Face to Face
The Memory Keepers
By Jeanne Mettner
At long last, the paths of Alzheimer’s disease researchers Ronald Petersen and Karen Hsiao Ashe have converged. And the result of their collaborations could be mind-altering.
Words don’t effectively convey the threat that Alzheimer’s disease poses to the future of the U.S. health care system. Calling it a growing problem seems underwhelming, and describing it as a looming epidemic sounds histrionic. Only statistics seem to accurately portray the grimness of the forecasted picture: According to the National Institute on Aging and the Alzheimer’s Association, about 4.5 million people in this country (slightly less than the population of Minnesota) suffer from the disease—a number the Alzheimer’s Association estimates could quadruple within the next 50 years.
With one in 45 Americans potentially being stricken with the disease by 2050, and with the cost of caring for today’s Alzheimer’s patients estimated at $100 billion annually, it’s easy to imagine how the disease could overwhelm the individuals and institutions that provide and finance care. Current therapeutic regimens continue to fall well short of halting the disease (at best, drugs for “treating” Alzheimer’s disease simply slow progression; at worst, they make no difference at all).
But in neuroscience labs across the country, the focus has shifted from treatment to prevention. And that’s where leaders in the field believe the solution to this looming problem lies. “Research is bringing us closer and closer to discovering what the cause is of this disease,” says Martin Ramsden, Ph.D, a research fellow with the University of Minnesota’s newly created N. Bud Grossman Center for Memory Research and Care. “Once we know what’s causing it, we can target its action or stop its creation.”
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The University of Minnesota’s Karen Hsiao Ashe has identified the proteins that cause memory problems in people with Alzheimer’s disease.
Photo courtesy University of Minnesota
Mayo Clinic’s Ronald Petersen discovered mild cognitive impairment is a precursor to Alzheimer’s disease. Now he is attempting to answer the hard question—why?
Photo courtesy Mayo Clinic. |
Leading the effort to better understand the mechanisms behind this disease that robs people of their being are two Minnesota researchers: Ronald Petersen, M.D., Ph.D., director of Mayo Clinic’s Alzheimer’s Disease Research Center, and Karen Hsiao Ashe, M.D., Ph.D., director of the N. Bud Grossman Center. Just one short year ago, the two scientists were on separate-but-parallel disciplinary tracks—Petersen’s in the clinic, Ashe’s in the lab—trying to unlock the secrets of this disease before the baby boomers reach their 70s, the decade when Alzheimer’s is most likely to take hold. Today, they are collaborating on what could become one of the most important studies to date for how to potentially stave off the disease.
The Aging Brain
Petersen’s interest in age-related dementia began when he received his doctorate in experimental psychology (now called cognitive psychology) at the University of Minnesota in the 1970s, but it “came to a head,” as he says, after he received his medical degree from Mayo Medical School in 1980. While doing a fellowship in behavioral neurology at Harvard University, he witnessed the terrible toll that the condition could exact on aging patients. “Alzheimer’s disease was the most common disorder encountered,” he recalls. That experience brought Petersen back to Mayo in 1986 to start the Alzheimer’s Disease Patient Registry. The project, funded by the National Institute on Aging, evaluated patients age 70 and older within Rochester who have both normal and abnormal cognition. (Petersen and his team are still tracking those patients, some of whom are more than 100 years old now.)
What Petersen discovered through his observations was a nebulous diagnostic area within age-related cognitive dysfunction that wasn’t being adequately addressed. “There were people who were not completely normal with regard to aging and memory, but they didn’t have the fully developed syndrome of Alzheimer’s disease,” explains Petersen, who first diagnosed Ronald Reagan with the disease in 1994. “There were many participants who were kind of forgetful, more forgetful than they ought to be, and so we began focusing on this in-between area that became known as mild cognitive impairment.”
In the late 1990s, Petersen began pulling together descriptions of patients with mild cognitive impairment and developed clinical criteria for characterizing it. (The criteria were published in the Archives of Neurology in 1999.) “It really took off from there,” he recalls. “Physicians were coming up to us and saying, ‘Yeah, I see those people, too. I never really know what to do because they are kind of in a gray area. But now we know what to look for, now I know what to call them.’”
In the years following, Petersen immersed himself in studying the precursory role that mild cognitive impairment played in the progression of Alzheimer’s disease. Using data from the registry, he and his team found that those people who exhibited symptoms of mild cognitive impairment were more likely to develop Alzheimer’s disease than normal, age-matched subjects who had no cognitive decline. About half of the individuals with mild cognitive impairment went on to develop Alzheimer’s disease within five years; within a decade, about 80 percent were afflicted with the condition. What Petersen wanted to know more than ever was why. And to find the answer to that question, he needed a true random, population-based sample that he could follow over time to watch how individuals’ brains aged.
