Trial reportAnnals of neurology2009
A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system.
Trial report in Annals of neurology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 146 papers, 2 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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
146 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Has inhibition of Aβ production adequately been tested as therapeutic approach in mild AD? A model-based meta-analysis of γ-secretase inhibitor data.European journal of clinical pharmacology · 2013Pooled it
- Current and emerging drug treatment options for Alzheimer's disease: a systematic review.Drugs · 2011Pooled it
- A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with early Alzheimer's Disease.Alzheimer's research & therapy · 2024Trial
- Impact of frequent cerebrospinal fluid sampling on Aβ levels: systematic approach to elucidate influencing factors.Alzheimer's research & therapy · 2016Trial
- A single dose of the γ-secretase inhibitor semagacestat alters the cerebrospinal fluid peptidome in humans.Alzheimer's research & therapy · 2016Trial
- An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-β concentrations collected by lumbar puncture and indwelling lumbar catheter.Alzheimer's research & therapy · 2015Trial
- An antidepressant decreases CSF Aβ production in healthy individuals and in transgenic AD mice.Science translational medicine · 2014Trial
- Aβ1-15/16 as a potential diagnostic marker in neurodegenerative diseases.Neuromolecular medicine · 2013Trial
- Effects of single doses of avagacestat (BMS-708163) on cerebrospinal fluid Aβ levels in healthy young men.Clinical drug investigation · 2012Trial
- Amyloid-β(1-15/16) as a marker for γ-secretase inhibition in Alzheimer's disease.Journal of Alzheimer's disease : JAD · 2012Trial
- Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2011Trial
- The roles of biomarkers in Alzheimer's disease clinical trials.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Review
- Mass Spectrometry-Based Quantification of Orexin Species in Human Cerebrospinal Fluid Reveals Differential Dynamics Associated with Sleep.medRxiv : the preprint server for health sciences · 2025Article
- Interactions between daily sleep-wake rhythms, γ-secretase, and amyloid-β peptide pathology point to complex underlying relationships.Biochimica et biophysica acta. Molecular basis of disease · 2025Article
- Endogenous γ-Secretase Is Linked to Phagocytic Activity in Microglial Cells.Sensors (Basel, Switzerland) · 2025Article
- Divergent actions of physiological and pathological amyloid-β on synapses in live human brain slice cultures.Nature communications · 2025Article
- Proposed Therapeutic Strategy to Combat Alzheimer's Disease by Targeting Beta and Gamma Secretases.Current Alzheimer research · 2025Review
- The manipulator behind "Scissors": γ -secretase and its modulators in Alzheimer's disease.Frontiers in aging neuroscience · 2025Review
- The role of macrophage plasticity in neurodegenerative diseases.Biomarker research · 2024Review
- A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with Early Alzheimer's Disease.medRxiv : the preprint server for health sciences · 2024Article
86 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors.
Funding
Abstract
objectiveAccumulation of amyloid-beta (Abeta) by overproduction or underclearance in the central nervous system (CNS) is hypothesized to be a necessary event in the pathogenesis of Alzheimer's disease. However, previously, there has not been a method to determine drug effects on Abeta production or clearance in the human CNS. The objective of this study was to determine the effects of a gamma-secretase inhibitor on the production of Abeta in the human CNS.
methodsWe utilized a recently developed method of stable-isotope labeling combined with cerebrospinal fluid sampling to directly measure Abeta production during treatment of a gamma-secretase inhibitor, LY450139. We assessed whether this drug could decrease CNS Abeta production in healthy men (age range, 21-50 years) at single oral doses of 100, 140, or 280mg (n = 5 per group).
resultsLY450139 significantly decreased the production of CNS Abeta in a dose-dependent fashion, with inhibition of Abeta generation of 47, 52, and 84% over a 12-hour period with doses of 100, 140, and 280mg, respectively. There was no difference in Abeta clearance.
interpretationStable isotope labeling of CNS proteins can be utilized to assess the effects of drugs on the production and clearance rates of proteins targeted as potential disease-modifying treatments for Alzheimer's disease and other CNS disorders. Results from this approach can assist in making decisions about drug dosing and frequency in the design of larger and longer clinical trials for diseases such as Alzheimer's disease, and may accelerate effective drug validation. Ann Neurol 2009.
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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.