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.
Reference:
Keenan A. Walker, Jingsha Chen, Jingning Zhang, Myriam Fornage, Yunju Yang,
Linda Zhou, Morgan E. Grams, Adrienne Tin, Natalie Daya, Ron C. Hoogeveen,
Aozhou Wu, Kevin J. Sullivan, Peter Ganz, Scott L. Zeger, Elias F.
Gudmundsson, Valur Emilsson, Lenore J. Launer, Lori L. Jennings, Vilmundur
Gudnason, Nilanjan Chatterjee, Rebecca F. Gottesman, Thomas H. Mosley, Eric
Boerwinkle, Christie M. Ballantyne, Josef Coresh. Large-scale plasma
proteomic analysis identifies proteins and pathways associated with dementia
risk. Nature Aging, 2021; 1 (5): 473 DOI:
10.1038/s43587-021-00064-0