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Abnormal blood levels of proteins associated with dementia and Alzheimer’s disease

 


The development of dementia, often due to Alzheimer’s disease, is often associated with abnormal blood levels of dozens of proteins up to five years ago, according to a new study led by researchers at the Johns Hopkins Bloomberg School of Public Health. I will. Most of these proteins were previously unknown to be associated with dementia, suggesting new targets for prophylactic therapy.

The findings are based on a new analysis of blood samples from more than 10,000 middle-aged and older people. These samples were collected and stored during a large study decades ago as part of an ongoing study. Researchers have linked abnormal blood levels of 38 proteins to an increased risk of developing Alzheimer’s disease within 5 years. Of these 38 proteins, 16 appeared to predict the risk of Alzheimer’s disease 20 years ago.

Most of these risk markers may be just an accidental by-product of the slow disease process leading to Alzheimer’s disease, but analysis shows high levels of one protein, SVEP1, that is likely to be responsible for the disease process. Was shown to be.

This study was published on May 14th Nature aging..

This is the most comprehensive analysis to date, shedding light on multiple biological pathways associated with Alzheimer’s disease.Some of these proteins we have discovered are merely indicators of the potential for disease, but subsets may be causal and target these proteins in future treatments. Exciting to increase the possibilities.. “

Josef Coresh, MD, PhD, MHS, Study Senior Author, George W. Comstock Professor, Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University

It is estimated that more than 6 million Americans have Alzheimer’s disease, the most common type of dementia. This is an irreversible fatal condition that leads to loss of cognitive and physical function. Despite decades of intensive research, there is no cure that can slow the progression of the disease, much less stop or reverse it. Scientists widely believe that the best time to treat Alzheimer’s disease is before the onset of dementia symptoms.

Efforts to measure the risk of Alzheimer’s disease in people before the onset of dementia are primarily a mass of amyloid beta protein known as plaque and tau protein entanglement, two of the most obvious features of Alzheimer’s disease brain pathology. Has focused on. Scientists have shown that brain imaging of amyloid plaque, and blood or cerebrospinal fluid levels of amyloid beta or tau, are of some value to predict years before Alzheimer’s disease.

However, humans have tens of thousands of other different proteins in their cells and blood, and techniques for measuring many of these from a single small blood sample have advanced in recent years. Will a more comprehensive analysis using such techniques reveal other precursors to Alzheimer’s disease? That’s the question Coresh and colleagues tried to answer in this new study.

The researchers’ first analysis was from 2011 to 2013, with more than 4,800 people in the Atherosclerosis Community Risk (ARIC) study, a large epidemiological study of risk factors associated with heart disease and their consequences. Blood samples taken from late middle-aged participants were included. Collaborators at an technology company called SomaLogic used a recently developed technology, SomaScan, to record nearly 5,000 different protein levels in banked ARIC samples.

Researchers analyzed the results and found 38 proteins whose abnormal levels were significantly associated with an increased risk of developing Alzheimer’s disease 5 years after blood collection.

Next, SomaScan was used to measure protein levels from over 11,000 blood samples taken from much younger ARIC participants between 1993 and 1995. They found that 16 of the 38 previously identified proteins had abnormal levels associated with the development of Alzheimer’s disease for nearly 20 years from their blood draw to the 2011-13 follow-up clinical evaluation. did.

To validate these findings in different patient populations, scientists reviewed the results of previous SomaScans of blood samples taken in 2002-06 during an Icelandic study. The study analyzed proteins containing 13 of the 16 proteins identified in the ARIC analysis. Of these 13 proteins, 6 were again associated with Alzheimer’s disease risk over a follow-up period of approximately 10 years.

In a further statistical analysis, the researchers compared the identified proteins with data from previous studies on their genetic association with Alzheimer’s disease. Comparison strongly suggested that one of the identified proteins, SVEP1, is not only an accidental marker of risk for Alzheimer’s disease, but also involved in the induction or promotion of the disease.

SVEP1 is a protein whose normal function remains somewhat mysterious, but a study published earlier this year found it associated with the condition of the thickened arteries underlying heart attacks and strokes, atherosclerosis. It was.

Other proteins associated with the risk of Alzheimer’s disease in a new study included several important immune proteins. This is consistent with decades of findings linking Alzheimer’s disease to abnormally strong immune activity in the brain.

Researchers plan to use techniques like SomaScan to analyze proteins in stored blood samples from long-term studies to identify potential pathways to trigger Alzheimer’s disease.

Scientists are also studying how protein levels in ARIC samples are associated with other disorders, such as vascular (vascular-related) disorders of the brain, heart, and kidneys.

The lead author, Dr. Keenan Walker, worked on this analysis as a faculty member at the Johns Hopkins University School of Medicine and the Welch Center for Prevention, Epidemiology, and Clinical Research at Bloomberg School. He is currently a researcher in the National Institute on Aging’s on-campus research program.

“Large-scale plasma proteomics analysis identifies proteins and pathways associated with dementia risk,” said Keenan Walker, Jingsha Chen, Jingning Zhang, Myriam Fornage, Yunju Yang, Linda Zhou, Morgan E. Grams, and Adrienne Tin. , Natalie Daya, Ron Hoogeveen, Aozhou Wu, Kevin Sullivan, Peter Ganz, Scott Zeger, Elias Gudmundsson, Valur Emilsson, Lenore Launer, Lori Jennings, Vilmundur Gudnason, Nilanjan Chatterjee, Rebecca Gottesman, Thoma

Source:

Journal reference:

Walker, KA, et al.. (2021) Extensive plasma proteomics analysis identifies proteins and pathways associated with the risk of dementia. Nature aging.. doi.org/10.1038/s43587-021-00064-0..

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