Rethinking Tau in Alzheimer’s Disease: From Therapeutic Lessons to Biomarker-Guided and Combination Strategies

Alzheimer’s disease remains one of the most prevalent and challenging neurodegenerative disorders, with the pathological aggregation of tau protein a defining feature that correlates closely with cognitive decline. For this reason, tau has attracted intense interest as a therapeutic target. Yet the clinical record has been sobering: across numerous human trials, single-target anti-tau strategies, including immunotherapies and aggregation inhibitors, have shown limited efficacy in halting or slowing disease progression. This gap between strong mechanistic rationale and disappointing clinical outcomes has prompted a reassessment of how tau should be approached.Two lessons are emerging. First, tau may be most powerful not as a standalone drug target but as one node within a wider pathological network, suggesting that combination and upstream strategies could succeed where mono-target approaches have not. Second, tau has proven to be an exceptional biomarker: tau PET imaging and fluid measures such as p-tau217 and p-tau181 now enable early, minimally invasive detection, staging and, crucially, patient selection for clinical trials. Recent work on next-generation tau modulation, including microRNA (miRNA)-based strategies, drug repositioning and novel inhibitors, remains promising, but requires realistic translational appraisal in light of past failures. A more nuanced understanding of tau biology, combination approaches and biomarker-guided design is therefore opening new avenues.This Research Topic aims to catalyze multidisciplinary research that reinterprets tau’s role in Alzheimer’s disease, moving beyond single-target inhibition toward combination, network-level and biomarker-guided strategies. Recognising that anti-tau therapies have so far shown limited clinical efficacy, we seek studies that draw lessons from completed trials, that position tau within broader intervention strategies, and that leverage tau as a precision biomarker to guide treatment and trial design. We welcome work advancing the mechanistic understanding of tau pathology, evaluating combination and upstream approaches, appraising next-generation tau-directed interventions such as miRNA-based modulation and drug repositioning, and refining biomarkers and clinical endpoints. We particularly encourage contributions that bridge basic science and clinical application, testing the hypothesis that integrated, biomarker-informed approaches to tau can yield benefits that mono-target strategies have not.The scope of this Research Topic spans cellular, molecular, translational and clinical research on tau in Alzheimer’s disease, with an emphasis on approaches that move beyond single-target inhibition. We invite contributions addressing, but not limited to:• Lessons from completed anti-tau trials: why efficacy has been limited and what this implies for future design• Combination and multi-target strategies pairing tau modulation with anti-amyloid, anti-inflammatory or synaptic approaches• Upstream and network-level mechanisms that drive tau pathology as points of intervention• Next-generation tau-directed approaches, including miRNA-based modulation, drug repositioning and novel aggregation inhibitors, with realistic translational appraisal• Mechanistic insights into miRNA regulation of tau expression and aggregation• Tau biomarkers (tau PET, p-tau217, p-tau181) for patient selection, staging and trial enrichment• Preclinical models that better predict clinical response, and clinical endpoints for evaluating therapeutic efficacyWe encourage a wide range of submissions, including original research, methods papers, brief research reports, data reports, systematic reviews, mini reviews and perspectives. Topic editors: Montasir Elahi, Rijwan U. Ahammad, Md.Shamim Hossain Source: https://www.frontiersin.org/research-topics/79484/rethinking-tau-in-alzheimers-disease-from-therapeutic-lessons-to-biomarker-guided-and-combination-strategies