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Vol. 64, No. 2

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Alzheimer's New Science New Hope?

Since the '70s, Rochester scientists have been leading the way in uncovering the secrets of Alzheimer's. But only in the past few years have they, and others around the country, begun talking about "prevention" and "cures" for the disease.

By Mark Liu '87

Paul Coleman, professor of neurobiology and anatomy, received the 1999 Pioneer Award for Alzheimer's Disease Research, the highest honor given by the national Alzheimer's Association.

At the forefront of Alzheimer's research for more than 20 years, Coleman and his team have developed a technology to analyze the activity of several genes -perhaps as many as 20,000 -in a single cell simultaneously. The work could one day form the basis for a test to tell whether otherwise healthy people are in the earliest stages of the disease.

Dick Rankin '65 pays close attention to Alzheimer's research.

The debilitating neurological disease has become an entangled piece of his own family memories-like the day in 1992 when his mother called to say that his father no longer recognized her.

Or the day, weeks later, when his mother was hospitalized following a heart attack, and his father was staying with Rankin's sister. Normally mild-mannered, the elder Rankin had to be restrained by police after he flew into an unprovoked rage and chased his daughter with a pair of shears.

When Rankin's mother died days later, his father didn't remember that she had had a heart attack or understand that he was attending her funeral.

"He was just receiving his friends," Rankin says.

Rankin, who works for an information technology company in northern Virginia, helplessly watched Alzheimer's steal his father's sense of self and eventually his father's life, but the specter of the disease didn't vanish there. He's all too aware that studies indicate that offspring of sufferers stand at least a fourfold greater risk of having the disease than children whose parents show no signs of Alzheimer's.

That's why he wrote to Pierre Tariot, director of the Rochester component of the first nationwide, large-scale attempt to study whether Alzheimer's can be prevented. Rankin offered his services as a volunteer.

"I have a selfish reason for wanting a cure," says Rankin, who, ultimately, was not able to participate in the study.

Such preventive possibilities-unimaginable just a decade ago-and other genetic and medical insights are giving a new aura of hope to finding a solution to the chilling puzzle of Alzheimer's. And while the optimism is tempered with the medical caveat that the path to discovery is often filled with dead-ends and disappointments, researchers at Rochester and elsewhere are beginning to speak in terms of "prevention" and "cure."

"The question is simple: Can we delay or prevent the onset of Alzheimer's disease?" asks Tariot, who heads the University's part of the four-site national study. "It's really quite remarkable that we have progressed to the point where we can ask that question."

At Rochester, which throughout the '90s was one of only about 30 centers funded by the National Institutes of Health as an official Alzheimer's Disease Research Center, scientists have established a reputation for their innovative and promising discoveries. The multipronged assault includes:

  • Prevention and treatment, exemplified in the work of scientists such as Tariot, director of the University's Geriatric Neurology and Psychiatric Clinic at Monroe Community Hospital;
  • Genetic and neurological research, led by Howard Federoff, professor of neurology and director of the Center for Aging and Developmental Biology;
  • Detection, led by Paul Coleman, professor of neurobiology and anatomy and recipient of the 1999 Alzheimer Association's Pioneer Award;
  • Neurological function, led by Charles Duffy, associate professor of neurology;
  • And patient care, led by Nancy Watson, director of the Center for Clinical Research on Aging in the School of Nursing.

Smarter Mice
Using a line of genetically altered mice developed by his research team, Howard Federoff, director of the Center on Aging and Developmental Biology, and colleagues have shown that boosting the amount of nerve growth factor in the brains of the mice improves the animals' ability to learn new tasks.

In a pair of recent studies, center scientists found that "smart mice" that were challenged with new tasks developed more new neuronal connections-as much as 60 percent more-than mice who did not have the molecular boost.

The studies focused on activity connecting the basal forebrain and the hippocampus, two areas of the brain that are vital for learning and memory and of special interest to Alzheimer's researchers.

By most accounts, solving the mystery of Alzheimer's will take success on all those fronts. First identified in 1906 by German pathologist Alois Alzheimer, the biological machinery behind the disease has remained notoriously cryptic.

Conducting an autopsy on an elderly patient with symptoms of memory loss, disorientation, and profound physical and psychological dissipation, the German scientist pinpointed the now-telltale markers of the disease: clots of an abnormal protein, known as "amyloid protein," and broken pieces of nerve structures, known as "neurofibrillary tangles," littered throughout the cells of the brain.

As Rudolf Tanzi '80, professor of neurology at Harvard Medical School and director of the Massachusetts General Hospital's Genetics and Aging Research Unit, points out in his 2000 book, Decoding Darkness, the discovery was well known in the medical community. But it was considered of little clinical help, in part because the common version of Alzheimer's disease-known as "late-onset"-occurs in people over the age of 60, relatively late given human life expectancy
in the first half of the century.

