Explore the effect of donanemab on plasma biomarker levels associated with Alzheimer’s disease (AD) and their association with amyloid and tau imaging measurements.

TRAILBLAZER-ALZ (NCT03367403) was a randomized, double-blind, placebo-controlled, phase 2 study of donanemab (antibody targeting mature amyloid plaques) in early, symptomatic AD. In this trial, donanemab demonstrated robust amyloid plaque reduction and slowing of tau accumulation as measured using positron emission tomography (PET). 

Plasma samples were collected regularly from baseline through week 76. Plasma biomarkers, including Aβ 42/40, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and phosphorylated (P)-tau217, were measured using Quanterix Simoa HD-X technology. All plasma values were log10-transformed in pre-specified analyses. Spearman’s rank analyses were performed for correlation coefficients.

At baseline, plasma P-tau217 levels were statistically significantly correlated with amyloid plaque level (R=0.148, p=0.0243) and global tau deposition (R=0.361, p<0.0001) on PET. Plasma levels of P-tau217 and GFAP were significantly reduced after 12 weeks of donanemab treatment versus placebo. This reduction was sustained over the 76 weeks of study. No significant differences in plasma levels of Aβ 42/40 and NfL were observed between treatment arms at 76 weeks. The changes in plasma P-tau217 and GFAP levels were positively correlated with percent change in amyloid plaque level on PET (R=0.484, p<0.0001 and R=0.453, p<0.0001, respectively). A significant positive correlation was observed between the change in plasma P-tau217 and change in tau deposition on PET in the frontal (R=0.243, p=0.0019) and temporal (R=0.177, p=0.0247) lobes at 76 weeks and trended towards significance in the parietal lobe (R=0.154, p=0.0516). Additionally, plasma P-tau217 and GFAP levels were significantly correlated at baseline and for 76-week change. 

P-tau217 and GFAP plasma levels significantly lowered with donanemab treatment, suggesting that plasma biomarkers may be useful as pharmacodynamic measures of downstream treatment effects of amyloid plaque reduction in early AD.