Using a new technology that relies on thousands of synthetic molecules to fish for disease-specific antibodies, researchers have developed a potential method for detecting Alzheimer's disease with a simple blood test. The same methodology might lead to blood tests for many important diseases, according to the report in the January 7th issue of the journal Cell, a Cell Press publication.
"If this works in Alzheimer's disease, it suggests it is a pretty general platform that may work for a lot of different diseases," said Thomas Kodadek of The Scripps Research Institute. "Now we need to put it in the hands of disease experts to tackle diseases where early diagnosis is key."
The new method relies on the notion that many diseases lead to the production of modified proteins. At some point, the adaptive immune system might begin to recognize those proteins as foreign and mount a response. If tests could be developed to recognize those disease-specific proteins or the antibodies that recognize them, it could be the basis for early diagnosis. But in most cases, researchers have had little luck identifying those abnormal proteins.
Kodadek's team decided to take a different tack. They used a large library of randomly selected, unnatural molecules known as "peptoids" to screen for antibodies found in the bloodstream of animals or patients with specific diseases and not in healthy controls.
"The peptoids are really just random shapes," Kodadek explained. The method is really practical, he says, because it allows for the assembly of enormous chemical libraries with little effort. It also offers a way to "step outside of the usual biological or chemical space" in search of molecules that might just fill the pockets of antibodies playing unknown roles in disease.
As a proof of concept, the researchers started with mice with experimental autoimmune encephalitis, a condition that resembles multiple sclerosis in humans. It was an easy first choice because the mice have little variation and the condition has obvious immune system involvement, and it worked. Using a few thousand peptoids, the researchers landed on a handful that could distinguish blood samples taken from healthy versus sick mice.
The next challenge was to see whether the same method would also work in the case of human Alzheimer's disease. Kodadek describes it as a dubious choice, but the risk paid off. Their method uncovered three peptoids that appear to discriminate between healthy and Alzheimer's disease blood samples with high accuracy.
Kodadek says they have since extended the test to more patients and it appears to be holding up well. Nevertheless, development of a clinically useful test will depend on further validation. It's possible that the test might not work as reliably well in a collection of patients representing different ethnic groups or different forms of dementia, he cautions. They'll also need to transition their peptoid technology to a simpler platform better suited for use outside of a research laboratory.
It's not entirely clear whether an early test for Alzheimer's disease would be broadly useful today given that there aren't any real treatment options, he added. Such a test might initially be most useful to pharmaceutical companies, by allowing them to better identify patients with early Alzheimer's for enrollment into clinical trials.
Kodadek says they plan to test their method now in the context of diseases, such as pancreatic cancer, where it is clear that early diagnosis could have significant implications for patient survival. It's possible that antibody-based tests might identify such cancers years before they could be detected otherwise.
If those antibodies and the natural antigens that they recognize could be found using the new technology, it might even aid the development of new and more effective cancer vaccines designed to bolster the body's natural defenses against the disease. "That's the dream scenario," Kodadek says.
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