Until the early '80s Alzheimer's was considered a "backwater disease," Tanzi notes, which didn't attract much attention from researchers. (For more on Tanzi, see AfterWords.)

By 2001, that view has vastly changed. And selfish or not, Rankin's interest in Alzheimer's research mirrors a growing national awareness of the disease's toll among older people in the United States and around the world. An estimated 4 million Americans now suffer from the disease, and as many as 14 million may be afflicted 50 years from now if no treatments or cures are found.

As medical advances have allowed people to live longer, healthier lives, symptoms once passed off as "senile dementia" have taken on new dimensions. As many as 20 percent of Americans between the ages of 75 and 84 years old and as many as 40 percent of Americans over the age of 85 are estimated to have late-onset Alzheimer's.

"No other neurodegenerative disease takes so many lives," writes Tanzi, who is investigating a genetic link to the disease.

Comprehending the toll has not simplified finding a solution. In some respects, the disease is similar to well-researched conditions like hardening of the arteries, in which an unwelcome protein blocks a critical pathway. In others, it resembles an overly rampant response of the body's own immune system to fight off an invader. Scientists debate whether the plaques and tangles are the cause of the disease or merely the destructive remnant of an underlying mechanism.

'A Family Catastrophe'

Alzheimer's is often called a cruel disease because of its gradual, relentless attack on the very things that make people who they are. The memory goes, then memories themselves fade until loved ones become strangers and the past disappears under an ever-
thickening fog.

When the disease strikes early, the cruelty is magnified manyfold.

Gregg Rice '71 (PhD) had just turned 50 when his unfailing sense of direction began to falter. Soon the biology professor at Mercy College in Dobbs Ferry, New York, was having trouble preparing for lectures. After numerous tests, only one possibility remained: early-onset Alzheimer's.

As many as 40 percent of Americans 85 or older have Alzheimer's, but early-onset Alzheimer's-occurring in people under 65-accounts for less than 5 percent of cases.

After the diagnosis, Rice's wife, Laura Macy Rice '69, '71 (Mas), read all the books on the subject she could find. Still, she couldn't quite fathom what was happening.

"Where we are now was really inconceivable to me three years ago," says Laura, who lives in Hastings, New York, and teaches high school English.

Where they are now is living separately, and mostly in silence. Gregg, known for his humorous lectures, rarely speaks. Last summer, he entered an assisted-living center, which relieved Laura of what she calls "the arduous, physical chore" of caring for someone who needs help simply getting into bed and eating.

But that hasn't made life easier overall.

"Every step is complicated," says Laura, who battles feelings of guilt and questions of whether she's doing the right thing.

And with the couple's two daughters still in their 20s, Laura is keenly aware that research points to genetic factors in Alzheimer's.

Gregg has had to leave the assisted-living center several times for aggressive behavior-something completely out of character for him. This is a common though lesser-known symptom in Alzheimer's, and one more way that the disease robs victims of their lives.

Laura calls Alzheimer's "a family catastrophe."

"It can lay waste to your finances," she says. "It can lay waste to your emotions."

Novelist Jonathan Franzen, in a New Yorker article last fall describing his father's battle with late-onset Alzheimer's, put it this way: "The disease's etiology is like the proverbial elephant-it looks like an inflammation of the brain but also like a disease of abnormal-protein deposition of the kind that occasionally strikes the heart and kidneys."

At Rochester, scientists have been tracking that etiological elephant since the late '70s, when researchers published their first paper on the disease.

In the thick of the hunt has been Federoff, professor of neurology, who has perfected a gene-transfer technique in mice that has made him a bright light in the fields of neurology and gene therapy. His technique involves slicing a piece of DNA, splicing in a new section, and introducing it into the brain, where a specific gene can then be "turned on" to produce a molecule called nerve growth factor. The result is what some people have dubbed "smart mice," which have improved abilities to learn.

His experiments indicate that the brain circuitry of the mice can be changed to create new neuronal growth in the spatial-learning centers. Only a few decades ago, it was thought that new growth in developed brains was impossible.

While Federoff has built a better mouse, so to speak, the implications are enormous. The mice experience growth in areas of the brain that are damaged in Alzheimer's-those involving memory and spatial learning.

Could this methodology be applied to humans? That's where more research will focus. But Federoff does say that, "from a purely technical point of view, yes, it can be done."

That wasn't the view of some scientists even a few years ago. When he began developing his innovative method, Federoff says that some researchers "thought it was folly" and lamented that he would spend years of his life on it. Even his grant was filed under "high-risk," which is science talk for "could easily fail."

Five years later, in October 2000, Federoff was named head of the newly established Nathan Shock Center of Excellence in Basic Biology of Aging at Rochester. One of only three other Shock centers nationwide, Rochester beat out a dozen institutions, including Harvard, Duke, and Baylor in earning the designation.

