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. As they report in a paper published the week
of Dec. 5 in the Proceedings of the National Academy of Sciences, their test – known by the acronym SOBA – could detect oligomers in the blood of patients
with Alzheimer’s disease, but not in most members of a control group who showed
no signs of cognitive impairment at the time the blood samples were taken.
Research has shown 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.
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 individuals, and all were diagnosed years later
with mild cognitive impairment or brain pathology consistent with Alzheimer’s
disease. Essentially, for these 10 individuals, SOBA had detected the toxic
oligomers before symptoms surfaced.
“What clinicians and researchers have wanted
is a reliable diagnostic test for Alzheimer’s disease — and not just an assay
that confirms a diagnosis of Alzheimer’s, but one that can also detect signs of
the disease before cognitive impairment happens. That’s important for
individuals’ health and for all the research into how toxic oligomers of
amyloid beta go on and 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
individuals 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 that this method can help in diagnosing and studying many other ‘protein
misfolding’ diseases.”
Daggett believes the assay has further potential.
“We believe that SOBA could aid in identifying
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
disease,” she said.
Reference:
“SOBA: Development and Testing of a
Soluble Oligomer Binding Assay for Detection of Amyloidogenic Toxic
Oligomers,” PNAS manuscript #2022-13157R
DOI: 10.1073/pnas.2213157119