Today, by and large,
patients receive a diagnosis of Alzheimer’s only after they exhibit well-known
signs of the disease, such as memory loss. By that point, the best treatment
options simply slow further progression of symptoms.
But 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.
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.
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.
Source:https://www.washington.edu/news/2022/12/05/alzheimers-blood-test/
Journal article: https://www.pnas.org/doi/10.1073/pnas.2213157119
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