New biomarker test can detect Alzheimer’s neurodegeneration in blood
Abstract: A newly developed blood test can detect brain-derived tau (BD-tau), a biomarker of Alzheimer’s disease neurodegeneration.
Source: University of Pittsburgh
A group of neuroscientists led by a University of 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 on their results was published today in Brain.
The biomarker, called “brain-derived tau,” or BD-tau, outperforms current diagnostic blood tests used to clinically detect neurodegeneration associated with Alzheimer’s disease. It is specific for Alzheimer’s disease and correlates well with biomarkers of Alzheimer’s neurodegeneration in cerebrospinal fluid (CSF).
“Currently diagnosing Alzheimer’s disease requires neuroimaging,” said senior author Thomas Karikari, Ph.D., assistant professor of psychiatry at Pitt. “These tests are expensive and take a long time to schedule, and many patients, even in the US, do not have access to MRI and PET scanners. Affordability is a big problem.”
Currently, clinicians 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 the detection of three distinct components of Alzheimer’s pathology — the presence of amyloid plaques, tau knots 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 suitable 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 disease in blood without compromising quality is an important step toward improved availability, 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 necessary tick boxes to reliably diagnose Alzheimer’s disease.
But the biggest hurdle in applying the AT(N) framework to blood samples lies in the difficulty of detecting brain-specific markers of neurodegeneration that are unaffected by potentially misleading contaminants produced elsewhere in the body.
For example, blood levels of neurofilament light, a protein marker of nerve cell damage, become elevated in Alzheimer’s disease, Parkinson’s disease and other dementias, making it less useful when trying to distinguish Alzheimer’s disease from other neurodegenerative conditions. On the other hand, the detection of total tau in the blood has been shown to be less informative than the monitoring of its level in the cerebrospinal fluid.
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 in Sweden, developed a technique to selectively detect BD-tau, avoiding free-floating “big tau” proteins produced by cells outside the brain.
To do this, they designed a special antibody that selectively binds to BD-tau, making it easily detectable in the blood. They validated their test in over 600 patient samples from five independent cohorts, including those patients whose Alzheimer’s disease diagnosis was confirmed after their death, as well as patients with memory deficits indicative of early-stage Alzheimer’s disease.
The tests showed that levels of BD-tau detected in blood samples from Alzheimer’s patients using the new test 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 loops in brain tissue confirmed by brain autopsy analyses.
The scientists hope that monitoring blood levels of BD-tau could improve the design of clinical trials and facilitate the screening and inclusion of patients from populations historically not included in research cohorts.
“There is a tremendous need for diversity in clinical research, not only by skin color, but also by socioeconomic background,” Karikari said.
“To develop better drugs, trials must 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 can improve clinical confidence in diagnosing Alzheimer’s disease and selecting participants for clinical trials and disease monitoring.”
Karikari and his team plan to conduct a large-scale clinical validation 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. In addition, these studies will include older adults without biological evidence of Alzheimer’s disease, as well as those at various stages of the disease.
These projects are critical to ensure that biomarker results can be generalized to people from all backgrounds and will pave the way for BD-tau to become commercially available for widespread clinical and prognostic use.
Fernando Gonzalez-Ortiz, BS, Przemysław Kac, BS, Nicholas Ashton, PhD, and Henrik Zetterberg, MD, PhD, from 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; Enrico Premi, MD, Valentina Cantoni, MD, Jasmine Rivolta, MD, and Barbara Borroni, MD; and Roberta Ghidoni, Ph.D., Luisa Benussi, Ph.D., and Claudia Saraceno, Ph.D., of the RCCS Instituto 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 for Neurochemistry Career Development Grant, the Swedish Alzheimer’s Association Foundation ( Alzheimerfonden; #AF-930627), Swedish Brain Foundation (Hjärnfonden; #FO2020-0240), Swedish Dementia Foundation (Demensförbundet), Swedish Parkinson Foundation (Parkinsonfonden), Gamla Tjänarinnor Foundation, Aina (Ann) Wallströms and Mary-Ann Foundation Sjöbloms, the Agneta Prytz-Folkes & Gösta Folkes Foundation (#2020-00124), the Gun and Bertil Stohnes Foundation, and the Anna Lis and Brother Björnsson Foundation, among other sources.
About this Alzheimer’s research news
Original research: Open access.
“Brain-derived tau: a novel blood-based biomarker for Alzheimer’s-type neurodegeneration” by Thomas Karikari et al. Brain
Brain-derived tau: a novel blood-based biomarker for Alzheimer’s-type neurodegeneration
Blood-based biomarkers for amyloid beta and phosphorylated tau show good diagnostic accuracy and agree with their corresponding CSF and neuroimaging biomarkers in amyloid/tau/neurodegeneration [A/T/(N)] framework for Alzheimer’s disease.
However, the blood-based neurodegeneration marker neurofilament light is not specific for Alzheimer’s disease, while total tau shows a lack of correlation with total CSF tau. Recent studies suggest that total tau in the blood mainly originates from peripheral sources outside the brain.
We sought to address this challenge by creating an anti-tau antibody that selectively binds brain-derived tau and avoids the peripherally expressed ‘big tau’ isoform. We applied this antibody to develop an ultrasensitive blood test for brain-derived tau and validated it in five independent cohorts (n = 609) including a blood-to-autopsy cohort, CSF biomarker-classified cohorts, and memory clinic cohorts.
In paired samples, brain-derived tau in serum and CSF correlated significantly (rho = 0.85, P < 0.0001), while total tau in serum and cerebrospinal fluid is not (rho = 0.23, P = 0.3364). Blood-based brain-derived tau demonstrated equivalent diagnostic performance to total CSF tau and brain-derived CSF tau to separate biomarker-positive Alzheimer disease participants from biomarker-negative controls.
Furthermore, brain plasma-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 performances were independent of the presence of accompanying pathologies. tau obtained from brain plasma (rho = 0.52–0.67, P = 0.003), but not neurofilament light (rho = −0.14–0.17, P = 0.501), was associated with global and regional numbers of amyloid plaques and neurofibrillary tangles.
These results were further confirmed in two groups of memory clinics where serum brain-derived tau distinguished Alzheimer’s disease from a variety of other neurodegenerative disorders, including frontotemporal lobar degeneration and atypical parkinsonian disorders (area under the curve up to 99.6%).
Namely, tau obtained from brain plasma/serum correlated with neurofilament light only in Alzheimer’s disease, but not in other neurodegenerative diseases. Across groups, tau derived from brain plasma/serum was associated with CSF and plasma AT(N) biomarkers and cognitive function.
Brain-derived tau is a novel blood-based biomarker that outperforms total plasma tau and, unlike neurofilament light, shows specificity for Alzheimer’s-type neurodegeneration.
Thus, brain-derived tau shows the potential to complete the AT(N) scheme in the blood, and will be useful for evaluating the neurodegenerative processes dependent on Alzheimer’s disease for clinical and research purposes.