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Cited by 264Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Association of Donanemab Treatment With Exploratory Plasma Biomarkers in Early Symptomatic Alzheimer Disease: A Secondary Analysis of the TRAILBLAZER-ALZ Randomized Clinical Trial

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Pontecorvo, Michael J., Lu, Ming, Burnham, Samantha C., Schade, Andrew E., Dage, Jeffrey L., Shcherbinin, Sergey, Collins, Emily C., Sims, John R., Mintun, Mark A.·2022·JAMA Neurology
DOI 10.1001/jamaneurol.2022.3392PMC PMC9577883
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Abstract

Importance: Plasma biomarkers of Alzheimer disease may be useful as minimally invasive pharmacodynamic measures of treatment outcomes. Objective: To analyze the association of donanemab treatment with plasma biomarkers associated with Alzheimer disease. Design, Setting, and Participants: TRAILBLAZER-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. Interventions: Randomized 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 Measures: Change in plasma biomarker levels after donanemab treatment. Results: In TRAILBLAZER-ALZ, 272 participants (mean [SD] age, 75.2 [5.5] years; 145 [53.3%] female) were randomized. Plasma levels of phosphorylated tau 217 (pTau 217 ) 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 pTau 217 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 pTau 217 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 Relevance: Significant reductions in plasma biomarkers pTau 217 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 Registration: ClinicalTrials.gov Identifier: NCT03367403

