Yanamandra K, Patel TK, Jiang H, Schindler S, Ulrich JD, Boxer AL, Miller BL, Kerwin DR, Gallardo G, Stewart F, Finn MB, Cairns NJ, Verghese PB, Fogelman I, West T, Braunstein J, Robinson G, Keyser J, Roh J, Knapik SS, Hu Y, Holtzman DM. Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy. Sci Transl Med. 2017 Apr 19;9(386) PubMed.

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  1. These are carefully conducted and informative measurements by a stellar group of investigators. It will be interesting to see how the tau antibodies in clinical trials may influence tau levels in CSF and plasma, which may differ to some extent between AD and PSP subjects. Since CSF tau levels increase in AD but not in PSP, extracellular tau may be less important for propagation of tau pathology in PSP than in AD. Thereby, antibodies that only work extracellularly may be less effective in PSP than in AD.

    In addition, since recent mass spectrometry studies indicate that most CSF tau has ragged N- and C-termini and consists mostly of tau fragments around amino acids 150-250 of the protein, it will be interesting to see how antibodies that bind within or outside this main region compare. Again, if the antibody works mainly by an extracellular mechanism, one would think it should preferably bind to this most prominent extracellular region.

    Regardless of the tauopathy or the binding site, the most effective antibodies will likely be those that can access tau in all compartments, including inside the neurons, where most of pathological tau resides.

    View all comments by Einar Sigurdsson

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