**Acknowledgements**

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

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

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 neu-

CSF t-tau and p-tau concentrations display good sensitivity and specificity in the discrimination of AD patients from non-demented control cases and a high diagnostic accuracy in the discrimination of sCJD cases. Both biomarkers become useful in the identification of patients at risk of progression to AD. The partial overlap between t-tau and p-tau levels among several neurodegenerative dementias indicates that more specific biomarkers are required in order to improve the accuracy in the differential diagnostic context. Alternative tau-based approaches have been recently developed and form the basis of the second-generation tau assays. On one side, the use of composite biomarkers, the development of non-p-tau assays and tau seeding methodologies, and the detection of tau truncated forms and alternative phosphorylation sites are promising alternatives that need further research to maximize their potential as diagnostic and prognostic tools. On the other side, the quantification of tau in blood-based fluids is gaining experimental momentum due to the advantages of using blood instead of CSF and to the implementation of high-sensitivity tests that can detect scarce tau amounts in plasma and serum. Several contradictory findings in the field might be related to the use of differential methodologies, which in some of the cases are not yet fully implemented and validated in

Finally, the clinical diagnostic utility of tau measurements is complemented by the role of this protein as a reporter of the degree of neuro-axonal damage in the brain and the pathological hyper-phosphorylation tau state, which is specifically present in tauopathies. Since we are in the dawning of second-generation tau assays, future studies are necessary to validate them in larger and independent cohorts of patients in order to prove their clinical utility while they

levels of t-tau protein in the CSF.

treatment [175].

78 Cognitive Disorders

rodegenerative process.

large and independent cohorts.

**6. Conclusion**

This study was funded by the Spanish Ministry of Health - Instituto Carlos III (Miguel Servet - CP16/00041) to FL, by the Red Nacional de priones (AGL2015-71764-REDT- MINECO) to FL, IZ and IF, by the Robert Koch Institute through funds from the Federal Ministry of Health (grant no. 1369–341) to IZ, by the Spanish Ministry of Health, Instituto Carlos III (Fondo de Investigación Sanitaria - FIS PI11/00968, FIS PI14/00757) to IF. AV-P is funded by a Dorothea Schlözer Scholarship (Georg August University – Göttingen).
