July 19, 2017

LONDON — A blood test that correlates well with brain amyloid levels could soon be available and may provide a simple screen to identify individuals at high risk of developing the condition.

Results from a new study showing that results from the blood test correlate with amyloid levels measured by cerebrospinal fluid (CSF) sampling and positron emission tomography (PET) were presented here at the Alzheimer's Association International Conference (AAIC) 2017. They are also published online July 19 in Alzheimer's and Dementia

"Our results show that this simple blood test tells us with very good specificity who has amyloid plaques and gives us a good idea who likely doesn't," lead author, Randall J. Bateman, MD, Washington University School of Medicine, St. Louis, Missouri, commented to Medscape Medical News. "This could revolutionize the field."

Dr Randall J. Bateman

Noting that amyloid plaques start to form many years before symptoms develop, Dr Bateman said the blood test represents a quick and easy way of finding people with these early plaques.

"They can then be enrolled into clinical trials of strategies to prevent or delay the disease, and eventually the test could be used to screen in mid-life to identify individuals for whom we need to target treatments.

"This is cutting edge," he added. "People have been trying to measure β-amyloid in the blood for many years without success."

Dr Bateman and Washington University have equity ownership interest in C2N Diagnostics, a company established to commercialize this test.

Commenting for Medscape Medical News, Cynthia Lemere, PhD, associate professor of neurology at Brigham & Women's Hospital, Boston, Massachusetts, called the findings "extremely exciting."

"We desperately need something like this," Dr Lemere said. "It is not practical to do PET scans or CSF taps on everybody, so something simple like this blood test would make a lot of difference."

"This would be an early test — a good way to rule in or rule out people who might be on the Alzheimer's path," she added. "If positive, then these are the ones in whom further tests, such as CSF and PET scans, can be justified."

Also commenting for Medscape Medical News,  Ron Petersen, MD, director of the Alzheimer's Disease Research Center at the Mayo Clinic, Rochester, Minnesota, said, "This is an exciting finding but it needs replicating by other institutions in other populations. Many others have tried to achieve a reliable blood measure that reflects amyloid levels in the brain, but their results haven't been able to be replicated by other groups.  If these current results can be reproduced in larger populations, it will be a great breakthrough."

The current study involved 41 participants who were research volunteers at Washington University's Alzheimer's Center. There was no requirement for Alzheimer's risk factors, and most participants were cognitively normal, although some had very mild cognitive impairment (average score on Mini-Mental State Examination, 28).

They underwent PET and/or CSF testing for amyloid, and the researchers used a technique known as stable isotope labeling kinetics, which involves administration of labeled leucine to track three forms of soluble amyloid-β in the blood.

Results showed that the key pathogenic form of amyloid (amyloid- β 42) has a shorter half-life and was present in lower concentrations in the blood in patients who had amyloid plaques in their brain.

Dr Bateman explained that this is the same thing as seen in the CSF. "It may be somewhat counterintuitive to see lower levels of β-amyloid 42 in the CSF and blood in patients with the disease, but this is because it is not getting cleared from the brain; instead it is getting stuck in the brain and that is the beginning of the formation of amyloid plaques."

He noted that measuring amyloid in the blood is very challenging. "Levels in blood are 50 times less than in the CSF, but the other problem — and what has really confounded the field — is that there are 1000 times more other proteins in the blood. So we call that the 50,000-fold problem. You have 50 times less of what you are looking for and 1000 times more of what you're not looking for."

He reported that a second, larger study has also been conducted in 180 people, including a larger spectrum of disease risk with typical Alzheimer's patients as well as healthy individuals and those with very early pathology. 

"This essentially replicated what we found in the first 41-patient study," he noted. "That's important as it was done in a different group, with samples collected in a different way, but showed the same results."

The team is now starting a larger multicenter study.

Test Will Accelerate Clinical Trials

Dr Bateman said the first practical use of the test will be in screening participants for clinical trials.

"We desperately need to accelerate trials for new interventions that could potentially slow or prevent the development of Alzheimer's," he said. "These trials need to be done in people who are at high risk for developing the condition, but you have to screen thousands of people to find a few hundred to enroll. Having to do CSF taps and PET scans in all these people would take years."

But thousands of blood samples could be screened using this approach, and CSF testing and PET would be performed only in those flagged as high risk, he said, potentially cutting enrollment times by years. "We need to test many more interventions to greatly increase our attempts at a shot on goal," Dr Bateman said. "This will help enormously. I would say the blood test would be available for this use within a year."

In terms of clinical use, Dr Bateman said this will come into its own when a treatment to slow disease progression becomes available. "Then we will need to screen millions of people in midlife."

But even now with the evidence available — that following a healthy lifestyle can be beneficial — having an easy test to assess your risk could be helpful, he suggests. "If you know you are one of those who will likely develop Alzheimer's in the future, that may be the incentive needed to start making lifestyle changes."

He points out that at present confirmation is needed from PET scans because the blood test can produce some false-positive results.

"These are people who show positive results on the blood test but do not appear to have amyloid plaques on PET scans," Dr Bateman said. "But they may not actually be completely false positives —these individuals may be on their way to getting amyloid plaques. Tests in the CSF and blood appear to detect amyloid earlier than PET scans — maybe because it takes time for amyloid to lay down in the brain."

He reports that the blood test currently seems to be able to correctly identify 95% of individuals who have amyloid plaques and about 75% of those who don't. "The question is in the 25% of those who don't have plaques: Will they go on to develop them in several years' time? We will have to do longitudinal studies to see this."

This work was supported by grants from the Alzheimer's Association and the MetLife Foundation. Dr Bateman and Washington University have equity ownership interest in C2N Diagnostics, a company established to commercialize this test.

Alzheimer's Association International Conference (AAIC) 2017. Abstract 19667. Presented July 19, 2017.  

Alzheimer's & Dementia. Published online July 19, 2017. Abstract

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