A group of neuroscientists led by a researcher from the University of Pittsburgh School of Medicine 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 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).
“Currently, the diagnosis of Alzheimer’s disease requires neuroimaging,” said lead 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. Availability is the main issue.”
Doctors 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 tangles, and neurodegeneration in the brain—either by imaging or by analyzing CSF samples.
Unfortunately, both approaches suffer from economic and practical limitations that dictate the need to develop suitable and reliable AT(N) biomarkers in blood samples that are minimally invasive and require fewer resources. Developing simple tools to detect signs of Alzheimer’s disease in blood without compromising quality is an important step toward improving availability, Karikari said.
“The most important contribution 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 check boxes for a reliable diagnosis of 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 brain-specific and unaffected by potentially misleading contaminants produced elsewhere in the body.
For example, the blood level of neurofilament light, a protein marker of nerve cell damage, is increased 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, detection of total tau in blood has been shown 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 from the University of Gothenburg, Sweden, developed a technique to selectively detect BD-tau while avoiding free movement. “big tau” proteins produced by cells outside the brain.
They designed a special antibody that selectively binds to BD-tau, making it easily detectable in the blood. They validated their test on more than 600 patient samples from five independent cohorts, including patients diagnosed with Alzheimer’s disease after their death, as well as patients with memory deficits indicative of early-stage Alzheimer’s disease.
Tests showed that levels of BD-tau detected in blood samples from Alzheimer’s patients using the new test matched tau levels in cerebrospinal fluid 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 researchers 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 huge need for diversity in clinical research, not just by skin color but also by socioeconomic background,” Karikari said. “In order to develop better drugs, studies need to involve people from different backgrounds, not just those who live near academic medical centers. The blood test is cheaper, safer and easier to perform and may improve clinical confidence in the diagnosis of Alzheimer’s disease and the selection of participants for clinical trials and disease monitoring.”
Karikari and his team plan to conduct large-scale clinical validation of blood BD-tau in a wide variety 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 individuals at various stages of the disease. These projects are key to ensuring that biomarker results are generalizable to people from all backgrounds and will pave the way to commercially available BD-tau for broad clinical and prognostic use.
By: Vaishali verma
