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New blood test differentiates neurodegeneration in Alzheimer's disease from other dementias

Summary: Researchers have developed a new blood test for brain-derived Tau that can follow and track the progression of Alzheimer’s disease, ruling out other dementias.

Source: University of Gothenburg

A new blood test that can track and follow the neurodegeneration in Alzheimer’s disease – and rule out other dementias. This is an innovation presented now by researchers from the University of Gothenburg, together with colleagues from Italy and the United States.

In recent years, much effort has been put into developing blood biomarkers that could help diagnose and monitor Alzheimer’s disease (AD). Tau – one of the main proteins involved in the pathology of AD – has been the focus of extensive research in the field of biomarkers.

The new blood-based phosphorylated tau markers for AD that have emerged over the past two years have proven that it is possible to have an affordable and effective test to screen patients with suspected Alzheimer’s disease.

However, measuring brain proteins in blood is a major challenge, even with current technologies. Scientists at the University of Gothenburg and their industry partners have created a new antibody that specifically targets tau isoforms originating in the brain, taking advantage of architectural differences in the structure of tau protein found in brain versus peripheral sources.

Meets an unmet need

This discovery allowed them to develop a new blood test that specifically and selectively measures unphosphorylated tau coming from the brain into the bloodstream. This innovation addresses an urgent unmet need; a blood test that screens for neurodegenerative changes specifically in Alzheimer’s disease, but not in other dementias.

The new brain-derived tau (BD-tau) assay showed robust and stable technical performances in blood. Clinically, there were strong correlations between blood and CSF levels of BD-tau, indicating that the assay was measuring brain tau. Thanks to a collaboration between Italy, USA and Sweden, they measured BD-tau levels in blood samples from 609 patients.

In a cohort of individuals who received an autopsy-verified diagnosis, plasma BD-tau was shown to be a marker of neurodegeneration that differentiated Alzheimer’s disease from non-Alzheimer-related dementias. Remarkably, plasma BD-tau, but not light neurofilament (NfL), correlated with amyloid plaque and tau tangle burdens in the brains of these individuals, further showing its specificity for Alzheimer’s disease.

High precision to differentiate

To demonstrate the clinical usefulness of these results, the researchers studied two separate memory clinic cohorts in which participants were given a diagnosis of Alzheimer’s disease, other dementias, or controls. Again, BD-tau plasma had a high accuracy in differentiating Alzheimer’s disease from other dementias, also outperforming NfL plasma.

This shows a researcher testing a blood sample.
The new blood-based phosphorylated tau markers for AD that have emerged over the past two years have proven that it is possible to have an affordable and effective test to screen patients with suspected Alzheimer’s disease. The image is in the public domain

The results show that plasma BD-tau is a new blood biomarker that can distinguish between AD and other types of dementia, and unlike other blood biomarkers such as NfL, BD-tau uniquely reflects the extent of neurodegeneration in patients with Alzheimer’s disease. Alzheimer’s. .

Ten years ago, the National Institutes on Aging and the US Alzheimer’s Association proposed a framework for identifying and assessing the progress of Alzheimer’s disease using biological evidence.

This structure, known as the AT(N) template, focuses on biomarkers of amyloid (A), tau (T), and neurodegeneration (N), and was authenticated using cerebrospinal fluid (CSF) and neuroimaging biomarkers. CSF AT(N) markers include amyloid beta (Aβ42/40), phosphorylated tau (p-tau) and total tau.

Fast and affordable blood test

However, it was not possible to fully implement the AT(N) system using blood biomarkers. This is because it lacks an N-marker that shows specificity for the pathophysiology of Alzheimer’s. Plasma BD-tau allows to complete the AT(N) scheme in the blood as a true neurodegeneration marker that is specific for Alzheimer-type pathology.

From a research perspective, BD-tau will be useful for understanding neurodegenerative processes in Alzheimer’s disease and how they differ from those in other dementias. From a clinical point of view, BD-tau can be easily implemented as a quick and affordable blood test to diagnose and monitor disease progression in patients with AD.

About This Alzheimer’s Research News

Author: Margareta Gustafsson Kubista
Source: University of Gothenburg
Contact: Margareta Gustafsson Kubista – University of Gothenburg
Image: The image is in the public domain

Original search: Free access.
“Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-like neurodegeneration” by Kaj Blennow et al. Brain


Summary

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

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It shows a brain and a question mark

Blood biomarkers for beta-amyloid and phosphorylated tau show good diagnostic accuracy and agreements with their CSF counterparts and neuroimaging biomarkers in amyloid/tau/neurodegeneration [A/T/(N)] picture of 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 tau in CSF. Recent studies suggest that total blood tau originates primarily from peripheral, not brain, sources.

We sought to meet this challenge by generating an anti-tau antibody that selectively binds to brain-derived tau and avoids the peripherally expressed ‘large tau’ isoform.

We applied this antibody to develop an ultrasensitive blood-based assay for brain-derived tau and validated it in five independent cohorts (n = 609), including an autopsy blood cohort, cohorts sorted by CSF biomarkers, and memory clinic cohorts.

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

Furthermore, brain plasma-derived tau accurately distinguished autopsy-confirmed Alzheimer’s disease from other neurodegenerative diseases (area under the curve = 86.4%), while neurofilament lumen did not (area under the curve = 54.3 %).

These actions were independent of the presence of concomitant pathologies. Tau derived from plasma brain (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 amyloid plaque and neurofibrillary tangle counts.

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

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

Brain-derived tau is a new blood-based biomarker that outperforms total plasma tau and, unlike neurofilament light, shows specificity for Alzheimer’s disease-like neurodegeneration. Thus, brain-derived tau demonstrates potential to complete the AT(N) pathway in the blood and will be useful for assessing Alzheimer’s disease-dependent neurodegenerative processes for clinical and research purposes.

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