LARGE STUDY OF PLASMA PROTEINS AND DEMENTIA ILLUMINATES THE BIOLOGY OF DEMENTIA AND ALZHEIMER’S AND MAY HELP LEAD TO TREATMENTS
May 17, 2021 -- The development of
dementia, often from Alzheimer’s disease, late in life is associated with
abnormal blood levels of dozens of proteins up to five years earlier, according
to a new study led by researchers at the Johns Hopkins Bloomberg School of
Public Health. Most of these proteins were not known to be linked to dementia
before, suggesting new targets for prevention therapies.
The findings are based on new analyses
of blood samples of over ten thousand middle-aged and elderly people—samples
that were taken and stored during large-scale studies decades ago as part of an
ongoing study. The researchers linked abnormal blood levels of 38 proteins to
higher risks of developing Alzheimers within five years. Of those 38 proteins,
16 appeared to predict Alzheimer’s risk two decades in advance.
Although most of these risk markers may
be only incidental byproducts of the slow disease process that leads to
Alzheimer’s, the analysis pointed to high levels of one protein, SVEP1, as a
likely causal contributor to that disease process.
The study was published May 14 in Nature
Aging
“This is the most comprehensive analysis
of its kind to date, and it sheds light on multiple biological pathways that
are connected to Alzheimer’s,” says study senior author Josef Coresh, MD, PhD,
MHS, George W. Comstock Professor in the Department of Epidemiology at the
Bloomberg School. “Some of these proteins we uncovered are just indicators that
disease might occur, but a subset may be causally relevant, which is exciting
because it raises the possibility of targeting these proteins with future
treatments.”
More than six million Americans are
estimated to have Alzheimer’s, the most common type of dementia, an
irreversible fatal condition that leads to loss of cognitive and physical
function. Despite decades of intensive study, there are no treatments that can
slow the disease process, let alone stop or reverse it. Scientists widely
assume that the best time to treat Alzheimer’s is before dementia symptoms
develop.
Efforts to gauge people’s Alzheimer’s
risk before dementia arises have focused mainly on the two most obvious
features of Alzheimer’s brain pathology: clumps of amyloid beta protein known
as plaques, and tangles of tau protein. Scientists have shown that brain
imaging of plaques, and blood or cerebrospinal fluid levels of amyloid beta or
tau, have some value in predicting Alzheimer’s years in advance.
But humans have tens of thousands of
other distinct proteins in their cells and blood, and techniques for measuring
many of these from a single, small blood sample have advanced in recent years.
Would a more comprehensive analysis using such techniques reveal other
harbingers of Alzheimer’s? That’s the question Coresh and colleagues sought to
answer in this new study.
The researchers’ initial analysis
covered blood samples taken during 2011–13 from more than 4,800
late-middle-aged participants in the Atherosclerosis Risk in Communities (ARIC)
study, a large epidemiological study of heart disease-related risk factors and
outcomes that has been running in four U.S. communities since 1985.
Collaborating researchers at a laboratory technology company called SomaLogic
used a technology they recently developed, SomaScan, to record levels of nearly
5,000 distinct proteins in the banked ARIC samples.
The researchers analyzed the results and
found 38 proteins whose abnormal levels were significantly associated with a
higher risk of developing Alzheimer’s in the five years following the blood
draw.
They then used SomaScan to measure
protein levels from more than 11,000 blood samples taken from much younger ARIC
participants in 1993–95. They found that abnormal levels of 16 of the 38
previously identified proteins were associated with the development of
Alzheimer’s in the nearly two decades between that blood draw and a follow-up
clinical evaluation in 2011–13.
To verify these findings in a different
patient population, the scientists reviewed the results of an earlier SomaScan
of blood samples taken in 2002–06 during an Icelandic study. That study had
assayed proteins including 13 of the 16 proteins identified in the ARIC
analyses. Of those 13 proteins, six were again associated with Alzheimer’s risk
over a roughly 10-year follow-up period.
In a further statistical analysis, the
researchers compared the identified proteins with data from past studies of
genetic links to Alzheimer’s. The comparison suggested strongly that one of the
identified proteins, SVEP1, is not just an incidental marker of Alzheimer’s
risk but is involved in triggering or driving the disease.
SVEP1 is a protein whose normal
functions remain somewhat mysterious, although in a study published earlier
this year it was linked to the thickened artery condition, atherosclerosis,
which underlies heart attacks and strokes.
Other proteins associated with
Alzheimer’s risk in the new study included several key immune proteins—which is
consistent with decades of findings linking Alzheimer’s to abnormally intense
immune activity in the brain.
The researchers plan to continue using
techniques like SomaScan to analyze proteins in banked blood samples from
long-term studies to identify potential Alzheimer’s-triggering pathways—a
potential strategy to suggest new approaches for Alzheimer’s treatments.
The scientists have also been studying
how protein levels in the ARIC samples are linked to other diseases such as
vascular (blood vessel-related) disease in the brain, heart and the kidney.
First author Keenan Walker, PhD, worked
on this analysis while on faculty at the Johns Hopkins University School of
Medicine and the Bloomberg School’s Welch Center for Prevention, Epidemiology
and Clinical Research. He is currently an investigator with the National
Institute of Aging’s Intramural Research Program.
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