To establish the center, the National Institute on Aging awarded Rochester a grant of $2.5 million over five years. That's big money, but the kind of research done at Rochester can rack up big bills.

A walk through one of the labs where Alzheimer's research is done is a grand tour of cutting-edge technology. Among such "toys" as a micro-manipulator with a miniscule vacuum to suck up a single cell for study, neuroscientist Coleman feels right at home.

The professor of neurobiology and anatomy is considered the pioneering member of Rochester's Alzheimer's researchers, and he has the Pioneer Award to prove it. That's the highest honor that the national Alzheimer's Association bestows, and it comes with a $1 million research grant.

Coleman, who earned his Ph.D. from Rochester, also has done groundbreaking work with genes but in a different way from Federoff. Coleman and his team have developed a technique to study gene activity on an unprecedented scale-within single brain cells.

Motion Detector
Charles Duffy, associate professor of neurology, was intrigued when a disoriented Alzheimer's patient told him, "I don't forget where I'm going. I can't seem to keep track of myself along the way."

Since then, Duffy has carried out several experiments that indicate "motion blindness" is a cause of disorientation for Alzheimer's patients. Such tests could eventually be used as a
diagnostic tool to identify people who need further treatment.

They are on their way to charting the simultaneous activity of 20,000 genes in a single cell, trying to understand the molecular cause and effect of Alzheimer's. They hope to see precisely which genes activate, which genes are then turned on by those genes, and how the process leads to sick cells in the brain. Already, Coleman has found that many of the genes affected in Alzheimer's are the same ones affected in some cancers, leading to the possibility that the disease is actually a form of cancer.

That, for the time being, is theory. In practice, Coleman has developed an experimental blood test that might be able to detect the disease.

Even today, the only way to confirm a diagnosis of Alzheimer's disease is through an autopsy. To the afflicted and their families, physicians can offer only a probable diagnosis after ruling out other possibilities such as Parkinson's disease or strokes.

Common sense might say that it doesn't matter-if you've got it, there's little to be done. But recent discoveries prove that notion wrong. New studies indicate that Alzheimer's disease can exist in the brain decades-even in people in their 20s-before the effects are noticed. If a test existed to detect Alzheimer's in its earliest stages, treatments could short-circuit the disease's progress. Alzheimer's would be like a rising river that never overflows and therefore never does any real damage.

That's where another piece of the puzzle comes in: treatment.

"Certainly a predictive test is of little value unless there's an effective therapy," says Coleman.

A mile from Coleman's office, Tariot is running several clinical trials on drugs that have shown promise in stopping the progress of Alzheimer's.

"Ten years ago, we had no treatment at all. We now know that it is treatable," says Tariot. "Five years ago, the notion of prevention was scoffed at. Now, we have clinical trials going on."

Tariot cites the work of Rebekah Loy, a Rochester researcher in neurogeriatrics, who has discovered drugs that could alter the course of the disease.

Drug Test
Pierre Tariot, director of the University's Geriatric Neurology and Psychiatry Clinic at Monroe Community Hospital, is leading the Rochester component of a four-site national test to study whether powerful anti-inflammatory drugs known as cox-2 inhibitors can prevent the onset of Alzheimer's.

The $25 million, five-year study by the National Institute on Aging will compare the health of people older than 70 who are taking a traditional medication that inhibits both the cox-2 and cox-1 enzymes, a more potent cox-2 inhibitor, and a placebo. The research behind cox-2 inhibitors, which are commonly used to treat arthritis, was pioneered at Rochester.

Tariot's group of about 30 doctors, nurses, and other staff has conducted more than 100 studies of Alzheimer's disease involving more than 2,000 patients from the Rochester area.

Several studies have shown that Alzheimer's results, at least in part, from a damaging inflammation triggered by the body's own immune system.

Tariot's team is testing several drugs, including an anti-inflammatory known as "super-aspirin" (a class of drugs whose groundwork was pioneered at Rochester), to see if they can slow the progress of the disease.

In another meeting of basic science and clinical testing-the point where real-life solutions could emerge-Rochester's clinical researchers are evaluating Coleman's blood test.

Such collaboration represents one of the University's strengths, Coleman says.

"I think this place is somewhat unusual in that people come at it from all sides," he says. "It's very advantageous for clinicians and basic scientists to work together closely."

Neurology professor Duffy, agrees.

"The research has gone far more multidimensional," says Duffy, whose own work epitomizes "out-of-the-box" research. Interested in spatial orientation, or how we know where we are and where we're going while in motion, Duffy has come upon an unexpected discovery: When Alzheimer's sufferers get lost, it's not a memory problem but a visual problem.

