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Effect of Immunotherapy With Bapineuzumab on Cerebrospinal Fluid Biomarker Levels in Patients With Mild to Moderate Alzheimer Disease
Abstract
BACKGROUND: Given the slow and variable clinical course of Alzheimer disease, very large and extended clinical trials are needed to identify a beneficial clinical effect of disease-modifying treatments. Therefore, biomarkers are essential to prove that an anti-β-amyloid (Aβ) drug candidate affects both Aβ metabolism and plaque load as well as downstream pathogenic mechanisms. OBJECTIVE: To evaluate the effect of the anti-Aβ monoclonal antibody bapineuzumab on cerebrospinal fluid (CSF) biomarkers reflecting Aβ homeostasis, neuronal degeneration, and tau-related pathology in patients with Alzheimer disease. DESIGN: Two phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trials of 12-month duration. SETTING: Academic centers in the United States (Study 201) and England and Finland (Study 202). PATIENTS: Forty-six patients with mild to moderate Alzheimer disease. INTERVENTIONS: Patients received either placebo (n = 19) or bapineuzumab (n = 27) in 3 or 4 ascending dose groups. MAIN OUTCOME MEASURES: Changes between end of study and baseline in the exploratory CSF biomarkers Aβ1-42, AβX-42, AβX-40; total tau (T-tau); and phosphorylated tau (P-tau). RESULTS: Within the bapineuzumab group, a decrease at end of study compared with baseline was found both for CSF T-tau (-72.3 pg/mL) and P-tau (-9.9 pg/mL). When comparing the treatment and placebo groups, this difference was statistically significant for P-tau (P = .03), while a similar trend for a decrease was found for T-tau (P = .09). No clear-cut differences were observed for CSF Aβ. CONCLUSIONS: To our knowledge, this study is the first to show that passive Aβ immunotherapy with bapineuzumab results in decreases in CSF T-tau and P-tau, which may indicate downstream effects on the degenerative process. Cerebrospinal fluid biomarkers may be useful to monitor the effects of novel disease-modifying anti-Aβ drugs in clinical trials. TRIAL REGISTRATIONS clinicaltrials.gov Identifier: NCT00112073, EudraCT Identifier: 2004-004120-12, and isrctn.org Identifier: ISRCTN17517446.
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“In phase 2 clinical studies involving patients with mild-to-moderate Alzheimer’s disease, patients who received bapineuzumab, as compared with those who received placebo, had a greater reduction in amyloid on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and reduced cerebrospinal fluid phosphorylated tau (phospho-tau), suggesting target engagement”
From Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease (2014) · cites this paper as [9]
In the citing paper
“In phase 2 clinical studies involving patients with mild-to-moderate Alzheimer’s disease, patients who received bapineuzumab, as compared with those who received placebo, had a greater reduction in amyloid on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and reduced cerebrospinal fluid phosphorylated tau (phospho-tau), suggesting target engagement”
From Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease (2014) · cites this paper as [9]
In the citing paper
“in phase II trials, the anti-Aβ antibody bapineuzumab reduced CSF phospho-tau levels in patients with AD182,183”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [182]
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Metadata
- Authors
- Zetterberg, H.
- Affiliations
- University of Gothenburg (SE)
- Corresponding author
- Zetterberg, Henrik
- ORCID
- Zetterberg, Henrik
- Venue
- Archives of Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2012-08-01
- Volume
- 69
- Issue
- 8
- Pages
- 1002
- ISSN
- 0003-9942 (ISSN-L)
- OpenAlex
- W2004535959
- Cited by
- 234
- References
- 29
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 5 · 2023: 9 · 2022: 8 · 2021: 12 · 2020: 10 · 2019: 4 · 2018: 16 · 2017: 12 · 2016: 24 · 2015: 25 · 2014: 44 · 2013: 39 · 2012: 18
- FWCI
- 27.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of Neurology (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- 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
- bapineuzumab, Alzheimer's disease, cerebrospinal fluid biomarkers, anti-amyloid monoclonal antibodies, passive immunotherapy, amyloid-beta, tau phosphorylation, total tau, amyloid-beta 42, Aβ40, disease-modifying therapy, neurodegeneration, amyloid plaques
- MeSH terms
- Aged, Alzheimer Disease, Double-Blind Method, England, Female, Finland, Humans, Immunotherapy, Male, Middle Aged, Peptide Fragments, United States, Cohort Studies, Biomarkers, Amyloid beta-Peptides, tau Proteins, Treatment Outcome, Antibodies, Monoclonal, Humanized
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