Tau pathology, particularly hyperphosphorylated tau forming neurofibrillary tangles, correlates more robustly with cognitive decline than amyloid burden, positioning tau as a high-priority therapeutic target. First-generation anti-tau immunotherapies, mainly targeting the N-terminal domain, have demonstrated pharmacodynamic engagement but inconsistent clinical benefits.

A systematic review and meta-analysis of Phase II and III randomized controlled trials (RCTs) published between 2020 and 2025 was conducted following PRISMA guidelines. Databases searched included PubMed, Web of Science, and Embase. Inclusion criteria comprised RCTs evaluating any anti-tau therapy versus placebo or standard care in AD patients, reporting cognitive, functional, or biomarker outcomes. Data extraction, quality assessment (Cochrane RoB 2), and statistical analysis (random-effects meta-analysis of mean differences and risk ratios) were performed.

Four RCTs encompassing patients with early-stage AD were included. Target engagement was confirmed, with >90% reduction of free N-terminal tau in cerebrospinal fluid for some interventions. Aggregated clinical outcomes revealed no significant benefit over placebo: CDR-SB (MD −0.21, 95% CI [−0.54, 0.11], p=0.20, I²=57%), ADAS-Cog (MD −0.51, p=0.61), ADCS-ADL (MD −0.53, p=0.40), and MMSE (MD −0.14, p=0.59). A sensitivity analysis excluding studies at higher risk of bias did not materially change these results, supporting the robustness of the findings. High dropout rates and heterogeneous tau spatial deposition were noted as potential confounders.

First-generation N-terminal anti-tau immunotherapies are ineffective in altering cognitive or functional decline in early AD, despite robust pharmacodynamic activity. Therapeutic failure is likely due to the structural complexity, heterogeneity, and regional variability of tau pathology. Future strategies should target alternative tau epitopes, employ multimodal approaches, and consider intervention at earlier, pre-symptomatic stages. These findings inform the refinement of precisely targeted tau therapies in AD.