Toxic amyloid may be detected in Alzheimer’s blood tests years before symptoms appear

Researchers at the University of Washington (UW) have developed a soluble oligomer binding assay (SOBA) that measures levels of amyloid-beta (Aβ) peptide oligomers in the blood and can detect Alzheimer’s disease at all stages, including presymptomatic cases. Developed a known clinical test. Results from the team’s human studies showed that the test can also distinguish Alzheimer’s disease from other amyloid diseases, including Parkinson’s disease.

“What clinicians and researchers have been asking for is a reliable diagnostic test for Alzheimer’s disease. An assay that not only confirms the diagnosis of Alzheimer’s disease, but also can detect signs of the disease before cognitive impairment occurs.” said Dr. Valerie Daggett. She is a UW Professor of Bioengineering and Faculty at the UW Molecular Engineering Science Institute. “This is important for individual health and for all research into how toxic oligomers of amyloid-beta progress and cause damage. …“SOBA not only helps identify at-risk individuals and harbors disease, but also serves as a readout of treatment efficacy to support early treatment development.” I think, for Alzheimer’s disease.”

Daggett is a senior author on papers published by the team. PNAS, titled “SOBA: Development and Testing of a Soluble Oligomer Binding Assay for the Detection of Amyloidogenic Toxic Oligomers”. Daggett is also the founder and CEO of AltPep, a spin-out company that is developing this technology into a diagnostic and therapeutic platform.

Amyloid diseases are associated with protein misfolding and aggregation of soluble oligomeric proteins of varying toxicity. In Alzheimer’s disease, the formation of toxic amyloid beta peptide oligomers is an early molecular trigger before other downstream events such as plaque deposition and aberrant phosphorylation of tau occur. “These oligomers trigger a variety of downstream effects, including impaired neuronal signaling, neuroinflammation, tau phosphorylation, and neurodegeneration. These events are estimated to begin 10 to 20 years before symptoms appear. ,” the authors write.

The aim is to intervene early in the disease pathway, before irreparable damage occurs that can begin decades before clinically evident disease. However, today’s patients may only receive a diagnosis of Alzheimer’s disease after exhibiting well-known signs of the disease, such as memory loss. “Early diagnosis and disease-modifying therapy for Alzheimer’s disease (AD) remains elusive,” the scientist continued.

SOBA takes advantage of the unique properties of toxic oligomers. When misfolded amyloid beta proteins begin to aggregate into oligomers, they form structures known as alpha sheets (α-sheets). Alpha sheets do not normally exist in nature. Past research Alpha sheets by the Daggett team showed a tendency to combine with other alpha sheets. SOBA uses team-designed synthetic α-sheets that can bind to these α-sheet oligomers in samples of cerebrospinal fluid or blood. The test then uses standard methods to confirm that the oligomer attached to the test surface is composed of amyloid beta protein. “The α-sheet is a non-canonical protein structure discovered in molecular dynamics (MD) simulations of various amyloid disease-related proteins,” the scientist explained. “We thought that this structure might be a unique target for early detection and designed a stable, soluble, non-toxic α-sheet peptide that complements the α-sheet structure of toxic species.”

The team evaluated the Alzheimer’s Disease SOBA Test (SOBA-AD) on 379 blood samples from 310 individuals who had previously made available blood samples and medical records for Alzheimer’s disease research. At the time blood samples were taken, participants were documented to have no signs of cognitive impairment, mild cognitive impairment (MCI), Alzheimer’s disease, or another form of dementia.

The results confirm that the SOBA assay can detect Aβ toxic oligomers in Alzheimer’s disease patients and distinguish them from other forms of dementia with 99% sensitivity and 99% specificity. Interestingly, this assay identified 13 samples from cognitively normal controls that exhibited high toxic oligomer levels. Over the next few years, 12 of these 13 samples were confirmed to progress to mild cognitive impairment or brain pathology consistent with Alzheimer’s disease. (One was not traceable.) Essentially, in these 10 of her individuals, SOBA had detected toxic oligomers before symptoms appeared. These results, the scientists argue, suggest that the SOBA assay can detect the early molecular pathology of Alzheimer’s disease before clinical symptoms appear. “SOBA-AD detected oligomers in non-cognitively impaired controls many years before conversion to MCI, suggesting that it may provide standalone preclinical detection of AD.” ,” said the authors.

To demonstrate the broad application of SOBA technology, CSF samples from patients with Parkinson’s disease and dementia with Lewy bodies were evaluated using a SOBA assay adapted for the detection of toxic oligomers associated with Parkinson’s disease. The results confirmed that these tests produced strong signals and good discrimination between Parkinson’s and Alzheimer’s patients, confirming the platform’s proof-of-concept for a modular and broad approach. “SOBA differentiated AD from other forms of dementia with 99% sensitivity and specificity compared to clinical and neuropathological diagnoses,” the team said. “To explore the broad potential of SOBA, we adapted an assay for α-synuclein oligomers and confirmed its presence in the CSF of a patient with Parkinson’s disease and dementia with Lewy bodies.”

Daggett’s team is working with AltPep to develop SOBA technology into a simple SOBA™ diagnostic blood test and a disease-modifying SOBIN™ therapy for amyloid disease that targets toxic soluble oligomers. Customized synthetic peptides are designed to selectively bind toxic oligomers, detecting and neutralizing them throughout disease progression. AltPep focuses on early detection and treatment before symptoms develop. Major programs focus on Alzheimer’s and Parkinson’s disease, with an eye to other amyloid diseases.

“We have found that many human diseases are associated with the accumulation of toxic oligomers that form these alpha-sheet structures.” As SOBA picks up on its unique alpha sheet structure, we hope that this method will be useful in diagnosing and studying many other ‘protein misfolding’ diseases. “

AltPep has been granted Breakthrough Designation by the FDA as a SOBA-AD diagnostic for Alzheimer’s disease. Inclusion in the FDA Breakthrough Device Program means you can expect AltPep to prioritize your diagnostic test submissions for review.