct effective studies with fewer numbers of participants. Addressing these challenges is an increasingly important part of the national Alzheimer's research agenda."
Prevention Instrument Project
The Prevention Instrument Project (PIP) is attempting to develop more efficient tools, such as home-based testing, so that Alzheimer prevention trials will be easier to do, less costly and less burdensome on participants and scientists. Steven Ferris, Ph.D., of the New York University School of Medicine, principal investigator for the project, presented the first findings from PIP at ICAD, showing that certain of the new home-based tests were valid when compared with those delivered in the clinic. PIP is part of the NIA-supported Alzheimer's Disease Cooperative Study (ADCS) clinical trials consortium.
"We're trying to find out if we can reduce the need for the participants to come in to the clinic," Ferris said. "We can save considerable time and expense if the participants don't have to come in so often."
ADCS investigators, many of whom are in the NIA's national network of Alzheimer's Disease Centers (ADCs), are developing and testing a variety of new "at-home" and "over-the-phone" instruments for six key areas: cognitive assessment by telephone, global assessment, activities of daily living, cognitive function mail-in assessment, quality of life, and service and resource use. Both the person participating in the study and their study partner will complete these tests.
PIP is being run like a small-scale prevention trial. Five hundred fifty (550) people are being tested for dementia with annual follow-ups for four years. All participants will be assessed with conventional instruments and try out the new tests. Half will try out the new tests in the clinic, and half will do them at home and mail them in. In this way, the new test instruments can be compared to existing methods, and remote participation can be compared with clinic results.
The team also is doing a pilot study with 55 people investigating web-based versions of the new tests. "It's like you are buying something on eBay, except you're filling out questionnaires," said Ferris. "Ten years from now, I think most elderly will be web users."
Imaging and Genetics Initiatives
Another route to expedite Alzheimer prevention trials is to identify those people most likely to get the disease in the next five years and recruit them into the studies. By finding the people most at risk of Alzheimer's disease, prevention studies could be done with far fewer people.
The Alzheimer's Association and the NIA are collaborating on two important initiatives, one in search of additional genes which may increase risk for late-onset Alzheimer's and the other a neuroimaging initiative seeking new ways to identify people who will develop Alzheimer's as well as measure whether drugs under study are effective.
Morrison-Bogorad described the Alzheimer's Disease Genetics Study, a nationwide push to find genes that play a role in late-onset Alzheimer's disease, the most common form of the disease. In major collaboration with the Alzheimer's Association, the NIA is stepping up efforts to create a large bank of genetic material, cell lines, and data from families with at least two siblings with late-onset Alzheimer's to identify those genetically predisposed to Alzheimer's. Scientists will use the data bank from these 1,000 families – some 350 families have been enrolled so far – to discover the risk factor genes that contribute to late-onset Alzheimer's.
"Discovery of risk factor genes will help illuminate the underlying disease processes, open up novel areas of research, and identify new targets for drug therapy," Morrison-Bogorad added. "Those who carry these risk factor genes would be high priority participants in Alzheimer prevention trials."
On another front, one of the most potentially fruitful areas in the search for valid biomarkers that would identify those at greater risk for Alzheimer's involves use of advanced imaging technologies, such as PET and MRI to "see" functional and structural changes in the brain. The NIA, with the support of the Alzheimer's Association, is bringing together scientists from academic medicine, industry, and the government in a Neuroimaging Initiative expected to start in late 2004.
Scientists hope to determine whether MRI and PET scans, or other imaging or biological markers, can be used to identify changes and progression of Mild Cognitive Impairment and Alzheimer's disease. One day, these measurements may be able to identify those people who are at risk of Alzheimer's before they develop symptoms and to more effectively assess efficacy of drug interventions.
As these projects move ahead, the Association and the NIA are working together as well to inform the public about currently-recruiting clinical trials, the benefits and cautionary notes about participating, and how potential participants can sign up. Each organization's website contains information about these trials, and news releases and articles offer regular updates on ongoing and new studies.
The 9th International Conference on Alzheimer's Disease and Related Disorders (ICAD), presented by the Alzheimer's Association, is the largest gathering of Alzheimer researchers in history. More than 4,500 scientists from around the world will present and discuss the findings of 2,000 studies showcasing the newest treatment advances in Alzheimer's disease and steps toward prevention. ICAD will be held July 17-22, 2004, at the Pennsylvania Convention Center in Philadelphia, Pennsylvania.
The Alzheimer's Association is the world leader in Alzheimer research and support. Having awarded more than $165 million to nearly 1,400 projects, the Alzheimer's Association is the largest private funder of Alzheimer research. To sustain the rapid progress, the Association calls for $1 billion in annual federal funding for Alzheimer research. For more information about Alzheimer's disease, visit www.alz.org or call 800-272-3900.
· Steven Ferris P1-407 – ADCS Prevention Instrument Project: Overview and Initial Results (Sun., 7/18, 8:00 am)