It was not long before Petersen had that investigational infrastructure in place. In 2004, the National Institute on Aging agreed to fund the five-year, $7.5 million Mayo Clinic Study of Aging, which involves a random sample of about 2,000 Olmsted County residents ages 70 to 89 years who have no clinical dementia upon enrollment. Every 12 to 18 months, participants undergo clinical interviews; cognitive testing for memory, language, and executive function; and neurological exams. Participants also submit blood samples and complete questionnaires about their lifestyle, diet, exercise patterns, and intellectual activities. Although funding continues through 2009, Petersen has already determined that about 16 percent of the study population had mild cognitive impairment at baseline. Over the next few years, he will determine the rate at which people with mild cognitive impairment develop Alzheimer’s disease—and the rate at which cognitively normal patients develop mild cognitive impairment and/or Alzheimer’s disease, if they develop it at all.
Ultimately, he will use that data to arrive at a model for predicting a person’s chance of developing the disease. The hope is that people who are at greatest risk will then be the first to get preventive therapies—when they are developed. Explains Petersen: “If we had the aspirin for Alzheimer’s disease that we do for cardiovascular disease, then it would be no problem. But the idea is that when we develop these drugs that have an impact on the underlying disease process, they will be expensive and/or risky.” Given those constraints, physicians will have to evaluate their patients and determine who will be best served by such treatments. “That’s where the predictive model will become useful,” he says.
Of Mice and Memory
As Petersen was conducting his first study of Rochester residents in the mid 1980s, Ashe was completing her residency in neurology at the University of California, San Francisco (UCSF). Back then, she says, it was still somewhat unclear whether Alzheimer’s disease was a normal part of aging or a disease process, and, like Petersen, she was witnessing how debilitating the disease could be. “I was seeing patients who could walk and talk and move around, but when I began to get to know them, I realized that they had lost everything that had identified them with who they were—their memory, their emotions, their thoughts,” Ashe says. “And it was devastating to their families.”
As Petersen looked for answers to the Alzheimer’s conundrum on a clinical level, Ashe sought solutions in basic science laboratories. Developing a mouse model was a natural next step for understanding the intricacies of the disease. In the early 1990s, most of the research on Alzheimer’s was being done on autopsied material or in Petri dishes with cell cultures; a living model, she knew, would become increasingly essential for understanding the mechanisms of memory and cognition and evaluating the effectiveness of drugs and therapies.
While completing her postdoctoral work at the UCSF, Ashe helped develop a transgenic mouse in the lab of Stanley Prusiner, M.D., who later won the Nobel Prize for identifying the cause of prion diseases such as mad cow. In 1992, Ashe moved back to her home state, Minnesota, to direct her own lab at the university and create a line of transgenic mice in which Alzheimer’s disease could be replicated. Her painstaking persistence paid off in 1996 when she and her coinvestigators developed the first transgenic mouse that could mimic the memory loss and amyloid beta (A beta) plaques found with the human form of the disease. Known as Tg2576, it is now the most widely used transgenic mouse model for studying Alzheimer’s disease in the world. (In 2005, Ashe and her team developed rTg4510, a mouse model that mimics the tangles and severe neuronal loss found in persons with late-stage Alzheimer’s.)
Using the A beta mouse model, Ashe and her team have made some remarkable discoveries that have changed what we thought we knew about the disease. Even as far back as 1906, when Alois Alzheimer, M.D., first discovered the disease that now bears his name, scientists believed that the presence of plaques and tangles within the brain prompted the memory loss so characteristic of the condition. But in 2002, Ashe and her team determined that the plaques had little to do with the disease’s devastating effects; in 2005, her team determined that the tangles had little to do with them as well.
Instead, Ashe and colleagues believed it was the presence of two then-unidentified mutant protein molecules in the brain—A beta-star and tau star—that cause memory problems. A beta-star and tau-star are generated from A beta and tau, the molecules that create the plaques and tangles, respectively. In 2006, Ashe and her research team succeeded in isolating the elusive A beta-star molecule, which, when injected into healthy rats, produced memory loss similar to that observed in Ashe’s Tg2576 mice. (The tau-star molecule is still in the process of being isolated.) “We found the A beta-star molecule in a mouse that represents an early form of the disease—before there is any degeneration or death of neurons,” explains Ashe, who oversees most of the basic science research and animal studies of Alzheimer’s disease at the University of Minnesota. “Because of the way we found it, we believe that A beta-star is the abnormal molecule that initiates what causes Alzheimer’s disease. But that hypothesis can only be tested in humans.”
