Tools to track, treat a devastating disease

Alzheimer’s disease (AD), the most prevalent form of dementia, affects some 4 million people in the United States, and yet, not only is there no cure, there is not even any accurate way to diagnose the disease until after death.
Only an autopsy can indicate for sure that a patient had AD, which is the third most costly disorder, after cancer and cardiovascular disease.

Now, Kelvin H. Lee, Gore Professor of Chemical Engineering and Delaware Biotechnology Institute (DBI) Faculty Fellow, is hoping that the work he and his research group are doing will contribute to the development of both an accurate diagnostic tool for Alzheimer’s and a strategy that will protect against the ravages of the disease.
Lee, who joined the University faculty in September, holds a doctorate in chemical engineering, with a minor in biology, from the California Institute of Technology. The biology minor reflects his interest in the life sciences and his focus on medical applications of chemical engineering research.

Lee’s vision is grand: He would like to contribute to the development of a tool like the medical “tricorder” seen in Star Trek. The handheld device could scan the body, interpret and display data from the scans and record information, helping doctors to diagnose disease. Given the rapid development of proteomics—the large-scale study of the structure and functions of proteins—this vision may not be as far-fetched as it seems.
“We’re looking for changes in protein expression in cerebrospinal fluid,” Lee says, “and trying to come up with a ‘barcode’ that can distinguish between patients who have AD and those who don’t, as well as between people with AD and those with other, similar diseases that can cause dementia.”

Doctors can currently diagnose living patients only as “probable AD” because it takes a post-mortem examination of brain tissue to provide definitive evidence of the amyloid plaques that characterize Alzheimer’s. Lee points out that an estimated 10-20 percent of people with this diagnosis are found to have other conditions that manifest similar symptoms.

“We need a tool that’s specific enough to distinguish among neurodegenerative diseases so that the proper treatment can be administered,” he says.

As a postdoctoral researcher at Caltech, Lee had worked with a group that was studying Creutzfeldt-Jakob disease, a rare and incurable brain disorder known as mad cow disease. “Mad cow was biologically interesting and was making headlines at the time because of an outbreak in England, but it’s not a disease that affects a lot of people,” he says.

He decided to focus on Alzheimer’s, instead. Working with Dr. Norman Relkin at the Cornell Medical Center in New York City, Lee received funding from the National Institutes of Health for a study aimed at finding biomarkers for the disease—in effect, a protein barcode unique to those with AD.

The results of the study, published in the Annals of Neurology in late 2006, yielded a set of validated biomarkers for Alzheimer’s. In the meantime, the research group had turned its attention from diagnosis to treatment.

“There has never been a good treatment for Alzheimer’s,” Lee says. “Most therapies treat the symptoms to improve quality of life for six months or so. At the end of that period, many patients are not any better off than untreated patients.

“My collaborators began to wonder whether people could be immunized against AD. The disease is characterized by the formation of amyloid plaques in the brain. Would it be possible to get the body to form antibodies to clear the damaging plaques when they’re formed?”

Relkin and colleagues from Cornell conducted a Phase I study in which they administered intravenous immunoglobulin (IVIg), a drug already being used to treat some patients with compromised immune systems, to Alzheimer’s patients. Lee says the AD patients’ cognitive abilities improved while they were being treated with the drug.

“This was a very encouraging outcome, despite the fact that it was preliminary and involved a very small number of subjects,” he says. “As a result, all of the subjects were put back on the drug, which resulted in positive effects in patients even after 18 months.”

A Phase II double-blind, placebo-controlled study also yielded positive results, and a Phase III study is set to launch in the future.

Lee points out that the Alzheimer’s research conducted by his team began in one direction and has changed over time. The initial goal, which has essentially been accomplished, was to identify diagnostic markers for Alzheimer’s and to determine what happens to the markers as patients are treated.

“We found that there are markers and that they mirror the clinical results,” Lee says. “In other words, improvement in patients’ cognitive functioning seemed to correlate with a reduction of the markers in their cerebrospinal fluid.”

The next step for the Cornell team is to obtain federal approval to treat Alzheimer’s patients with IVIg.

Lee is still collaborating with his Cornell colleagues to collect data that will validate the link between the disease-modifying effects of the drug and the observed clinical outcomes. He hopes that their work will lead not only to a noninvasive diagnostic tool and an effective treatment but also to an understanding of the mechanisms underlying the development of the disease.

“It would be ideal to have that medical tricorder,” he says. “But we’re not there yet.”

—Diane S. Kukich, AS ’73, ’84M