**5. Tau in the evaluation of disease-modifying therapies**

Several strategies have been considered in order to prevent tau deposition. Compounds inhibiting tau aggregation [171], stimulating immune system against misfolded and phosphorylated tau, as well as inhibiting of kinases responsible for tau hyper-phosphorylation, especially glycogen synthase kinase-3, have been proposed [172–174]. Therefore, tau and p-tau quantification in biological fluids is emerging as a potential tool in the evaluation of disease-modifying therapies. On one hand, alterations in p-tau levels would be informative of the phosphorylation and aggregation state of tau in the brain tissue. On the other hand, therapeutic approaches preventing neuronal damage would also alter the levels of t-tau protein in the CSF.

Interestingly, decreased CSF p-tau levels have been reported in patients treated with bapineuzumab, an antibody capable of binding to soluble and fibrillary forms of amyloid beta despite clinical trials do not lead to clinical benefit for intravenous bapineuzumab treatment [175].

However, as this research field is in its early phases, longitudinal studies are required to definitely demonstrate the relationship between temporal alterations in tau levels and clinical outcome. Additionally, as the effect of disease-modifying therapies on CSF biomarkers may be influenced by the mechanism of action of the therapeutic compound, alternative biomarkers should be used in order to assess the complete panel of hallmarks associated to the neurodegenerative process.