Meeting of the Minds (and Disciplines)
When you look at their CVs and hear their stories, it seems that Ashe’s and Petersen’s separate journeys toward demystifying Alzheimer’s disease seemed destined to converge. Each grew up in the Twin Cities area (Ashe in Arden Hills, Petersen in Anoka). Each had clinical experiences that led them to want to find a cure for Alzheimer’s disease. Each has worked with the same colleagues at different points in their careers and visited each other’s respective institutions to get updates on projects in the works. Each is eagerly described by peers as “dedicated,” “brilliant,” “persistent,” “creative,” and “hard-working.” Each has earned the coveted Metlife Award for Medical Research in Alzheimer’s Disease (Ashe in 2006, Petersen in 2004) and the American Academy of Neurology’s Potamkin Prize for Pick’s, Alzheimer’s, and Related Dementias, known in research circles as the “Nobel Prize of Neurology” (Petersen in 2005, Ashe in 2006). Each one has been serving on the National Institute on Aging’s Board of Scientific Counselors (Petersen since 2003, Ashe since 2004). And that’s when things started to click.
“We would get together two or three times a year in Washington, D.C., for this committee, and those are really the times when we talked about doing this collaborative work,” Petersen says. They discovered their research goals were parallel, with Ashe on the research track and Peterson on the clinical one. Early last year, during one of those meetings, Petersen and Ashe began talking in earnest about bringing Ashe’s lab discoveries to a clinical population. Ashe was already working with David Bennett, M.D., at Rush University’s Alzheimer’s Disease Center in Chicago, testing for the presence of A beta-star in the postmortem brain tissue of a small, nonrandomized sample of humans, and the results looked promising. (Ashe hopes to publish a paper on the findings later this year.) “Since we [at Mayo] had a good clinical population—elderly people who are being followed closely clinically but are not demented yet—we felt it would be a perfect test-bed for her [A beta-star] technology,” Petersen says.
Earlier this year, the Minnesota Partnership for Biotechnology and Medical Genomics, which funds researchers from the University of Minnesota and Mayo Clinic working on joint projects, awarded Petersen and Ashe a two-year, $850,000 grant. The researchers are hypothesizing that A beta-star will be present in the brain tissue of all patients with Alzheimer’s disease, in a subset of individuals with mild cognitive impairment (those who would have gone on to develop Alzheimer’s), and in a small number of individuals who were not affected but would have gone on to develop mild cognitive impairment and possibly Alzheimer’s disease had they lived longer. In order to test that theory, they will test for A beta-star in the postmortem brain tissue of 100 Mayo Clinic Study of Aging participants to determine whether it can be identified and measured to predict a person’s degree of cognitive impairment.
Next, Ashe and her team plan to develop a blood test and/or spinal fluid test for detecting A beta-star in living people. Ashe and Petersen hope to run that test on current and archived blood samples that Petersen has collected from his cohort of 2,000 nondemented elderly individuals. This is where the collaboration becomes most valuable. “If Ron hadn’t been conducting such a systematic evaluation of normal people, what we would have to do is enroll normal [cognitively healthy] people and then test them yearly to see whether they went on to develop Alzheimer’s disease, and that would take many, many years,” Ashe explains. She says developing the test could take a year or two. “Once we validate it, running the [stored blood] samples may take just a few months.” Petersen has received another National Institute on Aging grant to continue this work using participants in his longitudinal studies that likely will begin in 2009, once the blood test for detecting A beta-star has been validated.
Racing Time
Petersen and Ashe, both of whom are baby boomers themselves, are keenly aware of the urgency of their research—and the need for solutions with immediate clinical application—even in a climate of ever-decreasing NIH funding. Along with seeking additional grants to continue their work, they have been pushing the accelerator to raise awareness about and promote additional research into Alzheimer’s disease. Ashe, for example, chose not to license exclusively her amyloid mouse model in order to make it more readily available to other researchers looking for a cure. She has also structured her lab in a way that allows investigators such as Ramsden to focus on frontier-breaking work while expert technicians maintain the valuable mice, evaluate memory in them, and prepare samples.
Petersen is constantly looking for ways to collaborate with other researchers both within Mayo and elsewhere in order to help prevent or find effective treatment for the disease. “We are pushing genetic research, refining diagnostic criteria, and employing new imaging techniques,” he says, adding that in September Mayo opened a new neuroimaging facility.
One of the biggest frustrations in terms of making progress, in Ashe’s opinion, is the cost of testing drugs that could prevent or slow the progression of the disease. “It currently costs $100 million to test one drug, and drug companies cannot afford to fail if they are going to spend that much money on a prevention trail.” That makes the development of a test that can predict who is at greatest risk for Alzheimer’s disease all the more important—and all the more pressing.
Says Petersen: “If we don’t arrive at some meaningful solution by the time the baby boomers get to a significant period of risk, the projections are that the number of people with Alzheimer’s disease will swamp the medical system. It’s not an option for us to say, ‘Gee, it would be nice if we get there.’ We have to get there. It’s incumbent upon us to do it.” MM
Jeanne Mettner is a freelance writer in Minneapolis.