Plasma pTau-181 Exhibits Flat Longitudinal Trajectories and Weak Cognitive Correlation in UK Biobank: Implications for Anti-Tau Antibody Trial Failures

Background Monoclonal antibodies targeting pathological tau have repeatedly failed in Alzheimer’s disease (AD) clinical trials. Whether plasma phosphorylated tau (pTau) exhibits dynamic progression or cognitive relevance in population-based cohorts remains unclear. Methods Using UK Biobank, we analyzed 2,523 participants with plasma pTau-181 measured at imaging visits and stratified by APOE ε4 genotype. Mixed-effects models assessed longitudinal pTau-181 slopes. Cross-sectional associations between pTau and fluid intelligence were evaluated with genotype-stratified regression. Results Plasma pTau-181 declined modestly over 4.5 years (− 2.2%/year; p < 0.001). APOE ε4 carriers showed higher baseline pTau (+ 6.4%/allele) but no genotype-specific difference in slope. Fluid intelligence was only weakly and inconsistently associated with pTau-181, with overlapping regression lines across APOE strata. No participants with diagnosed AD had repeated pTau measurements. Conclusions Plasma pTau-181 demonstrates flat or declining longitudinal trajectories and minimal cognitive correlation, suggesting tau is a static biomarker rather than a dynamic therapeutic target in mid-to-late adulthood. These real-world findings help explain why anti-tau monoclonal antibodies have failed to demonstrate clinical efficacy.