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In the Pipeline-Alzheimer's Disease

Evidence for a Blood Test for Alzheimer's Disease

Fitzgerald, Susan

doi: 10.1097/01.NT.0000531198.45994.44
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A blood test was found effective for identifying amyloid-beta biomarkers for Alzheimer's disease, but the researchers said more testing is needed before it can be applied outside of a research setting.

A blood test that measures amyloid biomarkers was found to be a highly accurate predictor of whether a person has brain amyloid suggestive of Alzheimer's disease (AD), according to a report in the February 8 issue of Nature.

The paper by researchers from Japan and Australia comes just months after a team from Washington University in St. Louis independently described encouraging results on a similar blood test for amyloid-beta (Abeta).

“A body of evidence is growing that amyloid deposition in the brain is an initial pathological event of AD, which emerges 20 to 30 years before the onset of cognitive decline,” said Katsuhiko Yanagisawa, MD, one of the researchers who reported on the new blood test, in an email to Neurology Today.

“We strongly hope our method contributes to the understanding of AD and facilitates clinical trials of AD, in which early detection of amyloid deposition is crucially required,” said Dr. Yanagisawa, director-general of the Research Institute at the National Center for Geriatrics and Gerontology in Japan.

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The Japanese and Australian research team used a blood testing method that involved immunoprecipitation of Abeta peptides — a process used to isolate and concentrate a protein from a sample containing many thousands of different proteins — followed by mass spectrometry. They focused on three amyloid peptides, Abeta 40, Abeta 42, and APP 699-711. They used two existing datasets — one involving a cohort of 121 people in Japan and the other comprising 252 people in Australia — to compare findings to the results of positron emission tomography (PET) scans and cerebrospinal fluid (CSF) testing for amyloid.

The cohorts included cognitively normal people, people with mild cognitive impairment, and individuals with diagnosed Alzheimer's disease.



“All test biomarkers showed high performance when predicting brain amyloid-beta burden,” the researchers reported; the blood test demonstrated an accuracy rate of about 90 percent. The researchers also found a high correlation between blood tests and CSF results.

The researchers calculated ratios of the different amyloid biomarkers and a composite score of the various biomarkers. Increases in the composite score suggest that amyloid is building up in the brain, Dr. Yanagisawa said.

“These results demonstrate the potential clinical utility of plasma biomarkers in predicting brain amyloid-beta burden at an individual level,” the researchers reported. “These plasma biomarkers also have cost-benefit and scalability advantages over current techniques, potentially enabling broader clinical access and efficient population screening.”

The reported test is not available outside the research team's labs, Dr. Yanagisawa said, and it still needs to be replicated and further refined before it will be ready for use in research studies and physician offices.

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Independent researchers interviewed by Neurology Today said the finding is highly promising, but that testing and analytic methods used by the Japanese and Australian team need to be replicated and confirmed.

Randall Bateman, MD, who was part of the Washington University team that earlier reported on a similar blood test, described the new report from Japan and Australia as “brilliant.”

“People have been trying for a long time to get a highly precise and accurate blood test for Alzheimer's disease,” said Dr. Bateman, the Charles F. and Joanne Knight Distinguished Professor of Neurology. “They independently came to the same conclusions we did. When you have two independent groups that have similar findings and conclusions...that is an indication that this is really going to work.”



Dr. Bateman, whose team published its findings last year in Alzheimer's & Dementia, said that while it would take time and more research to replicate findings from the two studies, he expects that a blood test to screen for amyloidosis related to Alzheimer's is coming in the next few years. “I think we are going to look back on these early findings and see that they were a great development for our field,” said Dr. Bateman, who has a financial stake in a company set up to develop such a test.

Dr. Bateman said his Washington University team is now moving to further evaluate their amyloid blood test using a larger sample of people. He said having such a test could be useful in clinical practice “as a first pass, to see whether someone may have amyloid plaque in their brain or not.” Follow-up testing of CSF or a PET scan could be done if indicated.

“It is difficult to accurately diagnose someone with Alzheimer's,” Dr. Bateman said, and a probable diagnosis is typically made using clinical and cognitive tests. He said that one day there may be a panel of biomarkers to screen for Alzheimer's disease. Tau is another target of interest, and blood tests for that protein are under development, he noted.



“This is almost the exact same method as was used in St. Louis, but it was done using a larger cohort,” said Douglas R. Galasko, MD, professor of neurology of at the University of California. San Diego (UCSD). (The Washington University team tested its method using a cohort of 41 people.)

“Right now, this suggests that this could be a useful screening test,” said Dr. Galasko, director of the UCSD Shiley-Marcos Alzheimer's Disease Research Center. He said researchers investigating a new drug could narrow their pool of potential study participants by giving them an amyloid biomarker screening test.

“We critically need drugs that work. That is a major mission of everyone in the Alzheimer's field,” Dr. Galasko said. Having a reliable screening tool for Alzheimer's could “be a critically useful tool to get the right people into clinical trials.”

Dr. Galasko said there have been instances in which it was discovered after the fact that participants in Alzheimer's drug trials did not have the disease. Such shortcomings can skew results. Another problem is that it can be hard to identify people with early signs of disease, a stage where they might most benefit from drug therapy because significant brain injury hasn't yet occurred.

As for its value as a diagnostic tool, “Further work is needed to evaluate whether this type of plasma test could be used for diagnostic purposes,” Dr. Galasko said.

John C. Morris, MD, FAAN, the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology at Washington University, who also is part of the team that is investigating the blood test, said this new study from Japan and Australia of amyloid biomarkers confirms that “there is a signal in the blood that seems to correlate with the presence of amyloid in the brain,” but he likewise cautioned that more work will be necessary to make the test “ready for clinical trials, much less for use in the clinic.”

Dr. Morris, director of the Knight Alzheimer's Disease Research Center, said additional questions need to be addressed, including whether the test could differentiate Alzheimer's disease dementia from other dementing disorders such as Lewy body dementia and frontal lobe dementia.

He said the test might also be beneficial for tracking disease progression over time, or inversely, a positive response to therapy, but studies to demonstrate the effectiveness of such uses have yet to be done.

A downside to screening is the issue of what to do with the information. “Even if the blood test is validated, its use for routine screening for Alzheimer's risk poses several difficulties, including the fact that there currently are no effective therapies to prevent or treat Alzheimer's,” said Dr. Morris. “Should truly effective therapies be developed, then using the test to screen for Alzheimer's can be reconsidered.”

But even then, some people with amyloid plaque in the brain will never exhibit symptoms of Alzheimer's disease, so a blood test, no matter how accurate, is not the final word on a person's fate, he noted.



Dr. Morris said the goal is to use blood testing as part of an Alzheimer's prevention effort early on in the disease process, in the same way people are tested for high cholesterol and put on statin drugs to ward off cardiovascular disease.

“We want to identify risk factors before they accumulate and cause a problem,” he said.

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Several of the study authors are employees of Shimadzu, which holds patents related to the study results. Dr. Bateman has equity ownership interest in C2N Diagnostics and receives royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics, and has received income from serving on the C2N scientific advisory board. Drs. Morris and Galasko reported no conflicts.

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•. Nakamura A, Kaneko N, Villemagne VL, et al High performance plasma amyloid-β biomarkers for Alzheimer's disease Nature 2018; 554(7691):249–254.
•. Ovod V, Ramsey KN, Mawuenyega KG, et al Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis http:// Alzheimers Dement 2017:13(8):841–849.
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