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Figures

Figure 1. Baseline Plasma Phosphorylated Tau217 (pTau217) Levels Correlated With Baseline Amyloid and Tau Positron Emission Tomography (PET) End Points Baseline amyloid PET (placebo n = 111; donanemab n = 121) (A), and tau PET (placebo n = 112; donanemab n = 120) (B) levels compared with baseline plasma pTau217 levels. Plasma levels were log10 transformed. Linear regression of all data points, regardless of treatment, is indicated by the straight line. Spearman rank was used for correlation coefficient. PERSI indicates parametric estimation of reference signal intensity; SUVR, standardized uptake value ratio.
Figure 1. Baseline Plasma Phosphorylated Tau217 (pTau217) Levels Correlated With Baseline Amyloid and Tau Positron Emission Tomography (PET) End Points Baseline amyloid PET (placebo n = 111; donanemab n = 121) (A), and tau PET (placebo n = 112; donanemab n = 120) (B) levels compared with baseline plasma pTau217 levels. Plasma levels were log10 transformed. Linear regression of all data points, regardless of treatment, is indicated by the straight line. Spearman rank was used for correlation coefficient. PERSI indicates parametric estimation of reference signal intensity; SUVR, standardized uptake value ratio.CC BY-NC-ND · PubMed Central
Figure 2. Change in Plasma Levels Following Donanemab Treatment Least square (LS) mean change from baseline in plasma phosphorylated tau217 (pTAU217) (A), glial fibrillary acidic protein (GFAP) (B), neurofilament light chain (NfL) (C), and amyloid-β (Aβ) 42/40 (D) for placebo and donanemab. Plasma values were log10 transformed. Error bars indicate standard error. The dotted line indicates baseline. aP < .01 vs placebo. bP < .001 vs placebo. cP < .05 vs placebo.
Figure 2. Change in Plasma Levels Following Donanemab Treatment Least square (LS) mean change from baseline in plasma phosphorylated tau217 (pTAU217) (A), glial fibrillary acidic protein (GFAP) (B), neurofilament light chain (NfL) (C), and amyloid-β (Aβ) 42/40 (D) for placebo and donanemab. Plasma values were log10 transformed. Error bars indicate standard error. The dotted line indicates baseline. aP < .01 vs placebo. bP < .001 vs placebo. cP < .05 vs placebo.CC BY-NC-ND · PubMed Central
Figure 3. Correlations of Change in Plasma Phosphorylated tau217 (pTau217) and Glial Fibrillary Acidic Protein (GFAP) With Change in Amyloid Positron Emission Tomography (PET) End Points Percent change in amyloid PET levels from baseline to 76 weeks compared with change in plasma levels of pTau217 (placebo n = 85; donanemab n = 84) (A) and GFAP (placebo n = 66; donanemab n = 66) (B) from baseline to 76 weeks. Plasma levels were log10 transformed. Linear regression of all data points, regardless of treatment, is shown in light blue. Spearman rank was used for correlation coefficient.
Figure 3. Correlations of Change in Plasma Phosphorylated tau217 (pTau217) and Glial Fibrillary Acidic Protein (GFAP) With Change in Amyloid Positron Emission Tomography (PET) End Points Percent change in amyloid PET levels from baseline to 76 weeks compared with change in plasma levels of pTau217 (placebo n = 85; donanemab n = 84) (A) and GFAP (placebo n = 66; donanemab n = 66) (B) from baseline to 76 weeks. Plasma levels were log10 transformed. Linear regression of all data points, regardless of treatment, is shown in light blue. Spearman rank was used for correlation coefficient.CC BY-NC-ND · PubMed Central
Figure 4. Correlations of Change in Plasma Phosphorylated Tau217 (pTau217) With Change in Tau Positron Emission Tomography (PET) End Points Change in tau PET levels compared with change in plasma pTau217 levels from baseline to 76 weeks in frontal (A), temporal (B), parietal (C), and occipital (D) lobes as well as globally (E). Plasma levels were log10 transformed. Linear regression of all data points, regardless of treatment, is shown in light blue. Spearman rank was used for correlation coefficient. There were 78 individuals in the placebo group and 83 in the donanemab group. SUVR indicates standardized uptake value ratio.
Figure 4. Correlations of Change in Plasma Phosphorylated Tau217 (pTau217) With Change in Tau Positron Emission Tomography (PET) End Points Change in tau PET levels compared with change in plasma pTau217 levels from baseline to 76 weeks in frontal (A), temporal (B), parietal (C), and occipital (D) lobes as well as globally (E). Plasma levels were log10 transformed. Linear regression of all data points, regardless of treatment, is shown in light blue. Spearman rank was used for correlation coefficient. There were 78 individuals in the placebo group and 83 in the donanemab group. SUVR indicates standardized uptake value ratio.CC BY-NC-ND · PubMed Central
Figure 5. Correlations of Plasma Phosphorylated tau217 (pTau217) Levels With Plasma Glial Fibrillary Acidic Protein (GFAP) Levels Plasma GFAP levels compared with plasma pTau217 levels at baseline (placebo n = 103, donanemab n = 104) (A), 76 weeks (placebo n = 78, donanemab n = 83) (B), and change from baseline to 76 weeks (placebo n = 67, donanemab n = 69) (C). Plasma levels were log10 transformed. Linear regression of all data points, regardless of treatment, is shown in light blue. Spearman rank was used for correlation coefficient.
Figure 5. Correlations of Plasma Phosphorylated tau217 (pTau217) Levels With Plasma Glial Fibrillary Acidic Protein (GFAP) Levels Plasma GFAP levels compared with plasma pTau217 levels at baseline (placebo n = 103, donanemab n = 104) (A), 76 weeks (placebo n = 78, donanemab n = 83) (B), and change from baseline to 76 weeks (placebo n = 67, donanemab n = 69) (C). Plasma levels were log10 transformed. Linear regression of all data points, regardless of treatment, is shown in light blue. Spearman rank was used for correlation coefficient.CC BY-NC-ND · PubMed Central

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Authors
Pontecorvo, M. J., Lu, M., Burnham, S. C., Schade, A. E., Dage, J. L., Shcherbinin, S., Collins, E. C., Sims, J. R., & Mintun, M. A.
Affiliations
  • Eli Lilly (United States) (US)
  • Indiana University Indianapolis (US)
Corresponding author
Pontecorvo, Michael J.
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2022-12-01
Volume
79
Issue
12
Pages
1250
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2022.3392
PMC
PMC9577883
OpenAlex
W4306663551
Cited by
261
References
35
Citations by year
2026: 50 · 2025: 83 · 2024: 75 · 2023: 50 · 2022: 3
FWCI
32.98
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • JAMA Neurology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
donanemab, Alzheimer's disease, plasma biomarkers, pharmacodynamic biomarkers, phosphorylated tau217, glial fibrillary acidic protein, amyloid-beta, neurofilament light chain, anti-amyloid therapy, treatment response monitoring, neuroinflammation
MeSH terms
Aged, Alzheimer Disease, Antibodies, Monoclonal, Double-Blind Method, Female, Glial Fibrillary Acidic Protein, Humans, Male, Plasma, Biomarkers, Amyloid beta-Peptides

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