Most people diagnosed with Alzheimer’s today have already shown typical symptoms including memory loss. Once symptoms have progressed so far, the best treatment choices do nothing more than slow the disease’s progression.
However, studies have revealed that the seeds of Alzheimer’s are planted years, if not decades, before the onset of any cognitive deficits that would allow for a diagnosis. Amyloid beta proteins misfold and cluster into oligomers, which serve as the seeds. Scientists believe that Alzheimer’s disease is caused by the accumulation of “toxic” oligomers of amyloid beta over time.
Laboratory testing has been established to determine amyloid beta oligomer concentrations in human blood, and it was developed by a group of researchers at the University of Washington. Their test, called SOBA, was able to detect oligomers in the blood of patients with Alzheimer’s disease, but not in most participants of a control group who showed no evidence of cognitive deficits at the time the blood samples were taken, as reported in a paper published the week of Dec. 5 in the Proceedings of the National Academy of Sciences.
Conversely, 11 control subjects had oligomers in their blood that were detected by SOBA. Examined again years later, 10 of these people were diagnosed with mild cognitive impairment or brain pathology indicative of Alzheimer’s disease. Thus, for these 10 people, SOBA had discovered the harmful oligomers before the onset of symptoms.
Clinicians and scientists have long sought a reliable diagnostic test for Alzheimer’s disease, ideally an assay that may identify indications of the illness prior to the onset of cognitive impairment rather than merely confirming a diagnosis of Alzheimer’s. That’s critical for both individual well-being and the study of how amyloid beta oligomers become toxic and produce their harmful effects. UW Molecular Engineering & Sciences Institute faculty member and bioengineering professor Valerie Daggett is cited as the paper’s senior author. In this paper, the researchers demonstrate that SOBA has the potential to serve as the foundation for such an examination.
The acronym SOBA stands for soluble oligomer binding assay and is used to take advantage of a specific property of the hazardous oligomers. Misfolded amyloid beta proteins generate an alpha sheet shape when they start to cluster together in oligomers. Previous study by Daggett’s group demonstrated that alpha sheets had a tendency to bond to other alpha sheets. Alpha sheet are so seldom observed in nature. SOBA relies on a synthetic alpha sheet developed by her team to bind oligomers in cerebrospinal fluid or blood. The oligomers bound to the test surface are then confirmed to be amyloid beta proteins using industry-standard techniques.
The scientists put SOBA to the test on blood samples from 310 study participants who had donated blood and medical data for Alzheimer’s disease study. At the time of the blood draws, the patients were not showing any symptoms of dementia, Alzheimer’s disease, or moderate cognitive impairment.
Researchers using SOBA found oligomers in the blood of people with Alzheimer’s disease ranging from mild cognitive impairment to severe cases. Autopsy confirmed the diagnosis of Alzheimer’s disease in 53 of the study’s participants, and toxic oligomers were found in the blood samples of 52 of them, obtained years before their deaths.
Records demonstrate that participants in the control group who later acquired moderate cognitive impairment were similarly found to have oligomers by SOBA. Toxic oligomers were absent in the blood samples of the unaffected members of the control group.
Currently, Daggett’s group is collaborating with researchers at UW spinout company AltPep to transform SOBA into an oligomer diagnostic test. They also demonstrated the ease with which SOBA may be modified to identify hazardous oligomers of a different protein type linked to Parkinson’s disease and Lewy body dementia.
It has been shown that many human illnesses are linked to the buildup of harmful oligomers into alpha sheet formations, as Daggett put it. These include not just Alzheimer’s and Parkinson’s but also type 2 diabetes and others. Since SOBA is able to detect this distinct alpha sheet structure, the researchers are optimistic that this approach may prove useful in the diagnosis and investigation of a wide variety of disorders caused by “protein misfolding.”
Daggett thinks there’s a lot of room for growth in the test.
The researchers believe that SOBA might help in identifying persons at risk or incubating the illness, as well as act as a readout of therapy efficacy to aid in development of early therapies for Alzheimer’s disease.
Shea, D., Colasurdo, E., Smith, A., Paschall, C., Jayadev, S., Keene, C. D., Galasko, D., Ko, A., Li, G., Peskind, E., & Daggett, V. (2022). SOBA: Development and testing of a soluble oligomer binding assay for detection of amyloidogenic toxic oligomers. Proceedings of the National Academy of Sciences of the United States of America, 119 (50), e2213157119. https://doi.org/10.1073/pnas.2213157119
University of Washington. (2022, December 5). New blood test can detect ‘toxic’ protein years before Alzheimer’s symptoms emerge, study shows. ScienceDaily. Retrieved January 7, 2023 from www.sciencedaily.com/releases/2022/12/221205153722.htm