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New biomarker test can detect Alzheimer’s neurodegeneration in blood

New biomarker test can detect Alzheimer’s neurodegeneration in blood

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Summary: A newly developed blood test can detect brain-derived tau (BD-tau), a biomarker for Alzheimer’s disease neurodegeneration.

source: University of Pittsburgh

A group of neuroscientists led by a Pittsburgh School of Medicine researcher has developed a test to detect a new marker of Alzheimer’s disease neurodegeneration in a blood sample.

A study of their results was published today in the brain.

The biomarker, called “brain tau,” or BD-tau, outperforms current diagnostic blood 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).

“Currently, the diagnosis of Alzheimer’s disease requires neuroimaging,” said senior author Thomas Carikari, Ph.D., assistant professor of psychiatry at Pitt. “These tests are expensive and time-consuming to schedule, and many patients, even in the US, do not have access to MRI and PET scanners. Accessibility is a major issue.”

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

Unfortunately, both approaches suffer from economic and practical limitations, dictating the need to develop convenient and reliable AT(N) biomarkers in blood samples, the collection of which is minimally invasive and requires fewer resources.

Developing simple tools to detect signs of Alzheimer’s in blood without compromising quality is an important step toward improved accessibility, Karikari said.

“The most important benefit of blood biomarkers is to make people’s lives better and to 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, marking two of the three necessary markers for a confident diagnosis of 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 luminal, a protein marker of nerve cell damage, are elevated in Alzheimer’s, Parkinson’s, and other dementias, making it less useful when trying to distinguish Alzheimer’s from other neurodegenerative conditions. On the other hand, detection of total tau in the blood proved to be less informative than monitoring its levels in CSF.

By 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 from the University of Gothenburg, Sweden, developed a technique to selectively detect BD-tau while avoiding free-floating ” large 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 more than 600 patient samples from five independent cohorts, including those from patients whose Alzheimer’s disease diagnosis was confirmed posthumously, as well as from patients with memory deficits indicative of early-stage Alzheimer’s.

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

The scientists hope that tracking blood levels of BD-tau can improve clinical trial design and facilitate the screening and inclusion of patients from populations that have historically not been included in research cohorts.

Current blood diagnostic methods can accurately detect abnormalities in plasma amyloid beta and the phosphorylated form of tau, marking two of the three necessary markers for a confident diagnosis of Alzheimer’s. Image is in the public domain

“There is a huge 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 include people from different backgrounds, not just those who live near academic medical centers. The blood test is cheaper, safer and easier to administer, and may improve clinical confidence in diagnosing Alzheimer’s and selecting participants for clinical trials and monitoring the disease.

Karikari and his team plan to conduct large-scale clinical validation of blood-based BD-tau in a wide range of research groups, including those that recruit participants from different racial and ethnic backgrounds, from memory clinics, and from the community. Additionally, these studies will include older people without biological evidence of Alzheimer’s disease, as well as those in various stages of the disease.

These projects are critical 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.

Fernando Gonzalez-Ortiz, BS, Przemysław Kac, BS, Nicholas Ashton, PhD, and Henrik Zetterberg, MD, PhD, 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 Galasco, MD; Dr. Enrico Premi, Dr. Valentina Cantoni, Dr. Jasmine Rivolta and Dr. Barbara Boroni; and Dr. Roberta Guidoni, Dr. Luisa Benusi, and Dr. Claudia Saraceno of the RCCS San Giovanni di Dio Fatebenefratelli Center, Brescia, Italy.

Financing: This research was supported by the Swedish Research Council (Vetenskåpradet; #2021-03244), the Alzheimer’s Association (#AARF-21-850325), the BrightFocus Foundation (#A2020812F), the International Society of Neurochemistry Career Development Grant, the Swedish Alzheimer Foundation (Alzheimerfonden; #AF-930627), The Swedish Brain Foundation (Hjärnfonden; #FO2020-0240), The Swedish Dementia Foundation (Demensförbundet), The Swedish Parkinson Foundation (Parkinsonfonden), Gamla Tjänarinnor Foundation, Aina (Ann) Wallströms and Foundation Mary-Ann Sjöbloms, 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.

For this Alzheimer’s research news

Author: Anastasia Gorelova
source: University of Pittsburgh
Contact: Anastasia Gorelova – University of Pittsburgh
Image: Image is in the public domain

See also

New biomarker test can detect Alzheimer’s neurodegeneration in blood

Original research: Free access.
Brain-derived tau: a novel blood biomarker for Alzheimer’s disease-type neurodegeneration” by Thomas Karikari et al. brain


Summary

Brain-derived tau: a novel blood biomarker for Alzheimer’s disease-type neurodegeneration

Blood-based biomarkers for amyloid beta and phosphorylated tau show good diagnostic accuracy and agreement with their corresponding CSF biomarkers and neuroimaging biomarkers in amyloid/tau/neurodegeneration [A/T/(N)] framework for Alzheimer’s disease.

However, the blood-based neurodegeneration marker neurofilament light was not specific for Alzheimer’s disease, while total tau showed no correlation with CSF total tau. Recent studies have shown that total blood tau originates mainly from peripheral, non-brain sources.

We sought to address this challenge by generating an anti-tau antibody that selectively binds brain-derived tau and avoids the peripherally expressed “large tau” isoform. We applied this antibody to develop an ultrasensitive blood assay for brain-derived tau and validated it in five independent cohorts (n = 609), including a blood-to-autopsy cohort, cohorts classified by CSF biomarkers, and memory clinic cohorts.

In paired samples, serum and CSF brain-derived tau were significantly correlated (rho = 0.85, P < 0.0001), whereas total tau in serum and CSF was not (rho = 0.23, P = 0.3364). Blood-based brain-derived tau showed equivalent diagnostic performance as CSF total tau and brain-derived tau to separate biomarker-positive participants with Alzheimer’s disease from biomarker-negative controls.

Furthermore, plasma brain-derived tau accurately distinguished autopsy-confirmed Alzheimer’s disease from other neurodegenerative diseases (area under the curve = 86.4%), whereas neurofilament light did not (area under the curve = 54.3%) . These indicators do not depend on the presence of concomitant pathologies. Brain-derived plasma tau (rho = 0.52–0.67, P = 0.003) but not neurofilament light (rho = −0.14–0.17, P = 0.501), was associated with the number of global and regional amyloid plaques and neurofibrillary tangles.

These results were further confirmed in two memory clinic cohorts, where brain-derived serum tau differentiated Alzheimer’s disease from a number of other neurodegenerative diseases, including frontotemporal lobar degeneration and atypical parkinsonian disorders (area under the curve up to 99.6%).

Of note, plasma/serum brain-derived tau correlated with neurofilament brightness only in Alzheimer’s disease but not in other neurodegenerative diseases. In cohorts, brain-derived plasma/serum tau was associated with CSF and plasma AT(N) biomarkers and cognitive function.

Brain-derived tau is a novel blood biomarker that outperforms total plasma tau and, unlike neurofilament light, shows specificity for Alzheimer’s-type neurodegeneration.

Thus, brain-derived tau demonstrates the potential to complete the AT(N) circuit in blood and will be useful for assessing Alzheimer’s disease-dependent neurodegenerative processes for clinical and research purposes.


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