Scientists from the University of Texas Medical School at Houston say they have shown that they can detect tiny, misfolded protein fragments in patients’ cerebrospinal fluid—fragments which have been suggested to be the main culprit in Alzheimer's disease. The study (“Detection of Misfolded A Oligomers for Sensitive Biochemical Diagnosis of Alzheimer's Disease”) appears in Cell Reports.
The finding lends hope that doctors might soon have a way to diagnose the disease while treatments might have a better chance of working before extensive brain damage and dementia set in.
Researchers used to think amyloid plaques were the problem in Alzheimer's disease. “Now it seems clear that the aggregates are not the main culprits, it's their precursors,” so-called Aβ oligomers, said Claudio Soto, Ph.D., a researcher at the medical school. “This is the key molecule and could be the best, most reliable way to make an early diagnosis. That's been the biggest problem in the field: You can't identify patients until they are already sick.”
According to Dr. Soto, Aβ oligomers may be circulating in the body years if not decades before cognitive symptoms arise. In the new study, he and his colleagues applied a technology they developed earlier for detection of the misfolded proteins responsible for prion diseases including mad cow disease. When mixed with the equivalent normal protein, the misfolded fragments act as seeds for the formation, in the case of Aβ, of amyloid clumps like those found in the Alzheimer's brain.
“The protein misfolding cyclic amplification assay (Aβ-PMCA), exploits the functional property of Aβ oligomers to seed the polymerization of monomeric Aβ,” wrote the investigators. “Aβ-PMCA allowed detection of as little as 3 fmol of Aβ oligomers. Most importantly, using cerebrospinal fluid, we were able to distinguish AD patients from control individuals affected by a variety of other neurodegenerative disorders or nondegenerative neurological diseases with overall sensitivity of 90% and specificity of 92%. These findings provide the proof-of-principle basis for developing a highly sensitive and specific biochemical test for AD diagnosis.”
The next step, noted Dr. Soto, is to adapt the technology for use with blood or urine samples, which would be much easier to obtain for screening perfectly healthy people for biochemical signs of Alzheimer's disease. They will also continue to explore its utility for detecting the disease before symptoms appear.
If additional research can confirm the utility of the test in Alzheimer's and perhaps other conditions (e.g., Parkinson's disease), an FDA-approved test could be on the market in as little as three years, said Dr. Soto, whose team is already involved in commercializing the PCMA technology for application in prion diseases.
