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Cited by 210Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Association of Amyloid Reduction After Donanemab Treatment With Tau Pathology and Clinical Outcomes: The TRAILBLAZER-ALZ Randomized Clinical Trial

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Shcherbinin, Sergey, Evans, Cynthia D., Lu, Ming, Andersen, Scott W., Pontecorvo, Michael J., Willis, Brian A., Gueorguieva, Ivelina, Hauck, Paula M. +3 more·2022·JAMA Neurology
DOI 10.1001/jamaneurol.2022.2793PMC PMC9468959
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Abstract

Importance: β-amyloid plaques and neurofibrillary tau deposits biologically define Alzheimer disease. Objective: To perform post hoc analyses of amyloid reduction after donanemab treatment and assess its association with tau pathology and clinical measures. Design, Setting, and Participants: The Study of LY3002813 in Participants With Early Symptomatic Alzheimer’s Disease (TRAILBLAZER-ALZ) was a phase 2, placebo-controlled, randomized clinical trial conducted from December 18, 2017, to December 4, 2020, with a double-blind period of up to 76 weeks and a 48-week follow-up period. The study was conducted at 56 centers in the US and Canada. Enrolled were participants from 60 to 85 years of age with gradual and progressive change in memory function for 6 months or more, early symptomatic Alzheimer disease, elevated amyloid, and intermediate tau levels. Interventions: Donanemab (an antibody specific for the N-terminal pyroglutamate β-amyloid epitope) dosing was every 4 weeks: 700 mg for the first 3 doses, then 1400 mg for up to 72 weeks. Blinded dose-reduction evaluations occurred at 24 and 52 weeks based on amyloid clearance. Main Outcomes and Measures: Change in amyloid, tau, and clinical decline after donanemab treatment. Results: The primary study randomized 272 participants (mean [SD] age, 75.2 [5.5] years; 145 female participants [53.3%]). The trial excluded 1683 of 1955 individuals screened. The rate of donanemab-induced amyloid reduction at 24 weeks was moderately correlated with the amount of baseline amyloid (Spearman correlation coefficient r, −0.54; 95% CI, −0.66 to −0.39; P < .001). Modeling provides a hypothesis that amyloid would not reaccumulate to the 24.1-centiloid threshold for 3.9 years (95% prediction interval, 1.9-8.3 years) after discontinuing donanemab treatment. Donanemab slowed tau accumulation in a region-dependent manner as measured using neocortical and regional standardized uptake value ratios with cerebellar gray reference region. A disease-progression model found a significant association between percentage amyloid reduction and change on the integrated Alzheimer Disease Rating Scale only in apolipoprotein E (APOE) ε4 carriers (95% CI, 24%-59%; P < .001). Conclusions and Relevance: Results of post hoc analyses for donanemab-treated participants suggest that baseline amyloid levels were directly associated with the magnitude of amyloid reduction and inversely associated with the probability of achieving complete amyloid clearance. The donanemab-induced slowing of tau was more pronounced in those with complete amyloid clearance and in brain regions identified later in the pathologic sequence. Data from other trials will be important to confirm aforementioned observations, particularly treatment response by APOE ε4 status. Trial Registration: ClinicalTrials.gov Identifier: NCT03367403

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  • In the phase 2 TRAILBLAZER-ALZ study, donanemab met its primary endpoint of delaying decline by 32% compared with placebo, determined on the basis of iADRS scores.

    “The trial met its primary endpoint of delaying decline—which was determined on the basis of iADRS scores—by 32% compared with placebo.”

    From Clinical trials of new drugs for Alzheimer disease: a 2020–2023 update (2023) · cites this paper as [48]

  • Amyloid burden reduction was correlated with improvement in iADRS scores only in ApoE4 carriers.

    “Amyloid burden reduction was correlated with improvement in iADRS scores only in ApoE4 carriers [48].”

    From Clinical trials of new drugs for Alzheimer disease: a 2020–2023 update (2023) · cites this paper as [48]

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Research works printed but not linked: 1

  1. [29]Shcherbinin S, Lu M, Morris A,. Flortaucipir in the TRAILBLAZER-ALZ trial. J Prev Alzheimers Dis. 2021; 8(1): S22- S23.

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Authors
Shcherbinin, S., Evans, C. D., Lu, M., Andersen, S. W., Pontecorvo, M. J., Willis, B. A., Gueorguieva, I., Hauck, P. M., Brooks, D. A., Mintun, M. A., & Sims, J. R.
Affiliations
Eli Lilly (United States) (US)
Corresponding author
Sims, John R.
ORCID
Venue
JAMA Neurology
Publisher
American Medical Association (AMA)
Published
2022-10-01
Volume
79
Issue
10
Pages
1015
ISSN
2168-6149 (ISSN-L)
DOI
10.1001/jamaneurol.2022.2793
PMC
PMC9468959
OpenAlex
W4296546783
Cited by
210
References
29
Citations by year
2026: 51 · 2025: 60 · 2024: 56 · 2023: 37 · 2022: 6
FWCI
24.62
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)
Topics
  • Health Sciences › Medicine › Physiology › 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, amyloid plaques, tau pathology, Alzheimer's disease, tau accumulation, amyloid PET, standardized uptake value ratio, disease progression model, clinical deterioration
MeSH terms
Aged, Alzheimer Disease, Amyloid, Amyloidosis, Epitopes, Female, Humans, Infant, Pyrrolidonecarboxylic Acid, Amyloid beta-Peptides, tau Proteins, Positron-Emission Tomography, Apolipoprotein E4, Plaque, Amyloid

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