Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies.

Converging evidence continues to point towards Tau aggregation and pathology formation as central events in the pathogenesis of Alzheimer's disease and other Tauopathies. Despite significant advances in understanding the morphological and structural properties of Tau fibrils, many fundamental questions remain about what causes Tau to aggregate in the first place. The exact roles of cofactors, Tau post-translational modifications, and Tau interactome in regulating Tau aggregation, pathology formation, and toxicity remain unknown. Recent studies have put the spotlight on the wide gap between the complexity of Tau structures, aggregation, and pathology formation in the brain and the simplicity of experimental approaches used for modeling these processes in research laboratories. Embracing and deconstructing this complexity is an essential first step to understanding the role of Tau in health and disease. To help deconstruct this complexity and understand its implication for the development of effective Tau targeting diagnostics and therapies, we firstly review how our understanding of Tau aggregation and pathology formation has evolved over the past few decades. Secondly, we present an analysis of new findings and insights from recent studies illustrating the biochemical, structural, and functional heterogeneity of Tau aggregates. Thirdly, we discuss the importance of adopting new experimental approaches that embrace the complexity of Tau aggregation and pathology as an important first step towards developing mechanism- and structure-based therapies that account for the pathological and clinical heterogeneity of Alzheimer's disease and Tauopathies. We believe that this is essential to develop effective diagnostics and therapies to treat these devastating diseases.