Validity of tau as both a biomarker and target for AD and the dynamics of tau over the course of the disease

Background Brain tau aggregates are, together with amyloid plaques, hallmarks of Alzheimer Disease (AD). Structural characterization of tau aggregates in AD, Pick’s disease and Chronic Traumatic Encephalopathy demonstrate distinct folds leading to tau aggregation. However, initiation and propagation mechanisms involved are still unknown. One hypothesis includes modification in tau metabolism affecting tau isoforms abundance and clearance. Understanding these mechanisms can both identify potential targets for treatment, biomarkers for monitoring disease stages and response to tau‐directed therapies. Method Recent developments in characterizing tau species by Mass Spectrometry in brain and biofluids have provided new insights on the diversity of tau isoforms and their changes associated to Alzheimer’s disease over the course of the disease. We will review past and new results from these techniques and discuss which tau isoforms are the most promising biomarkers to identify and stage AD. We will then discuss how these changes can be related to abnormal tau metabolism and, potentially, aggregation. Result In brain, soluble tau is phosphorylated at more than 30 sites and tau phosphorylation occupancy is modified in AD in a site‐dependent manner and appears to occur decades before substantial tau aggregation. Contrarily, AD brain aggregates are hyperphosphorylated compared to AD soluble tau at specific sites. In cerebrospinal fluid (CSF), the longitudinal monitoring of 11 phosphorylated sites in autosomal dominant AD demonstrates different behavior of these sites over disease trajectory. The CSF tau truncation profile, particularly in the protein domain enriched in brain aggregates, changes with disease. This suggests brain tau aggregates may impact the nature of tau isoforms released extracellularly. Yet, initial stages of tau hyperphosphorylation appears to occur many years before substantial tau aggregation. Critically, certain tau hyperphosphorylation sites observed in CSF are recapitulated in plasma tau in the preclinical stages of disease. Conclusion Both CSF tau phosphorylation and tau truncation profiles can serve as biomarkers to complement p‐tau and tau levels for AD diagnosis and staging. For target validation, the multiplicity of tau isoforms complicates the identification of the most relevant species to target. Notably, the uncertain role of abnormal tau phosphorylation as the initiator or a consequence of tau aggregation remains to be addressed.