The microtubule-associated protein tau has been implicated in the pathogenesis of Alzheimer’s disease and a range of other neurodegenerative disorders (called “tauopathies”). As the number of people with tauopathies is rising in aging populations across the world, interest in the fundamental biology of this protein and in the development of tau-targeting treatments has been expanding rapidly. Recent insights into the complexity of this intrinsically disordered protein suggest that tau is a worthy but challenging target whose multifaceted nature will likely require a multipronged therapeutic approach. Derived from a single gene by alternative splicing, six major isoforms of tau have been identified in the human brain. In addition, tau is subject to many different posttranslational modifications, further indicating that it may be regulated by multiple processes and may participate in diverse functions.

Tau is widely presumed to stabilize microtubules. However, the experimental reduction or ablation of tau in vivo does not alter many neural properties and processes that likely depend on microtubules, including neuronal integrity, axonal transport, synapse formation, and complex brain functions. Although tau reduction seems to have minimal effects on otherwise unmanipulated brains, it can prevent or diminish aberrant cell signaling, neural network dysfunctions (e.g., epileptic activity), and behavioral alterations caused by diverse disease processes, which suggests that tau activities are needed for other pathogenic triggers to cause these derangements. In addition to this “enabling bystander” role, tau’s interactions with a large number of other proteins can cause adverse gains of function, which are associated with—and possibly caused by—the formation of abnormal tau structures and assemblies. Because abnormal forms of tau trigger a plethora of pathomechanisms, targeting individual downstream mechanisms may have limited therapeutic impact, unless the relative pathogenic importance of the specific mechanism has been well established in experimental models that allow for conclusive validation of cause-and-effect relationships. Although much attention has focused on the abnormal aggregation of tau in tauopathies and on the ability of tau “seeds” to spread from neuron to neuron, internalization of propagating tau does not appear to impair neuronal survival or brain functions. Moreover, tau reduction prevents or diminishes neural network dysfunction and behavioral abnormalities also in disease models that do not have abnormal tau inclusions, which suggests that there is more to tau than aggregation and propagation. A promising diversification of tau-targeting therapeutic strategies is beginning to address this complexity. Lowering overall tau levels may have the greatest potential, as this strategy bypasses the unresolved questions of which forms of tau and which downstream mechanisms are most detrimental in any given condition.

Many efforts to develop better treatments for neurodegenerative diseases have failed, in large part because of an inadequate understanding of disease mechanisms and, perhaps, because too many fundamental knowledge gaps, alternative interpretations of data, and methodological complexities did not receive the attention they deserved. This Review highlights important gaps in the understanding of tau and the methodological advances needed to fill them. It also pinpoints obstacles that could complicate the translation of tau-related scientific discoveries into better therapeutics and offers pragmatic strategies to overcome these challenges. Despite the extraordinary progress that has …