FEATURE — Winter 2007

Photo: Digital Vision Ltd./Superstock, Collage: Donna Boyd

Seeking the ‘Mind’s Thief’

Across the University, scientists dedicate themselves to discovering the intricacies of diseases that rob older adults of their mental capabilities. Great strides are being made, especially toward understanding the early stages of Alzheimer’s.

By Candace O’Connor

What disease do you fear most? In 2006, that was the question posed by MetLife Foundation interviewers to more than 1,000 Americans over the age of 18. In the survey, several life-threatening problems—diabetes, stroke, heart disease, and cancer—attracted votes. But the most frightening to adults 55 and older was Alzheimer’s disease, often called the “mind’s thief,” since it cruelly steals language, memory, even personality before extinguishing life itself.

“The reality is that Alzheimer’s disease is an epidemic,” says John C. Morris, the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology and professor of pathology and immunology and of physical therapy. With five million Americans affected, “our health-care system is already under stress, and as baby boomers age that could bankrupt the system.”

For 25 years, Morris has worked at the heart of the University’s groundbreaking efforts to combat this fearsome disease. He is director of its Alzheimer’s Disease Research Center (ADRC), a collaborative effort of some 200 University researchers that ranks at the top of the 32 such centers supported by the National Institute on Aging (NIA). He also heads the campus-wide Harvey A. Friedman Center for Aging, which promotes initiatives that help older adults remain healthy and active.

Within the ADRC, Morris’ colleagues come from a rich mix of disciplines. Molecular biologists and geneticists are tracing the roots of Alzheimer’s and investigating the causes of cell death within the brain, while neurologists are moving basic science toward the bedside by identifying biomarkers that predict the disease. Radiologists are using new imaging agents in brain-scanning projects to evaluate the risk or progress of Alzheimer’s.

“What each of us does is scientifically quite different yet complementary,” says Eugene M. Johnson, Jr., the Norman J. Stupp Professor of Neurology and professor of molecular biology and pharmacology. “Even though my work is very basic, I have always enjoyed working with the ADRC because it represents an integrated effort to understand this disease and, ultimately, to do something about it.”

The Alzheimer’s Disease Research Center includes some of the pre-eminent scientists working on Alzheimer’s disease today. Morris, David M. Holtzman, and Alison M. Goate all have won the two major awards in Alzheimer’s research—the MetLife Foundation Award for Medical Research and the Potamkin Prize from the American Academy of Neurology—a record unmatched by any other center. In 2006, three Alzheimer’s researchers—Holtzman, Randall Bateman, and John Cirrito—were named to the Scientific American 50, a list of scientific “prime movers.” Some ADRC members have leadership positions within the field, including Morris and Johnson who have both served on the council of the NIA.

“Last week, I was visiting a leading researcher in California, and he said: ‘You have the best ADRC in the world,’” says Holtzman, the Andrew B. and Gretchen P. Jones Professor of Neurology and professor of molecular biology and pharmacology. “Lots of people think that. We have incredibly good physicians and scientists, and they all work together well; we also have had strong leadership. Altogether, it creates a great environment.”

Dementia Research Spans Four Decades
The ADRC owes its existence to Leonard Berg, A.B. ’45, M.D. ’49, a revered St. Louis clinician and later full-time neurology faculty member, who died in January 2007. In his own practice, he had seen patients with dementia and, convinced that it was not a normal part of aging, wondered about its cause. Though Alzheimer’s disease had first been identified by German physician Alois Alzheimer in 1906, little was known about it.

John C. Morris (right), the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology, director of the Alzheimer’s Disease Research Center (ADRC), and director of the Friedman Center for Aging, examines a research subject’s MRI brain scan with neurologist Joy Snider, an ADRC colleague. They are searching for any indicators of Alzheimer’s disease.

“In the early 1970s, Leonard asked the neurology chair, Bill Landau, whether he could convene a multidisciplinary group—neurologists, psychiatrists, radiologists, statisticians—to discuss what they knew about dementia,” Morris says. “They met on Tuesdays for a brown-bag lunch and eventually decided there were few prospective studies of dementia. So they said: ‘Why don’t we study it?’”

Berg became a kind of “Pied Piper” for dementia research. Recalls Johnson: “More than 20 years ago, Leonard went around the University identifying people who were doing science related to dementia and said, ‘Why don’t you come work with us?’ He would also negotiate with department chairs who did the hiring and ask, ‘Can you help us by recruiting someone we need for our research?’”

