A group of neuroscientists led by a University of Pittsburgh School of Medicine researcher developed a test to detect a new marker of Alzheimer’s disease neurodegeneration in a blood sample. A study on its results was published today in Brain.
The biomarker, called “brain-derived 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 disease neurodegeneration in cerebrospinal fluid (CSF).
“Currently, the diagnosis of Alzheimer’s disease requires neuroimaging,” said lead author Thomas Karikari, Ph.D., an 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.”
Currently, to diagnose Alzheimer’s disease, doctors 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 detection of three distinct components of Alzheimer’s pathology: the presence of amyloid plaques, tau tangles, and neurodegeneration in the brain, either by imaging or by analysis of CSF samples. .
Unfortunately, both approaches have 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 that detect signs of Alzheimer’s in blood without compromising quality is an important step toward better accessibility, 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 checkmarks needed to confidently diagnose Alzheimer’s disease. But the biggest hurdle in applying the AT(N) Framework to blood samples lies in the difficulty of detecting markers of neurodegeneration that are specific to the brain and not influenced by potentially misleading contaminants produced elsewhere in the body.
For example, blood levels of light neurofilaments, a protein that markers nerve cell damage, are elevated in Alzheimer’s, Parkinson’s, and other dementias, making it less useful when trying to differentiate Alzheimer’s from other neurodegenerative conditions. On the other hand, the detection of total tau in the blood turned out to be less informative than the monitoring of its levels in the CSF.
By applying their knowledge of molecular biology and biochemistry of tau proteins in different 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 and prevent free floating. . “Large 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 assay in more than 600 patient samples from five independent cohorts, including those from patients whose diagnosis of Alzheimer’s disease was confirmed after their death, as well as from patients with memory deficits indicative of early-stage Alzheimer’s.
The tests showed that BD-tau levels detected in blood samples from Alzheimer’s disease patients using the new assay matched CSF tau levels 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 monitoring BD-tau blood levels could improve clinical trial design and facilitate detection and recruitment of patients from populations that have not historically been included in research cohorts.
“There is a great need for diversity in clinical research, not only because of skin color but also because of socioeconomic status,” Karikari said. “To develop better medicines, trials need to enroll people of 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 the diagnosis of Alzheimer’s disease and the selection of participants for clinical trials and disease monitoring”.
Karikari and her team plan to conduct a large-scale clinical validation of BD-tau in blood in a wide range of research groups, including those recruiting participants from diverse 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 different stages of the disease. These projects are crucial to ensuring that biomarker results can be generalized to people of all backgrounds and will pave the way for BD-tau to be commercially available for widespread clinical and prognostic use.
Other authors of this study are Fernando Gonzalez-Ortiz, BS, Przemys?aw 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, from the University of Brescia, Italy; and Roberta Ghidoni, Ph.D., Luisa Benussi, Ph.D., and Claudia Saraceno, Ph.D., of the RCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
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, Swedish Alzheimer’s Association (Alzheimerfonden; #AF-930627), Swedish Brain Foundation (Hjärnfonden; #FO2020-0240), Swedish Dementia Foundation (Demensförbundet), Swedish Parkinson’s Foundation (Parkinsonfonden), the Gamla Tjänarinnor Foundation, the Aina (Ann) Wallströms and 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’s Foundation, among other sources.
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