Researchers are now able to detect “toxic” small aggregates of a particular protein in the blood of people with Alzheimer’s disease, as well as in those showing no signs of cognitive impairment at the time the blood sample was taken, but who developed it at a later date.
The blood test picks up oligomers – or small, misfolded aggregates – of the amyloid beta protein, which scientists believe triggers the development of Alzheimer’s, paving the way to earlier identification and treatment of the disease
Generally, patients receive an Alzheimer’s diagnosis only after they exhibit well-known signs of the disease, like memory loss. By then, the best treatment options simply slow further progression of symptoms.
But this latest research shows that the seeds of Alzheimer’s are planted years, even decades, earlier, long before the cognitive impairments surface that make a diagnosis possible. Those seeds are amyloid beta proteins that misfold and clump together, forming small aggregates called oligomers. Over time, through a process scientists are still trying to understand, those “toxic” oligomers of amyloid beta are thought to develop into Alzheimer’s.
A team led by researchers at the University of Washington has developed a laboratory test that can measure levels of amyloid beta oligomers in blood samples. In a paper published in the Proceedings of the National Academy of Sciences, they said their test, known by the acronym SOBA, could detect oligomers in the blood of patients with Alzheimer’s, but not in most members of a control group who showed no signs of cognitive impairment at the time the samples were taken.
However, SOBA did detect oligomers in the blood of 11 individuals from the control group. Follow-up examination records were available for 10 of these people, and all were diagnosed years later with mild cognitive impairment or brain pathology consistent with Alzheimer’s disease. Essentially, for these 10, SOBA had detected the toxic oligomers before symptoms surfaced.
“What clinicians and researchers have wanted is a reliable diagnostic test for Alzheimer’s – not just an assay that confirms a diagnosis, but one that can also detect signs of the disease before cognitive impairment happens. That’s important for people’s health and for all the research into how toxic oligomers of amyloid beta cause the damage that they do,” said senior author Valerie Daggett, a UW professor of bioengineering and faculty member in the UW Molecular Engineering & Sciences Institute.
“What we show here is that SOBA may be the basis of such a test.”
SOBA, which stands for soluble oligomer binding assay, exploits a unique property of the toxic oligomers. When misfolded, amyloid beta proteins begin to clump into oligomers, they form a structure known as an alpha sheet. Alpha sheets are not ordinarily found in nature, and past research by Daggett’s team showed that alpha sheets tend to bind to other alpha sheets.
At the heart of SOBA is a synthetic alpha sheet designed by her team that can bind to oligomers in samples of either cerebrospinal fluid or blood. The test then uses standard methods to confirm that the oligomers attached to the test surface are made up of amyloid beta proteins.
The team tested SOBA on blood samples from 310 research subjects who had previously made their blood samples and some of their medical records available for Alzheimer’s research. At the time the blood samples had been taken, the subjects were recorded as having no signs of cognitive impairment, mild cognitive impairment, Alzheimer’s disease or another form of dementia.
SOBA detected oligomers in the blood of those with mild cognitive impairment and moderate to severe Alzheimer’s. In 53 cases, the research subject’s diagnosis of Alzheimer’s was verified after death by autopsy – and the blood samples of 52 of them, which had been taken years before their deaths, contained toxic oligomers.
SOBA also detected oligomers in those members of the control group who, records show, later developed mild cognitive impairment. Blood samples from other individuals in the control group who remained unimpaired lacked toxic oligomers.
Daggett’s team is working with scientists at AltPep, a UW spinout company, to develop SOBA into a diagnostic test for oligomers. In the study, the team also showed that SOBA easily could be modified to detect toxic oligomers of another type of protein associated with Parkinson’s disease and Lewy body dementia.
“We are finding that many human diseases are associated with the accumulation of toxic oligomers that form these alpha sheet structures,” said Daggett. “Not just Alzheimer’s, but also Parkinson’s, type 2 diabetes and more. SOBA is picking up that unique alpha sheet structure, so we hope this method can help in diagnosing and studying many other ‘protein misfolding’ diseases.”
Daggett believes the assay has further potential.
“We think SOBA could help identify individuals at risk or incubating the disease, as well as serve as a readout of therapeutic efficacy to aid in development of early treatments for Alzheimer’s,” she said.
Study details
SOBA: Development and testing of a soluble oligomer binding assay for detection of amyloidogenic toxic oligomers
Dylan Shea, Elizabeth Colasurdo, Alec Smith, Courtnie Paschall, Suman Jayadev, Dirk Keene, Douglas Galasko, Andrew Ko, Ge Li, Elaine Peskind, Valerie Daggett.
Published in Proceedings of the National Academy of Sciences on 9 December 2022.
Significance
Early detection and disease-modifying treatments are necessary to combat Alzheimer’s disease. A first step in that process is early diagnosis to intervene before irreparable damage occurs, which is estimated to begin 10 to 20 y before the presentation of symptoms. The earlier discovery of α–sheet structure during conformational changes associated with amyloidogenesis led to a potential target for selective and early detection of these oligomers. Here we show that a de novo designed α–sheet peptide neutralises the toxic effect of Aβ oligomers on neuronal signalling and serves as a capture agent for their detection. The presence of α–sheet Aβ oligomers in plasma, as detected with SOBA, is highly correlated with Alzheimer’s disease.
Abstract
The formation of toxic Amyloid β-peptide (Aβ) oligomers is one of the earliest events in the molecular pathology of Alzheimer’s Disease (AD). These oligomers lead to a variety of downstream effects, including impaired neuronal signalling, neuro-inflammation, tau phosphorylation, and neurodegeneration, and it is estimated that these events begin 10 to 20 y before the presentation of symptoms. Toxic Aβ oligomers contain a nonstandard protein structure, termed α-sheet, and designed α–sheet peptides target this main-chain structure in toxic oligomers independent of sequence. Here we show that a designed α–sheet peptide inhibits the deleterious effects on neuronal signaling and also serves as a capture agent in our soluble oligomer binding assay (SOBA). Pre-incubated synthetic α–sheet-containing Aβ oligomers produce strong SOBA signals, while monomeric and β-sheet protofibrillar Aβ do not. α–sheet containing oligomers were also present in cerebrospinal fluid (CSF) from an AD patient versus a noncognitively impaired control. For the detection of toxic oligomers in plasma, we developed a plate coating to increase the density of the capture peptide. The proof of concept was achieved by testing 379 banked human plasma samples. SOBA detected Aβ oligomers in patients on the AD continuum, including controls who later progressed to mild cognitive impairment. In addition, SOBA discriminated AD from other forms of dementia, yielding sensitivity and specificity of 99% relative to clinical and neuropathological diagnoses. To explore the broader potential of SOBA, we adapted the assay for a-synuclein oligomers and confirmed their presence in CSF from patients with Parkinson’s disease and Lewy body dementia.
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