Lower Amyloid Levels after Donanemab Treatment Correlated with Slower Clinical Decline

A secondary analysis of results from the TRAILBLAZER-ALZ 2 phase 3 trial (NCT04437511) published in JAMA Neurology demonstrated an association between lower posttreatment amyloid plaque levels and slower cognitive and functional decline in individuals with early Alzheimer disease (AD) treated with Kisunla (donanemab; Eli Lilly and Company, Indianapolis, IN). The results suggest that amyloid plaque removal drives the clinical benefits of Kisunla and support using amyloid level as a potential surrogate biomarker for treatment response in people with early AD.

The post hoc exploratory analysis evaluated data from 1582 participants aged 60 to 85 years with early symptomatic AD and amyloid and tau pathology. Participants were randomized to receive Kisunla (n=766) or placebo (n=816) for 76 weeks and stratified into deciles based on their lowest posttreatment amyloid PET values. Researchers evaluated correlations between posttreatment amyloid burden, clinical measures—including the Integrated Alzheimer’s Disease Rating Scale (iADRS) and Clinical Dementia Rating–Sum of Boxes (CDR-SB)—and plasma biomarkers of neurodegeneration.

Key findings from this analysis include the following:

• Lower posttreatment amyloid burden correlated with slower clinical decline in both iADRS (R², 0.73 [95% CI, 0.37 to 0.97]) and CDR-SB (R², 0.87 [95% CI, 0.70 to 0.97]) scores.
• Greater amyloid clearance was associated with reductions in plasma phosphorylated tau 217 (p-tau217) levels (R², 0.86 [95% CI, 0.73 to 0.97]), p-tau181 levels (R², 0.88 [95% CI, 0.77 to 0.97]), and glial fibrillary acidic protein (GFAP) levels (R², 0.87 [95% CI, 0.76 to 0.97]).
• No association was found between amyloid levels and neurofilament light chain (NfL) levels (R², 0.03 [95% CI, 0.00 to 0.54]).

Source: Lu M, Kim MJ, Collins EC, et al. Posttreatment Amyloid Levels and Clinical Outcomes Following Donanemab for Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA Neurol. Published online October 13, 2025. doi:10.1001/jamaneurol.2025.3869.