Sensitive Test Detects Biomarker for Alzheimer's

Using bio-barcode amplification (BCA) technology that is a million times more sensitive than a commercial enzyme-linked immunoassay (ELISA), scientists have detected a biomarker in humans that is associated with Alzheimer's disease and holds the promise of early detection and treatment.

The BCA technology was developed in 2003 by a team of scientists at Northwestern University (Evanston, IL, USA). A study by the team shows that the BCA method can detect in human cerebrospinal fluid (CSF) miniscule amounts of a toxic protein that may be responsible for the early neurologic deterioration seen in Alzheimer's disease. Their findings were published in the January 31, 2005, online issue of the Proceedings of the [U.S.] National Academy of Sciences.

"We have demonstrated the first diagnostic test for the potential Alzheimer's biomarker known as an ADDL,” said Chad A. Mirkin, director of the Institute for Nanotechnology at Northwestern and one of the paper's authors.

An ADDL (pronounced "addle”) protein is five nanometers wide and is present in CSF at very low concentrations, which makes it difficult to detect. ADDLs are amyloid â-derived diffusible ligands. Clinical data support a recent theory in which ADDLs accumulate at the beginning of Alzheimer's disease and block memory function by a process predicted to be reversible.

"Detection of plaques in patients may be too late,” said William L. Klein, professor of neurobiology and physiology at Northwestern's Weinberg College of Arts and Sciences, who together with two colleagues reported the discovery of ADDLs in 1998. "We think the accumulation of ADDLs is likely to be the first biomarker in Alzheimer's disease, and now this extraordinary powerful detection technology has changed what we think might be possible.”

To detect ADDLs, a magnetic microparticle and a gold nanoparticle are each outfitted with an antibody specific to the ADDL antigen. When in solution, the antibodies "recognize” and bind to the ADDL, sandwiching the protein between the two particles. Attached to each tiny gold nanoparticle are hundreds to thousands of identical strands of DNA, called bar-code DNA by the scientists because they have designed it as a unique label specific to the target. After the "particle-ADDL-particle” sandwich is removed magnetically from solution, the bar-code DNA is removed from the sandwich and read, using standard DNA detection methods.

A research team used BCA technology to measure the concentration of ADDLs present in the CSF of 30 individuals. ADDL concentrations for the individuals who had been evaluated and determined to have Alzheimer's disease were consistently higher than the levels from the control group of healthy individuals who were not demented, and the two groups were easily differentiated. Next, the researchers would like to develop the technology so the test could be done by using a blood or urine sample instead of CSF.

The BCA technology has been exclusively licensed to Nanosphere, Inc. (Northbrook, IL, USA), which has announced its plans to expand the application of the early detection test to a variety of other applications, including cancer, coronary artery disease, and Mad Cow disease.



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