Alzheimer Biomarkers pTau217 and pTau181 Show High Group-Level Correlation With Trial End Points

Craig Mallinckrodt, PhD

Using recent trials of anti-amyloid antibodies for Alzheimer disease (AD), investigators found that changes on phosphorylated tau (p-Tau)217 and p-Tau181 correlated well with clinical end points like Clinical Dementia Rating-sum of boxes (CDR-SB). Overall, the data highlight these biomarker’s ability to predict clinical outcome in a clinical trial setting.¹

Presented at the 2025 AD/PD International Conference on Alzheimer’s and Parkinson’s Diseases, held April 1-5 in Vienna, Austria, study authors looked at the ENGAGE and EMERGE trials of aducanumab (Aduhelm; Biogen), the TRAILBLAZER studies of donenamab (Kisulna; Eli Lilly), and the Clarity AD trial of lecanemab (Leqembi; Eisai). Led by Craig Mallinckrodt, PhD, a consultant at Pentara Corporation, the study looked at both patient-level and group-level correlations between biomarkers and clinical outcomes, using Cohen’s d effect size for standardization and weighted Pearson correlation to assess group-level associations.

Together, EMERGE and ENGAGE had a total of 474 patients on 3-6 mg/kg aducanumab with available plasma p-tau181 or p-tau217 data, as well as 444 patients in the 6-10 mg/kg group. Overall, the Cohen’s d at 6 months for plasma p-tau181 or p-tau217 was 0.142 for EMERGE 3-6 mg/kg group, 0.176 for EMERGE 6-10 mg/kg, 0.234 for ENGAGE 3-6 mg/kg, and 0.325 for ENGAGE 6-10 mg/kg. All told, the Cohen’s d for CDR-SB at 12 months was 0.125, 0.068, 0.012, and –0.047 for those respective groups.

Donanemab, an FDA-approved antiamyloid therapy, was tested in 1400 mg doses in the TRAILBLAZER-ALZ-2 trial and 700/1400 mg doses in the original TRAILBLAZER-ALZ trial. At 6 months, the Cohen’s d for plasma p-tau181 or p-tau218 was 0.786 for TRAILBLAZER-ALZ-2 and 0.853 for TRAILBLAZER-ALZ. Between the two, there were a total of 895 patients who had amyloid PET available. Cohen’s d at 6 months for amyloid PET was 2.44 and 3.32, respectively, for TRAILBLAZER-ALZ-2 and TRAILBLAZER-ALZ, while the Cohen’s d was 0.262 and 0.388 for CDR-SB at 12 months.

Clarity AD, a large-scale trial that served as a confirmatory study for lecanemab, featured 688 patients with plasma p-tau181 or p-tau217, as well as 280 for amyloid PET. Overall, the plasma p-tau181 or p-tau217 Cohen’s d at 6 months was 0.42, while the Cohen’s d for amyloid PET was 1.78. At 12 months, the Cohen’s d for CDR-SB was 0.214.

READ MORE: Higher CSF Aß42/Total Tau Ratio Associated With Increased ARIA Risk in Lecanemab

Overall, the correlation of group-level plasma p-tau217 or p-tau181 with clinical outcome CDR-SB was approximately 0.786 with P values of 0.036, which were comparable to the published amyloid PET, CDR-SB correlation of 0.78. In addition, Cohen’s d effect size of plasma p-tau217 or p-tau181 as a biomarker was 3 times greater than the Cohen’s d values of clinical outcome CDR-SB, leading to higher power or lower sample sizes.

P-tau biomarkers, particularly p-tau217 and p-tau181, have emerged as reliable indicators of AD progression, aiding in earlier and more accurate diagnosis. Both biomarkers reflect tau pathology, a core hallmark of AD, but p-tau217 has gained significant attention for its superior accuracy in detecting amyloid and tau pathology, even in preclinical stages. Studies have shown that p-tau217 levels strongly correlate with amyloid PET and tau PET findings, making it a highly reliable predictor of AD pathology before cognitive symptoms appear.

The optimism surrounding these biomarkers is driven by their potential to enhance clinical trial design and patient stratification. P-tau181 was one of the first widely studied plasma biomarkers, showing promise in distinguishing AD from other neurodegenerative conditions. However, p-tau217 has demonstrated even greater diagnostic precision, rivaling cerebrospinal fluid (CSF) and PET measures. Their ability to reflect disease progression in real time makes them valuable for monitoring therapeutic responses, particularly as anti-amyloid and anti-tau therapies advance. As research continues, these biomarkers may enable earlier interventions and more targeted treatments, potentially altering the trajectory of AD before significant neurodegeneration occurs.

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REFERENCE
1. Hendrix SB, Duncan GB, Dickson SP, et al. Leveraging recent advances in plasma biomarkers to optimize early phase drug development in Alzheimer disease. Presented at: 2025 AD/PD meeting; April 1-5. Vienna, Austria.