The germ of the discovery came when Duffy met an Alzheimer's patient who was having trouble finding his way around. A classic symptom, but Duffy took notice when the patient said, "I don't forget where I'm going. I can't seem to keep track of myself along the way."

Using a machine that essentially simulates a snowstorm rushing at a windshield while driving, Duffy found that some Alzheimer's patients get lost because they experience "motion blindness." They have trouble interpreting if they or their surroundings are moving, if the snow is rushing by or they themselves are rushing by the snow.

Diagnosing the Economics of Alzheimer's Funding

The politics and economics of Alzheimer's research can be as complex and challenging as the science itself.

Even as research at Rochester has grown more promising, and even as its scientists win some of the most prestigious honors in the country, overall federal funding to Rochester for Alzheimer's research has decreased, in part because the University's multidimensional approach no longer fits within the confines of funding guidelines set out 15 years ago.

In the spring of 2001, the National Institute on Aging stopped funding Rochester as a designated Alzheimer's Disease Research Center, though the institute maintains Rochester as an "active center" because of the importance of the work done at the Medical Center.

As Howard Federoff, director of the Nathan Shock Center of Excellence in Basic Biology of Aging explains it:

"Rochester has gone beyond the conventional structure. We are really using cutting-edge techniques."

The national institute is in the process of rewriting its mandate, looking especially at funding the kind of genetics and advanced molecular biology studies that are Rochester's strengths.

"We know we're getting a little behind in certain areas," says Creighton Phelps, director of the institute's Alzheimer's Disease Center Program. "We definitely have to think about how we evolve the program."

Phelps says that Rochester might find a new niche under new rules.

The institute has asked Federoff, Paul Coleman, professor of neurobiology and anatomy, and Roger Kurlan, head of the Alzheimer's Center Clinical Core at the University-along with other scientists-to suggest ideas for a new mandate.

While Alzheimer's inflicts much of its damage to the hippocampus-the memory center of the brain-the disease also affects the area of the cerebral cortex responsible for interpreting motion.

Duffy has correlated motion-blindness with the "keep-in-lane" score on the New York State driver's exam. Alzheimer's patients, he learned, tend to drift between lanes while driving. Pinpointing such problems can drive clinical breakthroughs: Duffy hopes his work can help identify people at risk early on so that they can receive medication and other therapy.

Until therapies are ready, the growing population of people with Alzheimer's -and their families-will need care in coping with the damage already done.

At the School of Nursing, Watson and her team focus on the care of dementia patients and their quality of life. In a landmark study published in 1998, Watson and her team found that rocking in a rocking chair improved patients' psychological and emotional well-being and reduced their need for pain medication. Interest in the study was widespread.

"We got calls from nursing homes, institutions, clinicians from all over the world," Watson says.

In another recent study, Watson found that dementia patients in the middle of their decline are five times as likely to become intensely distressed and lose emotional control than patients either in the early or late stages of dementia.

"These patients may still be conscious of their cognitive losses, but they are losing their ability to cope or compensate for them, resulting in extreme emotional distress," says Watson.

Life Quality
Nancy Watson (left), director of the Center for Clinical Research on Aging in the School of Nursing, received the International Public Dissemination Award from Sigma Theta Tau, a national nursing honor society, for her 1998 study that showed rocking in rocking chairs can improve the emotional and psychological well-being of people with dementia.

The study is one of several that Watson has led on quality of care issues for people with late-onset Alzheimer's. For the rocking chair study, Watson and her team worked closely with residents of Kirkhaven, a Rochester nursing home. Watson is pictured with resident Julia Slusar.

"Caregivers have a tremendously difficult job, and this research could help them become more aware of who is most likely to have a problem," she says. "By understanding these reactions better, we may be able to lessen their impact and occurrence, improving the patient's quality of life during this phase of dementia."

Such findings are an invaluable benefit, caregivers say.

"There is a sense of hopefulness," says Sharon Boyd, program and public policy director for the Alzheimer's Association in Rochester. "Families know, within their own community, that there's a lot of research going on at the University, that their own community is involved."

But such complicated research takes years. It takes tenacity and creativity in the face of both scientific and funding obstacles.

It takes truly focused scientists-people such as Coleman, who has a diagram of a nerve cell displayed in his paper-packed office where some people might hang a pretty landscape.

As Watson says, "We would love to be out of business."

Until then, the closest thing to consolation that Alzheimer's has to offer is that many sufferers, in the end, are unable to realize that their awareness of the world is out of step or out of time. Rankin's father, in the three months after his wife's death, often thought she had simply gone out to get her hair done.

After moving to an assisted-living center, he wandered off several times, eventually walking for miles without shoes. He contracted pneumonia and died precisely three months after his wife.

"I don't think he ever recognized his wife was dead," says Rankin. "He was back in the early days of his marriage. And it was a happy marriage."

Mark Liu '87 is the editor of Rochester Medicine magazine.

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