Trial reportJournal of Alzheimer's disease : JAD2012
Amyloid-β(1-15/16) as a marker for γ-secretase inhibition in Alzheimer's disease.
Trial report in Journal of Alzheimer's disease : JAD, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
23 citing papers in PubMed.
- A single dose of the γ-secretase inhibitor semagacestat alters the cerebrospinal fluid peptidome in humans.Alzheimer's research & therapy · 2016Trial
- Aβ1-15/16 as a potential diagnostic marker in neurodegenerative diseases.Neuromolecular medicine · 2013Trial
- Alzheimer's Disease Biomarker Analysis Using Targeted Mass Spectrometry.Molecular & cellular proteomics : MCP · 2024Review
- Human cystatin C induces the disaggregation process of selected amyloid beta peptides: a structural and kinetic view.Scientific reports · 2023Article
- Biomarkers for Alzheimer's Disease: Context of Use, Qualification, and Roadmap for Clinical Implementation.Medicina (Kaunas, Lithuania) · 2022Review
- Drug Development for Psychotropic, Cognitive-Enhancing, and Disease-Modifying Treatments for Alzheimer's Disease.The Journal of neuropsychiatry and clinical neurosciences · 2021Article
- The "rights" of precision drug development for Alzheimer's disease.Alzheimer's research & therapy · 2019Review
- Article
- Human cerebrospinal fluid 6E10-immunoreactive protein species contain amyloid precursor protein fragments.PloS one · 2019Article
- Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry.The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry · 2018Review
- Lessons Learned from Alzheimer Disease: Clinical Trials with Negative Outcomes.Clinical and translational science · 2018Review
- Clinical Trials for Disease-Modifying Therapies in Alzheimer's Disease: A Primer, Lessons Learned, and a Blueprint for the Future.Journal of Alzheimer's disease : JAD · 2018Review
- Phenotypic Screening Identifies Modulators of Amyloid Precursor Protein Processing in Human Stem Cell Models of Alzheimer's Disease.Stem cell reports · 2017Article
- Amyloid beta modulators and neuroprotection in Alzheimer's disease: a critical appraisal.Drug discovery today · 2017Review
- Cerebrospinal fluid biomarkers in trials for Alzheimer and Parkinson diseases.Nature reviews. Neurology · 2015Review
- Alzheimer's disease--a panorama glimpse.International journal of molecular sciences · 2014Review
- Interpreting Alzheimer's disease clinical trials in light of the effects on amyloid-β.Alzheimer's research & therapy · 2014Review
- β-site amyloid precursor protein-cleaving enzyme 1(BACE1) inhibitor treatment induces Aβ5-X peptides through alternative amyloid precursor protein cleavage.Alzheimer's research & therapy · 2014Article
- Amyloid-beta isoform metabolism quantitation by stable isotope-labeled kinetics.Analytical biochemistry · 2013Article
- Cerebrospinal Fluid Biomarkers for Alzheimer's Disease: Emergence of the Solution to an Important Unmet Need.EJIFCC · 2013Article
Corrections and comments
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Authors and funding
15 authors.
Funding
Abstract
Amyloid-β (Aβ) producing enzymes are key targets for disease-modifying Alzheimer's disease (AD) therapies since Aβ trafficking is at the core of AD pathogenesis. Development of such drugs might benefit from the identification of markers indicating in vivo drug effects in the central nervous system. We have previously shown that Aβ(1-15) is produced by concerted β-and α-secretase cleavage of amyloid-β protein precursor (AβPP). Here, we test the hypothesis that this pathway is more engaged upon γ-secretase inhibition in humans, and cerebrospinal fluid (CSF) levels of Aβ(1-15/16) represent a biomarker for this effect. Twenty healthy men were treated with placebo (n = 5) or the γ-secretase inhibitor semagacestat (100 mg [n = 5], 140 mg [n = 5], or 280 mg [n = 5]). CSF samples were collected hourly over 36 hours and 10 time points were analyzed by immunoassay for Aβ(1-15/16), Aβ(x-38), Aβ(x-40), Aβ(x-42), sAβPPα, and sAβPPβ. The CSF concentration of Aβ(1-15/16) showed a dose-dependent response over 36 hours. In the 280 mg treatment group, a transient increase was seen with a maximum of 180% relative to baseline at 9 hours post administration of semagacestat. The concentrations of Aβ(x-38), Aβ(x-40), and Aβ(x-42) decreased the first 9 hours followed by increased concentrations after 36 hours relative to baseline. No significant changes were detected for CSF sAβPPα and sAβPPβ. Our data shows that CSF levels of Aβ(1-15/16) increase during treatment with semagacestat supporting its feasibility as a pharmacodynamic biomarker for drug candidates aimed at inhibiting γ-secretase-mediated AβPP-processing.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.