Twice Berg and his colleagues submitted a grant application to the National Institutes of Health (NIH) but failed to get funding. Reviewers asked why they had not included experts on aging from the University’s Department of Psychology, particularly distinguished faculty member Jack Botwinick and young researcher Martha Storandt. With their help, Berg re-submitted the application, and in 1979 he received a grant from the National Institute of Mental Health that evolved in 1984 into a program project grant called Healthy Aging and Senile Dementia (HASD). Funding for it has been renewed ever since.

So in 1979, they began studying senile dementia, particularly the mild, early stage of the disease, tracking changes that mark its onset. As part of that work, Berg and Charles Hughes, H.S. ’71, developed the Clinical Dementia Rating (CDR), now the standard worldwide system for evaluating and staging dementia; its latest version, with refinements by John Morris, was published in 1993.

They also evaluated study participants—some with mild dementia and others without—enrolling 117 people at first. By the time of Berg’s death, they had followed more than 3,000 people over 30 years. “They called that clinical research arm the ‘Memory and Aging Project,’” Morris says. “They didn’t want a pejorative term such as dementia or Alzheimer’s disease on the door—and that is still what we are called.”

Morris joined the group in the early 1980s and helped persuade Berg that they should apply to become one of the 10 original ADRCs funded by the NIA. That application succeeded, and the University’s ADRC’s funding has been consistently renewed to this day. While it overlaps with the HASD program project grant, most of the University’s clinical research is done through the HASD and its basic research through the ADRC.

Berg, a visionary but also a great gentleman, brought camaraderie to the dealings of those 10 centers. “Through their stature, good will, sense of humor, congeniality, and respect for everyone, Leonard and a few other giants in the formative period of the centers set a tone for cooperation that continues to this day,” Morris says.

Eventually, a major stroke ended Berg’s tenure as head. Before his retirement in 1998, he had developed a careful succession plan in which Morris and Eugene Johnson took over as co-directors of the ADRC and Morris as principal investigator of the HASD grant. Upon Berg’s retirement, Morris and the ADRC created the biennial Leonard Berg Symposium in his honor.

Not long before Berg suffered his stroke, Chancellor Mark Wrighton had asked Berg to establish a Center for Aging that would focus on aspects of aging beyond disease. This effort, which came to fruition in 2001 under Morris’ leadership, was inspired, funded, and facilitated by St. Louis businessman Harvey Friedman who, with his wife Dorismae Hacker Friedman, A.B. ’42, took a pioneering interest in academic programs on aging. In September 2007, the Center for Aging was re-named in Harvey Friedman’s honor.

Investigating Brain Changes: John Morris
Over the years, Morris has added many hats. Today, he is also head of the Aging and Dementia Section of the Department of Neurology and director of the Memory and Aging Project, and he leads a pioneering program project grant, The Adult Children Study. He is a respected researcher, with a focus on early-stage Alzheimer’s disease.

“Some people are doing fine mentally but are developing brain changes that will eventually cause dementia,” Morris says. “In The Adult Children Study, we are following healthy adults, 45 years and up, half of whom had parents with Alzheimer’s. We’re assessing when the earliest changes in memory and personality occur, and will evaluate genetic factors and changes in proteins suspected to be linked to Alzheimer’s.”

While the occurrence of the disease doubles every five years past 65, that still leaves many older adults with normal cognition. Morris has learned much about these people, some of whom serve as controls in the Alzheimer’s studies. In his Center for Aging role, he has been interested in factors that allow them to remain productive and stay in their homes.

He and the ADRC also have participated in some 30 clinical trials of agents—vaccines, antibodies, secretase inhibitors—intended to prevent, arrest, and treat the disease. For example, in 1987, he led the ADRC in a multi-center trial that resulted in the first drug approved for Alzheimer’s treatment.

Among the accomplishments he most values is a piece of Berg’s legacy. “Following in Leonard’s footsteps, I have tried to coalesce the extraordinarily talented people here and bring their multidisciplinary abilities together in productive collaboration,” he says. “Washington University is known for interaction and collegiality. People turn to us first whenever they have new studies because we do it, we do it well, and we do it together.”

