New Biomarker Can Detect Neurodegeneration in Blood

Neuroscientists have developed a groundbreaking test that can detect a unique marker of Alzheimer’s disease neurodegeneration in a blood sample.

A group of neuroscientists developed a test to detect a new marker of Alzheimer’s disease neurodegeneration in a blood sample. A study on their results, which was led by a researcher from the University of Pittsburgh School of Medicine, was published on December 27 in the journal Brain.

The biomarker, called “brain-derived tau,” or BD-tau, outperforms current blood diagnostic tests used to clinically detect Alzheimer’s-related neurodegeneration. It is specific for Alzheimer’s disease and correlates well with biomarkers of Alzheimer’s neurodegeneration in cerebrospinal fluid (CSF).

“Right now, diagnosing Alzheimer’s disease requires neuroimaging,” said senior author Thomas Karikari, Ph.D., assistant professor of psychiatry at Pitt. “Those tests are expensive and take a long time to schedule, and many patients, even in the US, don’t have access to MRIs and PET scanners. Accessibility is a major issue.”

Currently, to diagnose Alzheimer’s disease, clinicians use guidelines established in 2011 by the National Institute on Aging and the Alzheimer’s Association. The guidelines, called the AT(N) Framework, call for detecting three distinct components of Alzheimer’s pathology — the presence of amyloid plaques, tau tangles and neurodegeneration in the brain — either with imaging or by analyzing CSF samples.

Thomas Karikari, Ph.D. Credit: Thomas Karikari

Unfortunately, both approaches suffer from economic and practical limitations, dictating the need to develop suitable and reliable AT(N) biomarkers in blood samples, the collection of which is minimally invasive and requires fewer resources. Developing simple tools that detect signs of Alzheimer’s in blood without compromising quality is an important step toward improving access, Karikari said.

“The most important utility of blood biomarkers is to improve people’s lives and improve clinical confidence and risk prediction in the diagnosis of Alzheimer’s disease,” Karikari said.

Current blood diagnostic methods can accurately detect abnormalities in plasma amyloid beta and the phosphorylated form of tau, hitting two of the three markers needed to reliably diagnose Alzheimer’s. But the biggest hurdle in applying the AT(N) framework to blood samples lies in the difficulty of detecting markers of neurodegeneration that are brain-specific and unaffected by potentially misleading contaminants produced elsewhere in the body.

For example, blood levels of neurofilament light, a protein marker of nerve cell damage, are increased in Alzheimer’s disease, Parkinson’s disease, and other dementias, making it less useful when trying to distinguish Alzheimer’s disease from other conditions. other neurodegenerative. On the other hand, detection of total tau in blood proved to be less informative than monitoring its levels in CSF.

Applying their knowledge of the molecular biology and biochemistry of tau proteins in various tissues, such as the brain, Karikari and his team, including scientists at the University of Gothenburg, Sweden, developed a technique to selectively detect BD-tau by avoid free sailing. “Big tau” proteins produced by cells outside the brain.

To do this, they created a special antibody that selectively binds to BD-tau, making it easily detectable in the blood. They validated their analysis in over 600 patient samples from five independent groups, including those from patients whose diagnosis of Alzheimer’s disease was confirmed after their death, as well as from patients with memory deficits that indicate early-stage Alzheimer’s.

Tests showed that BD-tau levels detected in blood samples of Alzheimer’s patients using the new assay matched tau levels in CSF and reliably distinguished Alzheimer’s from other neurodegenerative diseases. BD-tau levels also correlated with the severity of amyloid plaques and tau tangles in brain tissue confirmed through brain autopsy analyses.

The scientists hope that monitoring blood levels of BD-tau can improve clinical trial design and facilitate the screening and enrollment of patients from populations historically underserved in research groups.

“There is a great need for diversity in clinical research, not only by skin color, but also by socioeconomic background,” Karikari said. “To develop better drugs, trials need to enroll people from diverse backgrounds and not just those who live near academic medical centers. A blood test is cheaper, safer and easier to administer and can improve clinical confidence in diagnosing Alzheimer’s and selecting participants for clinical trials and disease monitoring.

Karikari and his team are planning to conduct large-scale clinical evaluation of blood BD-tau in a wide range of research groups, including those recruiting participants from different racial and ethnic backgrounds, from memory clinics, and from the community . Additionally, these studies will include older adults with no biological evidence of Alzheimer’s disease, as well as those at different stages of the disease. These projects are essential to ensure that biomarker results are generalizable to people of all backgrounds and will pave the way to making BD-tau commercially available for widespread clinical and prognostic use.

Reference: “Brain-derived tau: a new blood-based biomarker for neurodegeneration of the Alzheimer’s disease type” by Fernando Gonzalez-Ortiz, Michael Turton, Przemyslaw R Kac, Denis Smirnov, Enrico Premi, Roberta Ghidoni, Luisa Benussi, Claindia Saraceno and Jasmine Rivolta, December 27, 2022, Brain.
DOI: 10.1093/tru/awac407

Additional authors of this study are Fernando Gonzalez-Ortiz, BS, Przemyslaw Kac, BS, Nicholas Ashton, Ph.D., and Henrik Zetterberg, MD, Ph.D., of the University of Gothenburg, Sweden; Michael Turton, Ph.D., and Peter Harrison, Ph.D., of Bioventix Plc, Farnham, UK; Denis Smirnov, BS, and Douglas Galasko, MD, of the University of California, San Diego; Enrico Premi, MD, Valentina Cantoni, Ph.D., Jasmine Rivolta, Ph.D., and Barbara Borroni, MD, of the University of Brescia, Italy; and Roberta Ghidoni, Ph.D., Luisa Benussi, Ph.D., and Claudia Saraceno, Ph.D., of RCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.

This research was supported by the Swedish Research Council (Vetenskåpradet; #2021-03244), Alzheimer’s Association (#AARF-21-850325), BrightFocus Foundation (#A2020812F), International Society for Neurochemistry Career Development, Swedish Grant, Alzheim , Foundation (Alzheimerfonden; #AF-930627), Swedish Brain Foundation (Hjärnfonden; #FO2020-0240), Swedish Dementia Foundation (Demensförbundet), Swedish Parkinson Foundation (Parkinsonfonden), Gamla Tjänarinnor Foundation, Aina Foundation (Ann and Wallströms) The Mary-Ann Sjöbloms Foundation, the Agneta Prytz-Folkes & Gösta Folkes Foundation (#2020-00124), the Gun and Bertil Stohnes Foundation, and the Anna Lisa and Brother Björnsson Foundation, among other sources.