EXPERT REACTION: A step towards a blood test for Alzheimer's

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A blood test for Alzheimer's looks to be one step closer, with promising results from two new studies which looked at levels of a modified protein in people's blood. The first study found that blood levels of the protein, known as p-tau-217, are elevated during the early stages of Alzheimer’s disease. Researchers found that p-tau-217 levels in the blood were extremely low in healthy volunteers but elevated in patients with amyloid plaques, a sign of Alzheimer's disease.  A second study showed that blood plasma p-tau-217 was able to discriminate Alzheimer's disease from other neurodegenerative diseases.

Journal/conference: Journal of Experimental Medicine/JAMA

DOI: 10.1084/jem.20200861

Organisation/s: The University of Adelaide, The University of Melbourne, Washington University School of Medicine, USA, Skåne University Hospital, Sweden

Funder: Paper 1 - Funding for this work includes the Alzheimer’s Association Research Fellowship AARF-16-443265 (to N.R. Barth´elemy), the Rainwater Charitable Foundation (to R.J. Bateman and N.R. Barth´elemy), the National Institutes of Health, National Institute of Neurological Disorders and Stroke grant R01NS095773 (R.J. Bateman), the Tau SILK Consortium (AbbVie, Biogen, and Eli Lilly and Company; principal investigator, R.J. Bateman), and the Coins for Alzheimer’s Research Trust grant (to C. Sato). Paper 2: Work at the authors’ research centers was supported by the Swedish Research Council, the Knut and AliceWallenberg Foundation, Region Skåne, the Marianne and MarcusWallenberg Foundation, the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, The Parkinson Foundation of Sweden, The Parkinson Research Foundation, the Skåne University Hospital Foundation, the Greta and Johan Kock Foundation, the Swedish federal government under the ALF agreement, the NIH Office of the Director, the Alzheimer’s Association, the Massachusetts General Hospital Executive Committee on Research, the National Institute of Neurological Disorders and Stroke (U24 NS072026), National Institute on Aging (P30 AG19610), the Arizona Department of Health Services, the Michael J. Fox Foundation for Parkinson’s Research, Banner Alzheimer’s Foundation, Sun Health Foundation, the State of Arizona, and Eli Lilly and Company. Eli Lilly and Company provided material support for P-tau217 sample analysis and salary for Dr Chai, Mr Proctor, and Dr Dage. The precursor of 18F-flutemetamol was provided by GE Healthcare and the precursor of 18F-RO948 was provided by Roche

Media release

From: Rockefeller University Press

Researchers make significant step toward blood test for Alzheimer’s disease

Researchers at Washington University School of Medicine in St. Louis have developed a technique to detect minute amounts of a protein fragment linked to Alzheimer’s disease in the blood. The study, which will be published July 28 in the Journal of Experimental Medicine (JEM ), shows that levels of p-tau-217 are elevated during the early stages of Alzheimer’s disease and could lead to a simple blood test capable of diagnosing the neurodegenerative disorder years before any symptoms begin to appear.

Alzheimer’s disease is characterized by the presence of plaques in the brain formed by a protein called amyloid-β, as well as aggregates of a protein called tau that form neurofibrillary tangles in the neurons of Alzheimer’s patients. Amyloid-β and tau start to change years before any cognitive symptoms, such as memory loss and confusion, become apparent, but previously the only way to detect them was with a positron emission tomography (PET) scan to visualize the brain, or a spinal tap to measure changing levels of amyloid-β and tau in the cerebrospinal fluid. For many years, researchers have tried to develop blood tests that could detect Alzheimer’s disease before the onset of symptoms while being cheaper and less invasive than PET scans and spinal taps.

Randall Bateman, Nicolas Barthélemy, and colleagues at Washington University School of Medicine in St. Louis previously found that a modified fragment of tau, known as p-tau-217, accumulates in the cerebrospinal fluid of Alzheimer’s patients before the onset of cognitive symptoms, increases with disease progression, and can accurately predict the formation of amyloid plaques.

The researchers suspected that p-tau-217 might also be present in the blood of Alzheimer’s patients, albeit at very low levels that would make it difficult to detect. “We therefore wanted to quantify the levels of different tau proteins, especially p-tau-217, in the blood and compare them with amyloid pathology and onset of dementia to assess their potential as blood-based Alzheimer’s disease biomarkers,” says Bateman, who is the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University School of Medicine.