Basic Molecular Research: Eugene Johnson
In his leadership role, Berg recruited Johnson, a basic scientist, to work with the ADRC. After Berg left the ADRC leadership, Johnson and Morris shared the role for a few years, then Johnson shifted into the associate director position. Some of his own research into the molecular mechanisms underlying neurodegenerative diseases—Alzheimer’s, Parkinson’s, Huntington’s—has received ADRC support.

“If you are interested in neurodegenerative disease, Alzheimer’s is the mother of them all in terms of the number of people affected and the impact it has—socially, economically, emotionally,” Johnson says. “Clearly, from a public health point of view, it is the most devastating and costly neurodegenerative disease.”

Although he has focused on broad developmental biology questions that apply to a number of diseases, two major aspects of his work may influence Alzheimer’s research. One is his decades-long effort to elucidate the mechanisms by which neurons die during normal development, and how those mechanisms might be related to ways in which neurons die in neurodegenerative disease.

Another is his work, in collaboration with pathologist Jeffrey Milbrandt, on the biology of “neurotrophic” factors: molecules that help control whether neurons live or die. They have discovered three such factors and have tried to shed light on the physiology of these molecules and the mechanisms by which they work. “We have helped to demonstrate which cell types are responsive to these factors, and that will help to indicate in which diseases they might be useful,” he says.

Genetic Roots of Alzheimer’s Disease: Alison Goate
Alison M. Goate, the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry and professor of genetics and of neurology, is a pioneer in Alzheimer’s research. In 1991, she won international renown for her discovery, published in the journal Nature, of a mutation in the beta-amyloid protein precursor gene on chromosome 21 that is linked to an inherited form of Alzheimer’s disease. This mutated gene produces amyloid-beta, found in plaques deposited in the brains of Alzheimer’s patients, and Goate’s work has strengthened the hypothesis that amyloid-beta abnormalities are central to the development of the disease.

Since that breakthrough, she has identified mutations in four other genes—two that cause familial, early-onset Alzheimer’s and two related to frontotemporal dementia—with patients recruited through the ADRC. She and her staff now have close ties to 10 to 15 early-onset families, who live with a grim certainty: 50 percent of their children will develop Alzheimer’s before they are 60 years old.

Still, most cases of Alzheimer’s are not inherited but “sporadic,” and Goate is working to understand the risk factors involved in this late-onset disease. In 2000, she and her group reported a possible linkage to chromosome 10, but further studies failed to identify a new gene. Now they are part of an NIA-sponsored consortium that will scour the genome for new risk genes.

“The long-term hope of genetics is that if you understand enough about the risk factors you can identify who is at highest risk and develop novel treatments based on the new understanding of the causes and risk factors for disease,” says Goate, also associate director of the ADRC, “and when you have identified these people, you can offer them treatment.”

Professor David Holtzman, chair of the Department of Neurology, holds cerebrospinal fluid (CSF), which bathes the brain. Researchers in his lab use CSF to identify biomarkers that help aid in the diagnosis of, and in predicting outcomes in, Alzheimer’s disease.

Biomarkers: David Holtzman
What causes amyloid-beta protein to build up in the brain and lead to Alzheimer’s disease? When David M. Holtzman came to the University in 1994, he began developing animal models to find out. Over the years, his research has shown one of the probable explanations: that the E4 form of apolipoprotein E (apoE) appears to accelerate the process by which amyloid-beta buildup occurs—making the inheritance of apoE4 the strongest genetic risk factor for the disease.

The apoE protein is not all bad; in fact, it normally shuttles cholesterol and lipids from cell to cell in the brain. But it influences late-onset Alzheimer’s in that it appears to take on a more insidious function by carrying around amyloid-beta and allowing this protein to accumulate and damage brain cells.

“If we modify apoE in the brain—causing it to be at higher or lower levels or have more lipid or cholesterol linked with it—is that a way to potentially treat the disease?” asks Holtzman, who is also chairman of the Department of Neurology and associate director of the ADRC. “Recently, we have found that if you cause the apoE to be more associated with lipid, that this remarkably delays the buildup of amyloid.”

As a graduate student in the Holtzman lab, John R. Cirrito, Ph.D. ’04—now a postdoctoral research associate in neurology and psychiatry—developed a technique to aid this research. By placing a small probe in the brain of the mouse model of Alzheimer’s, they could sample the level of amyloid-beta, hour by hour, day by day, and measure in real time the effect of the apoE manipulation.

