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A novel blood test to assess brain-derived tau detected Alzheimer's-related neurodegeneration and differentiated Alzheimer's from other neurodegenerative diseases.

The test outperformed total tau and, unlike neurofilament light, showed specificity to Alzheimer's disease-type neurodegeneration, reported Thomas Karikari, PhD, of the University of Gothenburg in Sweden and the University of Pittsburgh in Pennsylvania, and co-authors in .

"Thus, brain-derived tau demonstrates potential to complete the AT(N) scheme in blood, and will be useful to evaluate Alzheimer's disease-dependent neurodegenerative processes for clinical and research purposes," Karikari and colleagues wrote.

The requires three components of Alzheimer's pathology -- amyloid plaques, tau tangles, and neurodegeneration -- to be detected by imaging or in cerebrospinal fluid (CSF) samples for Alzheimer's disease to be diagnosed.

Blood-based biomarkers could make detecting Alzheimer's easier and more accessible. Blood tests have been developed to detect amyloid and tau, but a reliable blood test for neurodegeneration has remained elusive. For example, neurofilament light, a marker of axonal damage, is elevated in Alzheimer's disease but also is elevated in other forms of dementia and other neurodegenerative diseases.

As a marker of neurodegeneration, "current plasma total-tau (t-tau) assays do not show good diagnostic utility, contrary to CSF t-tau that reliably reflects neurodegeneration in Alzheimer's disease but not in other neurodegenerative diseases like Parkinson's disease, Lewy body dementia, and frontotemporal dementia," the researchers observed.

To selectively detect brain-derived tau, Karikari and colleagues developed an antibody that binds to an expressed glutathione S-transferase-linked protein construct for the MAPT gene exons 4–5 of tau and recombinant full-length tau-441 (rPeptide). The resulting TauJ.5H3 monoclonal antibody demonstrated specific reactivity to the junction between MAPT exons 4 and 5, excluding peripherally-originated tau species that have an exon 4a insert.

The researchers validated their assay in five cohorts that spanned 609 patient samples and found:

• Serum and CSF brain-derived tau identified with the antibody were significantly correlated (rho=0.85, P<0.0001), while CSF total-tau and blood-based tau measured with typical techniques were not (rho=0.23, P=0.3364).
• Blood-based brain-derived tau showed equivalent diagnostic performance to both CSF total-tau and CSF brain-derived tau in distinguishing biomarker-positive Alzheimer's disease participants from biomarker-negative controls.
• Blood-based brain-derived tau accurately distinguished autopsy-confirmed Alzheimer's disease from other neurodegenerative diseases with an area under the receiver operating curve (AUC) of 86.4%, while neurofilament light did not (AUC 54.3%).

Performances were independent of the presence of concomitant pathologies, the researchers noted. Results were verified in two memory clinic cohorts where serum brain-derived tau differentiated Alzheimer's from other neurodegenerative disorders -- including frontotemporal lobar degeneration and atypical parkinsonian disorders -- with AUCs up to 99.6%.

"Across cohorts, plasma/serum brain-derived tau was associated with CSF and plasma AT(N) biomarkers and cognitive function," Karikari and co-authors wrote. "Notably, plasma/serum brain-derived tau correlated with neurofilament light only in Alzheimer's disease, but not in the other neurodegenerative diseases."

The researchers plan to conduct large-scale clinical validation of blood brain-derived-tau in a wide range of cohorts including ones with diverse racial and ethnic backgrounds. Studies will include older adults with no biological evidence of Alzheimer's disease as well as those at different stages of the disease.

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