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 Dec. 9 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.
Lead author on the study is Dylan Shea, a doctoral student in the UW
Department of Bioengineering’s Molecular Engineering Program. Co-authors
are Elizabeth Colasurdo of the VA Puget Sound Health Care System; Alec Smith, a UW research assistant professor of physiology and biophysics; Courtnie Paschall, a student in the UW Medical Scientist Training Program; Dr. Suman Jayadev, a UW assistant professor of neurology; Dr. Dirk Keene, a UW professor of laboratory medicine and pathology; Douglas Galasko, a professor of neurosciences at the University of California, San Diego; Dr. Andrew Ko, assistant professor of neurological surgery at the UW; and Ge Li and Dr. Elaine Peskind,
both of the UW Department of Psychiatry and Behavioral Sciences and the
VA Puget Sound Health Care System. The research was funded by the
National Institutes of Health, the Washington Research Foundation and
the Northwest Mental Illness Research, Education and Clinical Center.
