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Brain-derived tau an important biomarker for Alzheimer’s disease

A brain-derived tau blood biomarker shows a high specificity for Alzheimer’s disease-type neuro-degeneration compared to other diseases

A brain-derived tau biomarker which can be easily measured in blood samples, represents an important step in the specific identification of Alzheimer’s disease-type neuro-degeneration according to a study by an international research group.

Biomarkers for the identification of Alzheimer’s disease (AD) are based on the A/T/N” system where ‘A’ refers to the value of a β-amyloid biomarker, ‘T’ the value of a tau biomarker and ‘N’, biomarkers of neuro-degeneration or neuronal injury. To date, at least two of these markers are satisfactory. For example, plasma β-amyloid marker measurement (A), accurately determines amyloid positron emission tomography status in cognitively normal research participants.

In addition, blood-based tau markers (T) could be used as a simple, accessible, and scalable test for screening and diagnosis of Alzheimer’s disease. Nevertheless, neuro-degeneration (N) markers such as plasma neurofilament light chain (NfL), which measures axonal injury, showed no discriminatory power for AD compared to other neurological diseases.

Rather than focusing on developing a more specific ‘N’, researchers recognised that since tau measurements can be contaminated by peripherally generated (i.e., from liver, kidney or heart), it might be better to focus to identifying a specific brain-derived tau. In the present study, researchers created an anti-tau antibody which was designed to selectively bind with only brain-derived tau and which would hopefully be specific for patients with Alzheimer’s disease. The team then set out to validate the biomarker in five independent cohorts, including autopsy samples.

Brain-derived tau and Alzheimer’s disease

Using paired cerebrospinal fluid (CSF) and serum samples from AD patients and controls, there was a strong correlation (Spearman’s rho = 0.85, p < 0.0001) between the brain-derived (BD) tau levels in serum and CSF samples. In contrast, serum and total tau measurements were no significantly correlated (Spearman’s rho = 0.23, p = 0.3364). In addition, plasma brain-derived tau accurately distinguished autopsy-confirmed Alzheimer’s disease from other neurodegenerative diseases, with an area under the curve (AUC) value of 86.4%.

Furthermore, using samples from patients in two memory clinic cohorts, serum brain-derived tau differentiated Alzheimer’s disease from a range of other neurodegenerative disorders (AUC = 99.6%). In another cohort, BD-tau levels were significantly increased in AD patient serum and CSF samples compared to controls (p < 0.0001). Finally, BD-tau levels were inversely correlated with clinical dementia rating global scores (Spearman’s rho = -0.30, p = 0.0352).

Taken together, the authors wrote ‘across cohorts, plasma/serum brain-derived tau was associated with CSF and plasma AT(N) biomarkers and cognitive function. Brain-derived tau is a new blood-based biomarker that outperforms plasma total-tau and, unlike neurofilament light, shows specificity to Alzheimer’s disease-type neuro-degeneration.’

They concluded that the 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.

Gonzalez-Ortis F et al. Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration. Brain 2022.