Baseline Amyloid Levels Predict One-Year Clearance on Donanemab, Analysis Shows

A post hoc analysis of Phase 3 clinical trial data has identified the characteristics that best predict which patients with early symptomatic Alzheimer’s disease achieve substantial amyloid plaque clearance after one year of treatment with donanemab, and links that clearance to slower tau accumulation. The study, published in Alzheimer’s Research & Therapy, drew on TRAILBLAZER-ALZ 2, a double-blind, placebo-controlled trial that enrolled 876 placebo-treated and 860 donanemab-treated participants, along with an open-label addendum of 1,053 participants.

Researchers split donanemab-treated participants into two subgroups based on their amyloid level at 52 weeks: those who reached amyloid clearance, defined as a level below 24.1 Centiloids (the ACW52 subgroup, N = 443), and those who did not (the NACW52 subgroup, N = 227). Both subgroups showed substantial average amyloid reduction over the year. Baseline amyloid burden, however, differed markedly between them: mean baseline levels were 95.8 Centiloids in the clearance subgroup versus 120.2 Centiloids in the non-clearance subgroup, and baseline amyloid was significantly correlated with 52-week amyloid levels, which averaged 4.8 Centiloids and 48.2 Centiloids respectively (p < 0.001). Lower baseline amyloid was inversely associated with the probability of achieving 52-week clearance (p < 0.001).

Using machine learning and multiple linear regression, the team ranked the baseline characteristics that differentiated the two subgroups. Lower baseline amyloid was the most important parameter, followed by older age, fewer APOE ε4 alleles, and lower body weight. When the analysis was repeated using data from the open-label addendum, the same pattern of findings was replicated, strengthening confidence in the predictive model.

The downstream consequences of clearance were examined by matching placebo-treated participants to each donanemab subgroup by propensity score and comparing outcomes with analysis of covariance or mixed models for repeated measures. Only the ACW52 subgroup showed significantly less tau accumulation at 76 weeks than matched placebo (p < 0.01); the NACW52 subgroup did not differ significantly from matched placebo on this measure. Both subgroups showed significant differences from their matched placebo groups in plasma P-tau217, but the change from baseline was greater in the clearance subgroup.

Clinical slowing was observed in both subgroups, however. At 76 weeks, slowing of clinical progression relative to matched placebo, measured by the Clinical Dementia Rating Scale–Sum of Boxes, was 29.6% for the ACW52 subgroup and 28.8% for the NACW52 subgroup. On the integrated Alzheimer’s Disease Rating Scale, the corresponding slowing was 25.9% and 18.8%. The authors conclude that donanemab-mediated 52-week amyloid clearance was associated with slower tau progression, while slowing of clinical progression occurred in both subgroups. As a post hoc analysis of trial data, the findings describe associations within the studied population of participants with early symptomatic Alzheimer’s disease rather than new prospective test results, and the trial is registered as NCT04437511.

Subject of Research: Post hoc analysis of baseline predictors of one-year amyloid clearance with donanemab and its association with tau and clinical outcomes in early Alzheimer's disease

Article Title: Post-hoc analyses of amyloid reduction after one year of treatment with donanemab using clinical trial data: prediction of amyloid clearance and association with downstream measurements

Article References: Shcherbinin, S., Lu, M., Wang, J., Battioui, C., Andersen, S. W., Wang, H., Nery, E. S., Evans, C. D., Hauck, P. M., Gueorguieva, I., Iaccarino, L., Kennedy, I., Brooks, D. A., Mintun, M. A., Collins, E. C., & Sims, J. R. (2026). Post-hoc analyses of amyloid reduction after one year of treatment with donanemab using clinical trial data: prediction of amyloid clearance and association with downstream measurements. Alzheimer's Research & Therapy. https://doi.org/10.1186/s13195-026-02163-9

Image Credits: AI Generated

DOI: 10.1186/s13195-026-02163-9

Keywords: donanemab, Alzheimer's disease, amyloid clearance, TRAILBLAZER-ALZ 2, tau biomarkers, plasma P-tau217, APOE ε4, Centiloids, clinical trials, post hoc analysis, Post-hoc, analyses