Total and phosphorylated tau protein as biological markers of Alzheimer's disease

Abstract

Advances in our understanding of tau-mediated neurodegeneration in Alzheimer's disease (AD) are moving this disease pathway to center stage for the development of biomarkers and disease modifying drug discovery efforts. Immunoassays were developed detecting total (t-tau) and tau phosphorylated at specific epitopes (p-tauX) in cerebrospinal fluid (CSF), methods to analyse tau in blood are at the experimental beginning. Clinical research consistently demonstrated CSF t- and p-tau increased in AD compared to controls. Measuring these tau species proved informative for classifying AD from relevant differential diagnoses. Tau phosphorylated at threonine 231 (p-tau231) differentiated between AD and frontotemporal dementia, tau phosphorylated at serine 181 (p-tau181) enhanced classification between AD and dementia with Lewy bodies. T- and p-tau are considered "core" AD biomarkers that have been successfully validated by controlled large-scale multi-center studies. Tau biomarkers are implemented in clinical trials to reflect biological activity, mechanisms of action of compounds, support enrichment of target populations, provide endpoints for proof-of-concept and confirmatory trials on disease modification. World-wide quality control initiatives are underway to set required methodological and protocol standards. Discussions with regulatory authorities gain momentum defining the role of tau biomarkers for trial designs and how they may be further qualified for surrogate marker status.

Figure 1

Six different tau isoforms produced from a single gene by alternative mRNA splicing are presented. The blue, green, and yellow boxes correspond to exon 2, 3, and 10, respectively. The longest isoform is composed of 441 amino acids. In the most commonly used commercial assay for t-tau (INNOTEST® hTau Ag), AT120 is used as capture antibody and HT7 and BT2 as detection antibodies. This assay will detect all different tau isoforms irrespectively of differential splicing and phosphorylation status.