Advances in Pick Disease, AD, and Related Disorders — and the Potamkin Prize Winners Who Made Them Happen
There are those eureka moments in Alzheimer disease (AD) research that changed the landscape of the disease forever: the discovery of the amyloid beta (Abeta) protein; the amyloid precursor protein (APP) mutation in families hard hit by early AD; the link between apolipoprotein E4 (APOE4) and late-onset AD; the first mouse with amyloid deposits; the idea that a snippet of amyloid could be used in a vaccine to set off an immune response to protect the brain against the sticky protein that settles into plaque; the presenilin mutations; and how tau damages the brain.
Like a train collecting cargo at every stop, AD investigators have amassed a body of weighty ideas and research to test theories that have for the first time in history led to clinical trials of treatments that might actually stop or slow the disease process. By combing the literature to know who's who in the field, a coveted prize has helped to tell the story of the modern research journey to understand and treat AD.
The Potamkin Prize for Research in Pick's, Alzheimer's and Related Diseases, awarded annually by the AAN since 1988, provides broad-brush strokes of the field — the discovery of the Abeta protein, the tauopathies, Lewy bodies in Pick disease, APOE mutations, the animal models, the risk genes, and the first drugs for the disease.
The prize is hotly pursued in the field because it is a measure of an individual's mark on the field. “It's an award for people who have made seminal contributions to AD,” said David M. Holtzman, MD, chairman of the department of neurology at Washington University School of Medicine in St. Louis, MO, a 2003 recipient of the prize who has spent three years judging the nominations.
This year, there are seven people vying for two or three spots and they are all on top of their game. Anyone can be nominated for the prize and the committee is made up of half a dozen AD experts, many former Potamkin winners.
“This isn't just about what scientists have done but what they will continue to do,” said Karen Duff, PhD, another Potamkin winner who was selected for her impressive work on developing an animal model of AD. In 2007, Dr. Duff left her tenured position at the Nathan Kline Institute to work at Columbia University, where she is a professor of pathology. She won the Potamkin Prize in 2006.
There is truth in her humor. “Two things that guarantee tenure are program grants and the Potamkin,” she said.
The Potamkin Prize comes with a $100,000 check that is split between the winners. Some years it is one person and other years three.
“The scientists who are being nominated this year, like previous years, have identified basic causes of AD, Pick disease, and related disorders and have helped increase research funding for research and inspired a generation of scientists to enter the field,” Dr. Holtzman said.
Following the identification of APOE4 as a major risk factor in AD, Dr. Holtzman and his colleagues showed how APOE4 interacts with Abeta protein and speeds up the accumulation of the sticky protein in the brain. Like others in the field, he is also studying the potential of a vaccine approach against Abeta aggregation.
Having animal models and tools to peer into the normal and diseased brain has helped in understanding AD. Thanks to imaging studies of at-risk people or those with mild cognitive impairment, it is now known that the course of pathology begins years, maybe decades, before the actual symptoms emerge. And Dr. Holtzman's lab has identified ways to detect changes in Abeta in CSF that could be used to identify the disease well before a person begins having memory or behavior problems.
A WINDOW INTO AD ADVANCES
The Potamkin Prize is also a window into where scientists have moved the field. Amyloid findings may be a big part of the research story, but clearly other areas of research are critical if scientists are going to identify targets for treatments and the treatments themselves, Dr. Duff said.
Scientific advances have led to shifts of thought in the triggers for AD. When amyloid was detected in the brains of patients it was believed that it was the accumulation of the sticky plaque that damaged the neurons. The other hallmark was the tau-filled tangles that surround the neurons.
Prize winners — Dennis J. Selkoe, MD, the Vincent and Stella Coates Professor of Neurologic Diseases at Harvard Medical School, and co-director of the Center for Neurologic Diseases at Brigham and Women's Hospital; Karen Hsiao Ashe, MD, PhD, Edmund Wallace and Anne Marie Tulloch Chairs in Neurology and Neuroscience and director of the N. Bud Grossman Center for Memory Research and Care at the University of Minnesota; and Bradley Hyman, MD, PhD, John B. Penney, Jr. Professor of Neurology at Harvard's Massachusetts General Hospital department of neurology — all conducted work in their independent labs on the much smaller aggregates of Abeta-42, called oligomers, and the field came to realize that these small pieces are also toxic to neurons.
“The prize is thought to be a big deal among scientists,” said Dr. Selkoe, who has devoted his career to AD. They all have. And they would have continued working on the problem with or without a prize.
But when the first one was handed out in 1988 to California scientist Robert Terry, MD, “it heightened the recognition that this was a distinct field” from other neurological disorders, said Dr. Selkoe. “It was a real shot in the arm. We were so far away from any ideas that could have clinical relevance.”
The award acknowledges other forms of dementia, including Pick disease and frontotemporal dementia. And prion disease also took a place on the list of conditions when Stanley Prusiner, MD, director of the Institute for Neurodegenerative Diseases and professor of neurology and biochemistry at the University of California-San Francisco, won in 1991 for the work. Six years later, the Nobel Prize committee agreed, awarding him the Nobel Prize in Physiology or Medicine.
Two years ago, in 2007, Richard Mayeux, MD, the Gertrude H. Sergievsky Professor of Neurology, Psychiatry and Epidemiology, and the director of the Gertrude H. Sergievsky Center at Columbia University, won the Potamkin prize for his genetic studies on risk genes for AD. He has worked on APOE4, like many others. But he has also identified a new variant — SORL1— that can increase the rate of Abeta-42 production. “Research is now directed at finding out how to increase SORL activity to counteract this genetic variation,” Dr. Holtzman said.
The work of John C. Morris, MD, the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology at Washington University; Ronald C. Petersen, MD, PhD, professor of neurology at the Mayo Clinic in Rochester, MN; and Dr. Hyman has also altered the way people identify illness. They have shown that memory loss can appear without actual dementia and that mild cognitive impairment can be a red flag for dementia in coming years.
The Potamkin Prize is funded through philanthropic contributions of the Potamkin family of Aspen, CO, and Miami, FL. The idea was to help attract scientists to study AD and other dementias. Victor Potamkin, a major auto dealer in New York, established the prize because his wife had Pick disease.
Indeed, there are scores of scientists deserving of the prize who have yet to end up on the who's who of the Potamkin Prize. Still, the prize is a window into how far the field has advanced in 20 years. Such advances were unimaginable when, at the turn of the century, Alois Alzheimer, MD, described the pathological plaques and tangles of brain tissue culled from one of his patients who lived and died at the asylum — a middle-aged woman with bizarre behavior and an inability to retain the memory of a short-term experience. Under the microscope, they used a staining technique that led to the first description of the plaques and tangles in this mind-robbing disease — one of those eureka moments.