Alzheimer’s: Progress Toward Elusive Cure

By Peter Saalfield ’06

As a young neurologist at Massachusetts General Hospital in the early 1960s, Don Price ’56 often encountered elderly patients who were losing their memories. Typically the mental lapses were trivial at first —misplaced car keys, forgotten appointments, a jumbled sentence here and there. But they eventually grew profound and painful: friends became unrecognizable and families forgotten. Ultimately, these people became strangers to themselves, tortured by awareness of growing debility and lost in a fog of confusion.

At that time, Alzheimer’s disease was rarely diagnosed and was not well understood. There was little Price or other physicians could do. They diagnosed “senile dementia,” prescribed sedatives and counseled families.

“When I was in Boston, old people with cognitive impairments would be discharged to one of the local chronic disease hospitals, like McLean Hospital in Belmont, and they would remain there until they developed an intercurrent illness and passed away,” says Price, who later became director of the Alzheimer’s Disease Research Center at The Johns Hopkins University School of Medicine. “There was nothing much you could do.”

The inability to help these patients pained Price, and, in 1971, he left clinical medicine to do research on neurodegenerative diseases full-time. In the ensuing decades he pushed the boundaries of our knowledge of Alzheimer’s disease, establishing a reputation as one of the nation’s chief authorities on the illness and as a mentor of many protégés who continue the research today.

Price’s work has helped establish the cellular and molecular basis of a broad range of neurodegenerative diseases that attack nerve cells, including amyotrophic lateral sclerosis, Huntington’s, Parkinson’s, and Alzheimer’s, which is the most prevalent of these disorders. His work has opened new avenues for development of treatments for them. For example, discoveries made with colleagues at Hopkins in the early 1980s led to the first FDA-approved Alzheimer’s drug, Aricept.

“He’s been at the forefront of addressing in mechanistic ways what causes neurodegeneration,” says Janice Naegele, Wesleyan professor of biology and neuroscience and behavior.

Even as Alzheimer’s verges on the status of an epidemic, there are no cures, which means there is still a great deal to do in dealing with a major unmet need in medicine—developing mechanism-based therapies. In the United States alone, there are more than 5 million cases of Alzheimer’s disease, and there are an estimated 35 million affected individuals worldwide. As modern medicine continues to extend the limits of the human lifespan, some experts expect these numbers to double by 2030.

Still, Alzheimer’s is now one of the best understood of all major neurodegenerative disorders, giving Price far greater optimism about the prospect for meaningful new treatments than was warranted even a decade ago, he says.

Price’s work on developing approaches for modeling Alzheimer’s in mice, along with similar work conducted by other scientists, has yielded important clues about the risk factors, character, progression, and treatment of the disease in humans. These studies have opened the door for the creation of so-called “smart” Alzheimer’s drugs, which are intended to strike the disease at its cellular, biochemical and molecular roots, rather than merely addressing clinical symptoms.

“We have real targets,” he says. Biotech and pharmaceutical companies, he points out, are working on compounds that cross into the brain, are efficacious, and safe.”

Price’s approach to science has been defined by the belief that in order to defeat brain diseases, we must first know them—the risk factors, disease mechanisms, critical pathways, potential therapeutic targets, and possibilities for interventions in animal models and then in patients. He has a reputation for never accepting untestable explanations.

“Don is a consummate scientist,” says Sangram ‘Sam’ Sisodia, a neuroscientist at the University of Chicago who got his start in Price’s lab at Hopkins in the early 1990s. “He is a no-nonsense guy. He is all about digging deep, using whatever approaches one can find that will allow us to understand extremely difficult and challenging problems.”

In the early 1980s, Price began studying a neurochemical pathway in the brain known as the “cholinergic system,” which plays an important role in learning and memory.

One day, during an autopsy on an Alzheimer’s victim, Price and his colleagues discovered that the system wasn’t merely damaged, as they expected, but destroyed.

“If there was an ‘aha!’ moment for us, it would be looking at microscopic slides of the brain of a control patient compared with  the slides of an elderly gentleman from Baltimore who had AD,” says Price. “We realized that the basal cholinergic cells in the AD patient were destroyed. This observation gave rise to the idea that if one could promote their survival or enhance their function for a while, one might possibly see a remission of the disease.”

The discovery was heralded in the press. Drug companies, hopeful that reinforcing the cholinergic system might delay or even cure Alzheimer’s, directed resources at developing new targeted medicines.

Price himself was not convinced: He didn’t believe that the disease was restricted to a single neurochemical system in the brain. By the time an effective drug was developed nearly 15 years later (Aricept was approved by the FDA in 1996), he and his colleagues had long moved on to new inquiries.

“People said Aricept was going to be the cure,” he recalls. “I never thought it was going to cure the illness. I thought that it was going to provide, at most, mild symptomatic relief for a brief time, and that’s about what it did.”

One key to Price’s success has been his eagerness to use the concepts and methods of scientific disciplines other than his own—biochemistry, molecular biology, and genetics among them. This attitude often led him to recruit younger scientists with different approaches and skills. Price has mentored dozens of protégés over the years, some of whom are now leaders in researching Alzheimer’s disease and other neurodegenerative disorders.

Sisodia, a molecular biologist by training, was a young post-doctoral scholar in molecular biology when he walked into Price’s lab looking for an opportunity.

