Expanding landscape of tau pathology in neurological disorders: A narrative review guiding diagnostic development and targeted therapeutics

Abstract

For decades, tau pathology was synonymous with Alzheimer’s disease, where it co-occurs with amyloid-β plaques. A paradigm shift has since established that tau is the primary pathogenic driver of a diverse spectrum of disorders known as primary tauopathies. This review synthesizes the expanding landscape of these conditions, which include progressive supranuclear palsy, corticobasal degeneration, and Pick’s disease. We explore how their distinct clinico-pathological phenotypes are rooted in fundamental molecular characteristics, specifically, the predominance of 3-repeat or 4-repeat tau isoforms and the existence of self-propagating, disease-specific conformational “strains.” A core mechanism underpinning progression across these disorders is the prion-like trans-synaptic spread of pathological tau, which propagates through neuroanatomically connected networks. This molecular understanding is now being translated into clinical practice. We detail revolutionary advances in biomarkers, including tau positron emission tomography ligands and ultrasensitive plasma phosphorylated-tau assays, which are enabling unprecedented antemortem diagnosis and biological staging. Simultaneously, we critically assess the challenging therapeutic pipeline, analyzing why strategies like immunotherapies have struggled, and highlighting emerging approaches such as tau-lowering antisense oligonucleotides. The review concludes that the future of the field lies in a precision medicine framework, where the molecular taxonomy of tau pathology guides the development of targeted diagnostics and therapeutics, moving beyond an Alzheimer’s-centric view to effectively confront the broad challenge of tau-mediated neurodegeneration.