Barthélemy and colleagues in Bateman’s lab developed a mass spectrometry–based method to measure the amount of p-tau-217 and other tau fragments in as little as 4 ml of blood, even though such small samples may contain less than a trillionth of a gram of p-tau-217. “To our knowledge, this is the lowest concentration ever measured by mass spectrometry for a protein marker in human blood plasma,” says Barthélemy, an assistant professor in Bateman’s laboratory.

The researchers found that, similar to p-tau-217 levels in cerebrospinal fluid, p-tau-217 levels in the blood were extremely low in healthy volunteers but elevated in patients with amyloid plaques, even in those who had yet to develop cognitive symptoms. Measuring blood plasma levels of p-tau-217 was able to accurately predict the presence of amyloid plaques in PET scans, performing better than another tau fragment, p-tau-181, which was previously proposed as a biomarker for Alzheimer’s disease.

“Our findings support the idea that tau isoforms in the blood are potentially useful for detecting and diagnosing Alzheimer’s disease pathology,” Bateman says. “Moreover, our assay for measuring plasma tau levels could be used as a highly sensitive screening tool to identify tau changes associated with amyloid plaque formation in normal subjects, replacing costly PET imaging.”

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  • Journal of Experimental Medicine
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    Paper 1 - Please link to the article in online versions of your report (the URL will go live after the embargo ends).
  • JAMA
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    Paper 2 - Please link to the article in online versions of your report (the URL will go live after the embargo ends).

Expert Reaction

These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.

Dr Ian Musgrave is a Senior Lecturer in the Faculty of Medicine, School of Medicine Sciences, within the Discipline of Pharmacology at the University of Adelaide.

Alzheimer’s disease is the commonest form of dementia in Australia and one of the largest causes of death in the elderly. It is a progressive disease with loss of memory central to it. Brain changes in Alzheimer’s include extensive death of brain cells, the accumulation of clumps of the protein beta-amyloid outside the brain cells, and accumulation of tangles of another protein, tau, inside the brain cells.

Until recently, diagnosis of Alzheimer’s was based on symptoms and post-mortem analysis. More recently, modern imaging systems have allowed brain volume loss to be measured. However, these are still only helpful once the disease has progressed. We would like a test that can pick up the disease early so we can intervene more effectively.

Tests have been developed that track the accumulation of beta-amyloid, but typically they require exposure to radioactive chemicals or invasive sampling. A blood test that could diagnose Alzheimer’s disease early is highly desirable.

The two publications in the Journal of Experimental Medicine and JAMA represent a step in that direction. Both report on measuring levels of a form of tau which is associated with Alzheimer’s disease in blood. Both show a good association with Alzheimer’s disease and the ability to discriminate between Alzheimer’s and other forms of neurodegeneration.

Importantly, these tests may be able to pick up Alzheimer’s before significant damage has occurred. However, there is still a way to go. The numbers of subjects are relatively low and these tests will need to be trialed in larger population groups with more diverse clinical conditions to ensure accuracy.

Also, the techniques are rather specialised and will not be generally available for some time. Finally, at the moment, our therapies for Alzheimer’s merely delay the progression of the disease. While early intervention is important, these tests may be more valuable for testing experimental therapies rather than routine diagnosis.

Last updated: 28 Jul 2020 1:17pm
Declared conflicts of interest:
None declared.
Professor Colin L Masters MD is Laureate Professor of Dementia Research at the Florey Institute and The University of Melbourne

These two independent papers provide compelling evidence that it is possible to use blood plasma assays of p-tau to diagnose Alzheimer’s disease specifically and with a high degree of accuracy.

Two different methods were used (mass spectrometry and immunoassay), and both methods worked very well. Using a large cohort of subjects at genetic risk of early-onset Alzheimer’s disease, the test appears to work many years before the onset of clinical symptoms.

It remains to be determined whether similar predictive results will be obtained in the more common forms of late-onset Alzheimer’s disease.

The performance of this p-tau test will now have to be assessed against another sensitive test which measures plasma beta-amyloid. Together, both tests look very good, and give us a method for early detection and to identify individuals who could be suitable for clinical therapeutic trials which are now progressing.

Last updated: 28 Jul 2020 1:16pm
Declared conflicts of interest:
None declared.

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