Abstract: Tauopathies encompass a collection of chronic, progressive neurodegenerative diseases, including Alzheimer’s disease (AD), chronic traumatic encephalopathy, and corticobasal degeneration, characterized by the accumulation of pathogenic aggregates of the microtubule-associated protein tau in neurons and/or glia (Reid et al., 2020). For decades before the onset of disease symptoms, local pathogenic misfolded tau replication and subsequent trans-synaptic transmission, silently propagates along anatomically connected regions. A spectrum of clinical symptoms begins to emerge once the brain’s compensatory and resistance measures are exhausted, ranging from behavioral, cognitive, and/or motor dysfunction. Recent therapeutic attempts to target soluble pathogenic species of tau have largely proven to be clinically ineffective and may have the same fate as so many amyloid-lowering therapies. To avoid the pitfalls that have contributed to the ongoing multi-decade long failures of amyloid-targeting strategies, it is critical to address the fundamental knowledge gaps regarding tau dynamics and processing in the brain.