Gonzalez-Ortiz F, Turton M, Kac PR, Smirnov D, Premi E, Ghidoni R, Benussi L, Cantoni V, Saraceno C, Rivolta J, Ashton NJ, Borroni B, Galasko D, Harrison P, Zetterberg H, Blennow K, Karikari TK. Brain-derived tau: a novel blood-based biomarker for Alzheimer's disease-type neurodegeneration. Brain. 2023 Mar 1;146(3):1152-1165. PubMed. Correction.

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  1. The finding of increased brain-derived tau in the blood plasma or serum is an important advance and helps resolve why total tau in the periphery wasn’t previously specific for Alzheimer’s disease. This study adds to the growing knowledge of blood biomarkers and the relationship of how different neurodegenerative diseases can be detected by the biomolecules that are differentially transported into the systemic circulation.

    The findings are consistent with our prior observation of increased tau production specifically in Alzheimer’s due to amyloid plaques (Sato et al., 2018). They provide an opportunity to track total, i.e. non-phosphorylated, tau levels in the blood, in addition to the already known specific p-tau measures of 181, 205, 217, and 231. This will add value to our understanding of Alzheimer’s pathophysiology. These are exciting times!

    References:

    Sato C, Barthélemy NR, Mawuenyega KG, Patterson BW, Gordon BA, Jockel-Balsarotti J, Sullivan M, Crisp MJ, Kasten T, Kirmess KM, Kanaan NM, Yarasheski KE, Baker-Nigh A, Benzinger TL, Miller TM, Karch CM, Bateman RJ. Tau Kinetics in Neurons and the Human Central Nervous System. Neuron. 2018 Mar 21;97(6):1284-1298.e7. PubMed.

    View all comments by Randall Bateman

  2. Karikari and colleagues demonstrated that brain-derived tau, measured in plasma, performed similarly to CSF in distinguishing AD-biomarker-positive individuals. They performed an impressive number of studies in five different cohorts to validate their assay. The correlation between CSF and plasma brain-derived tau was very high (rho=0.85), similar to the rho=0.89 correlation reported for the Wash U plasma p-tau217 assay with CSF p-tau217 in a recent paper by Janelidze (Janelidze et al., 2022). 

    It would be interesting to more clearly define what specific forms of tau “brain-derived tau” represents. The assay uses an antibody that binds an epitope that represents the junction of tau exons 4 and 5, but it seems that the assay could still be reflecting a variety of tau species with different post-translational modifications (e.g., phosphorylation). 

    The plasma biomarkers used for comparison in this paper, total tau and NfL, are known to be poor AD biomarkers. While the rationale for comparison with total tau and NfL is that these biomarkers have been thought to represent neurodegeneration (the N in the ATN framework), studies suggest that p-tau217 may reflect aspects of amyloid, tau and neurodegeneration (A, T, and N). It will be important to compare plasma brain-derived tau with plasma p-tau217, which is currently one of the most promising AD biomarkers.

    References:

    Janelidze S, Bali D, Ashton NJ, Barthélemy NR, Vanbrabant J, Stoops E, Vanmechelen E, He Y, Dolado AO, Triana-Baltzer G, Pontecorvo MJ, Zetterberg H, Kolb H, Vandijck M, Blennow K, Bateman RJ, Hansson O. Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer's disease. Brain. 2022 Sep 10; PubMed.

    View all comments by Suzanne Schindler

  3. It is exciting to read about the development of this brain-derived plasma Tau assay by this wonderful research group, including the way in which they have overcome the potentially confounding contributions of peripherally derived plasma total tau measurements.

    Since the findings appear to be specific for Alzheimer’s disease, it would be helpful to clarify the extent to which this new biomarker provides an indicator of amyloid plaque burden and amyloid-related tau pathophysiology similar to plasma pTau, or whether it might also provide additional information about AD-related neurodegeneration itself, even after accounting for its contributions to amyloid plaque and tau tangle burden.

    For instance, it would be interesting to see the extent to which brain-derived plasma Tau concentrations are associated with FDG PET measurements of cerebral glucose hypometabolism, SV2A PET measurements of synaptic loss, MRI measurements of hippocampal atrophy, and postmortem measurements of synaptic or neuronal loss in brain regions that are preferentially affected by AD after controlling for plasma pTau measurements in existing cohorts. In the meantime, I’d like to congratulate the team on its latest contribution to the development of promising blood-based biomarkers of AD.

    View all comments by Eric M. Reiman

  4. This novel work nicely highlights the potential of blood BD-tau as an Alzheimer’s-specific marker of neurodegeneration. There are several blood, MRI, and CSF markers of neurodegeneration but, to date, nothing that is specific to AD pathology. As the authors highlight, there are several next steps needed to understand the utility of this new blood marker, including whether it changes longitudinally with cognitive decline and brain atrophy across the AD clinical spectrum, and exactly what it’s added value is beyond plasma p-tau measures.

    View all comments by Michelle Mielke

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