Association of Donanemab Treatment With Exploratory Plasma Biomarkers in Early Symptomatic Alzheimer Disease

Abstract

ImportancePlasma biomarkers of Alzheimer disease may be useful as minimally invasive pharmacodynamic measures of treatment outcomes.ObjectiveTo analyze the association of donanemab treatment with plasma biomarkers associated with Alzheimer disease.Design, Setting, and ParticipantsTRAILBLAZER-ALZ was a randomized, double-blind, placebo-controlled clinical trial conducted from December 18, 2017, to December 4, 2020, across 56 sites in the US and Canada. Exploratory biomarkers were prespecified with the post hoc addition of plasma glial fibrillary acidic protein and amyloid-β. Men and women aged 60 to 85 years with gradual and progressive change in memory function for at least 6 months were included. A total of 1955 participants were assessed for eligibility. Key eligibility criteria include Mini-Mental State Examination scores of 20 to 28 and elevated amyloid and intermediate tau levels.InterventionsRandomized participants received donanemab or placebo every 4 weeks for up to 72 weeks. The first 3 doses of donanemab were given at 700 mg and then increased to 1400 mg with blinded dose reductions as specified based on amyloid reduction.Main Outcomes and MeasuresChange in plasma biomarker levels after donanemab treatment.ResultsIn TRAILBLAZER-ALZ, 272 participants (mean [SD] age, 75.2 [5.5] years; 145 [53.3%] female) were randomized. Plasma levels of phosphorylated tau217 (pTau217) and glial fibrillary acidic protein were significantly lower with donanemab treatment compared with placebo as early as 12 weeks after the start of treatment (least square mean change difference vs placebo, –0.04 [95% CI, –0.07 to –0.02]; P = .002 and –0.04 [95% CI, –0.07 to –0.01]; P = .01, respectively). No significant differences in plasma levels of amyloid-β 42/40 and neurofilament light chain were observed between treatment arms at the end of treatment. Changes in plasma pTau217 and glial fibrillary acidic protein were significantly correlated with the Centiloid percent change in amyloid (Spearman rank correlation coefficient [R] = 0.484 [95% CI, 0.359-0.592]; P < .001 and R = 0.453 [95% CI, 0.306-0.579]; P < .001, respectively) following treatment. Additionally, plasma levels of pTau217 and glial fibrillary acidic protein were significantly correlated at baseline and following treatment (R = 0.399 [95% CI, 0.278-0.508], P < .001 and R = 0.393 [95% CI, 0.254-0.517]; P < .001, respectively).Conclusions and RelevanceSignificant reductions in plasma biomarkers pTau217 and glial fibrillary acidic protein compared with placebo were observed following donanemab treatment in patients with early symptomatic Alzheimer disease. These easily accessible plasma biomarkers might provide additional evidence of Alzheimer disease pathology change through anti-amyloid therapy. Usefulness in assessing treatment response will require further evaluation.Trial RegistrationClinicalTrials.gov Identifier: NCT03367403

Longitudinal changes in Alzheimer’s-related plasma biomarkers and brain amyloid

“…This difference in the longitudinal correlations for brain and plasma amyloid is likely due to the different time windows in which these two measures are dynamic, with plasma amyloid exhibiting changes decades prior to brain amyloid. Our findings agree with the plasma biomarker findings from the TRAILBLAZER-ALZ clinical trial, where longitudinal change in brain amyloid correlated with change in plasma GFAP but not Aβ 42 /Aβ 40 [36].…”

“…Rates of change were highly correlated between p-tau181/Aβ ସଶ and p-tau231/Aβ ସଶ , and between GFAP and NfL. Our findings agree with the plasma biomarker findings from the TRAILBLAZER-ALZ clinical trial, where longitudinal change in brain amyloid was correlated with change in plasma GFAP but not Aβ ସଶ /Aβ ସ [36].…”

“…Our findings agree with the plasma biomarker findings from the TRAILBLAZER-ALZ clinical trial, where longitudinal change in brain amyloid correlated with change in plasma GFAP but not Aβ !" /Aβ !# [36].…”

Head-to-head comparison between plasma p-tau217 and Flortaucipir-PET in amyloid-positive patients with cognitive impairment

“…This finding is not in line with the common idea that plasma p-tau biomarkers are more closely associated with early markers of AD such as amyloid 1,6,9 , while tau-PET is more closely associated with downstream markers of disease progression such as cognitive decline and brain atrophy 37 , as discussed in the previous paragraph. Consistent with our data, an independent study of amyloid-positive patients found that p-tau217-to-tau-PET association was stronger than p-tau217-to-amyloid-PET 38 . Furthermore, it has been shown that associations between plasma p-tau217 and PET markers evolve over the course of the disease 5 : plasma p-tau217 is associated with amyloid-PET in the earliest stages of AD, when tau burden is restricted to the medial temporal lobe.…”

Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer’s trial selection and disease monitoring

“…If such a relationship can be established in clinical trials, future trials targeting early-stage AD might incorporate plasma p-tau217 as a potential surrogate endpoint 2 . Importantly, a recent clinical trial evaluating donanemab, an immunotherapy efficiently removing Aβ aggregates from the brain, has shown 23% reduction in levels of plasma p-tau217 within 6-18 months of treatment when the placebo group continued to increase 32 .…”