“Don and I cut a deal,” says Sisodia, who now directs the University of Chicago’s Center for Molecular Neurobiology. “He said, ‘I know relatively little about molecular biology, but I do know something about the brain and its diseases.  If you come here I’ll teach you everything that you need to know about the brain. What you need to do is take us into the 21st century.’ We shook hands, and it was done.”

Together Price, Sisodia, and their colleagues bridged a gap between brain science and molecular biology, enhancing our understanding of the cellular/molecular basis of brain diseases. Sisodia sees himself a member of what he calls “the empire of Don Price.”

In similar fashion, by working with molecular biologist Phil Wong, now a professor of neuroscience at Johns Hopkins, Price and Sisodia were able to introduce mutant genes into the brains of mice so that they developed many of the clinical and pathological-biochemical features of Alzheimer’s. Called transgenics, this approach, in which mutant genes are expressed in the brains of mice, allowed the team to study the influence of specific genes and proteins on the development and progression of Alzheimer’s.

Scientists initially used transgenic animals to study diseases such as cancer and heart disease. Price and colleagues were one of the first groups to apply this approach to brain diseases, particularly the neurodegenerative disorders, like Lou Gehrig’s disease (ALS), Parkinson’s disease, and Alzheimer’s disease.

“Price was a pioneer,” says Professor of Biology John Kirn, chair of Wesleyan’s Neuroscience and Behavior Department. “The whole field of transgenic modeling owes a debt to him . . . . It is now easy to manipulate genes in part due to the early work of Professor Price.”

In the early 1990s, Price and his team used the transgenic approach in combination with gene knockout methods to define the roles two enzymes play in forming the sticky, amyloid protein-based plaques that mysteriously appear in the brains of Alzheimer’s patients. Several drugs currently in development are designed to inhibit the activity of these enzymes.

Says Price, “These agents, in concert with strategies that facilitate the removal of amyloid plaques, are going to be critical in treating patients, because they’re mechanism-based treatments in contrast to symptom-based approaches.”

Price first became aware of neurodegenerative illnesses in a way that many other Americans of his generation did, through the story of Lou Gehrig, the New York Yankee whose spectacular career and life were ended by amyotrophic lateral sclerosis—best known as Lou Gehrig’s disease. Price’s father and grandfather were Brooklyn Dodgers fans, and they admired Gehrig (who had studied at Columbia) for both his athleticism and his intelligence. From his family, Price inherited a respect for Gehrig and a love of baseball and learning.

At Wesleyan, Price played varsity baseball and basketball. He majored in English, influenced greatly by Professors F. Millett and N. O. Brown. In studying the poetry and prose of Shakespeare, Dickens, Joyce, Eliot, and Frost, he nourished intellectual interests that would ultimately lead to a career involving studies of the brain and its disorders.

“I became interested in the psychological, particularly psychoanalytic, interpretations of literature, and then began to explore what was known about brain psychology,” he says. “Later, I discovered that the brain science in this area at that time was quite limited, but the interface between literature and psychology was certainly the stimulus that encouraged me to rethink my future career.”

(Price couldn’t have majored in neuroscience: Wesleyan first offered it as a major in 1989, supplanting a biopsychology major created in 1972. Today Neuroscience and Behavior is now one of the fastest growing majors at the university. In the fall of 2010, Introduction to Neuroscience was the most sought-after class on campus.)

Professor Naegele, who sometimes co-teaches the introductory course, suspects that more students are following in Price’s footsteps, coming to neuroscience from backgrounds in literature, philosophy, or economics. This is because the field is beginning to address a new range of topics that once were the preserve of humanists, such as decision-making and social behavior.

“One thing that Wesleyan students do particularly well is cross disciplines,” says Naegele. “Dr. Price is a perfect example of the sort of broad liberal arts education at work.”

Neurology has meanwhile grown from a relatively obscure branch of medicine to one of the fastest growing fields in science. Price believes brain science and its attendant clinical disciplines are on the brink of a golden age.

“Brain diseases represent enormous unmet needs, whether you are talking about Alzheimer’s, or Parkinson’s, or schizophrenia, or autism,” he says.

He believes the greatest obstacles facing the next generation of scientists are not primarily the scientific questions, but the political and economic issues centered on support of research. Future investigators may have less funding than scientists of the 20th century, he says.

When he meets with young neuroscientists today, Price urges them to read Siddhartha Mukherjee’s Pulitzer Prize-winning book The Emperor of All Maladies: A Biography of Cancer. He believes that neuroscientists can draw useful and encouraging lessons from the history of cancer research.

“The problems and the opportunities are similar. . . . There are genes, disease pathways, pathological mechanisms, model systems, and ways of intervening to benefit patients. We need to encourage our young people to take on these challenges that will greatly benefit society.

Price, in a sense, has spent his career trying to write a biography of neuro-degeneration, particularly Alzheimer’s disease. Each new discovery—from his early research into the cholinergic system to his more recent work using transgenics, gene targeting, animal models, and experimental therapeutics—represents a chapter. Thanks to his work, physicians and scientists in coming years will be able to ameliorate and, ultimately, prevent the destruction that Alzheimer’s causes to the brain, allowing seniors to live full, productive lives deep into old age.

Peter Saalfield is a freelance journalist living in New York City. He was formerly a producer for Charlie Roseon PBS.