The Holtzman group also has worked on a solution to the amyloid-beta buildup: the use of antibodies to clear it from the brain and the blood. A pharmaceutical company since has licensed this concept and is in Phase II trials of a commercial method to treat Alzheimer’s patients; however, proof is still years away.

ADRC member and Holtzman collaborator Anne M. Fagan, research associate professor of neurology, is focusing on biomarkers in the cerebrospinal fluid (CSF) and blood that indicate the disease is developing long before the patient has overt symptoms. Working with radiologist Mark Mintun, she has measured the amyloid-beta levels in the CSF, along with the levels of another molecule called “tau,” and found that those levels are highly predictive of who will become demented. If they can catch the disease at this point, that opens the possibility of reversing damage to the brain before neurons dysfunction and die.

Next, Holtzman and his colleagues will explore further the synthesis and clearance rates of apoE and other proteins in mouse models. “In animals and humans,” he says, “we are trying to understand protein metabolism in the brain, because we think that is what underlies Alzheimer’s disease and will likely lead to new treatments.”

“In animals and humans,” Holtzman says, “we are trying to understand protein metabolism in the brain, because we think that is what underlies Alzheimer’s disease and will likely lead to new treatments.”

Randall Bateman, assistant professor of neurology, meets with Elfriede Faulstich and her husband, Al Faulstich. Elfriede is a research participant in a study that directly measures the production and clearance rates of brain proteins. Bateman explains how the cerebrospinal fluid is collected through a small catheter.

Age, the Biggest Risk Factor: Randall Bateman
The greatest risk factor for Alzheimer’s disease is not family history, head trauma, or education level. “Nothing comes close to the effect of age in the risk of Alzheimer’s disease,” says Randall Bateman, assistant professor of neurology. “So we want to answer the question: What is it about aging that creates this increased risk?”

With a Paul B. Beeson Career Development Award in Aging Research, Bateman and his lab are studying the effect that aging has on amyloid-beta production. They hypothesize that, as people get older, their bodies’ ability to produce and clear away this protein undergoes a change, making them more at risk for its accumulation. Those who do not develop Alzheimer’s likely have an enhanced ability to remove or clear away this protein.

“One analogy is a faucet with water pouring into the sink and a drain with water running out,” he says. “We’re actually measuring how fast the water is pouring in and how fast the sink is draining. We think there will be an imbalance in Alzheimer’s disease: Either the faucet is putting out more amyloid-beta than the drain can handle or the drain is getting clogged, causing the amyloid-beta to build up to toxic levels.”

As yet, they don’t know which is true. In an initial study of young adults, they demonstrated that the sink and drain were working much faster than expected, though scientists have long thought amyloid plaques are slow-growing. Now Bateman is also working on another aspect of this problem: testing amyloid-beta modulating agents as treatments for the disease itself.

Early Detection Through Imaging: Mark Mintun
Since imaging is a key component of many brain studies, Mintun and his radiology colleagues often collaborate with other ADRC members on their Alzheimer’s-related research. He and Goate are studying the brains of sibling pairs over 70 with a goal of pinpointing genetic markers for an increased risk of Alzheimer’s disease.

With the help of the University’s cyclotron facility, headed by radiochemist Robert H. Mach, Mintun and John Morris have undertaken a series of studies involving “PIB,” an exciting new imaging agent that they use to identify amyloid plaques in adults with no outward signs of Alzheimer’s disease. They inject the subject with PIB, labeled with a short-lived, radioactive tag; it circulates rapidly in the body and sticks firmly to the plaques, which are easy to see on PET scans.

“So far, a fairly large number of people—up to 30 percent—have no symptoms but do indeed have plaques,” says Mintun, M.D. ’81, professor of radiology, director of the Center for Clinical Imaging Research, and interim director of the Division of Radiological Sciences. “Thus, we believe we are seeing changes in the brain prior to any symptoms. We also are identifying regions of the brain, such as the precuneus, that seem to turn positive early in this process.”

Once effective treatments are available, this knowledge may help such patients avoid cognitive symptoms. In fact, Mintun is optimistic that science will eventually deal this disease a fatal blow. “With the coming together of these new imaging techniques for the early detection of Alzheimer’s, and the new treatments that are being tested,” Mintun says, “my hope is that people of my generation won’t have to face Alzheimer’s disease.”

Candace O’Connor is a freelance writer based in St. Louis and author of the history book Beginning a Great Work: Washington University in St. Louis, 1853–2003.