Tau proteins in blood as biomarkers of Alzheimer’s disease and other proteinopathies

Alzheimer’s disease (AD), the most common age-dependent neurodegenerative disorder, is characterized neuropathologically by extracellular Aβ plaques and intracellular tau neurofibrillary tangles. While in AD tau pathology probably follows early alterations in Aβ metabolism, it develops independently in the so-called primary tauopathies, the main form being frontotemporal lobar degeneration with tau pathology. Tau pathology in AD brain is reflected in the cerebrospinal fluid (CSF) by elevated levels of the two AD tau biomarkers total and phosphorylated tau, which are now used for routine diagnostic purposes. On the contrary, no established neurochemical biomarkers exist for tau pathology in primary tauopathies. Thanks to recent technological advances, total and phosphorylated tau can now be quantified also on peripheral blood, and accumulating evidence shows that measurement of plasma phosphorylated tau species (P-tau181, P-tau217, and P-tau231) has high performances in discriminating AD patients from cognitively unimpaired subjects but also from patients with other dementias. Moreover, plasma P-tau levels are associated with tracer uptake on tau- and amyloid-PET as well as with brain atrophy, cognitive measures and longitudinal changes of these parameters. These features, together with the low invasiveness, scalability, and ease of longitudinal sampling, which differentiate plasma P-tau species from their CSF counterparts, make these proteins promising peripheral biomarkers for AD in both research and clinical setting. This review discusses the recent developments in the field of plasma tau proteins as diagnostic, pathophysiological and prognostic biomarkers of Alzheimer’s disease; additional findings from the fields of genetic forms of AD and of non-AD proteinopathies are also summarized.