Abstract
A marked evolution in Alzheimer’s disease (AD) therapy research is ongoing. In this perspective, we highlight emerging outcomes of tau-targeting approaches with disease-modifying potential evidenced by PET-based slowing of tau accumulation and early signs of cognitive benefit. We outline how decades of iterative amyloid β (Aβ)-trial refinement leading to the recent successes of approved anti-Aβ therapies have set the stage for accelerated optimization of next-generation trials. We summarize key learnings from first-generation tau immunotherapies and how these paved the way for early achievements in tau trials, while many challenges remain. Finally, we discuss the back-translation of clinical outcomes into fundamental insights on human tau pathobiology, and we outline challenges and future directions for AD therapy development including combination therapy and targets beyond Aβ/tau. Together, this provides a framework for next-generation AD and tau-therapy development toward increasingly efficient disease-halting interventions.