ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2014
Lessons from a BACE1 inhibitor trial: off-site but not off base.
Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 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.
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Who cites it
44 citing papers in PubMed, 78 citations in OpenAlex.
- Bacopa monnieri phytochemicals as promising BACE1 inhibitors for Alzheimer's disease therapy.Scientific reports · 2025Article
- A Novel RAGE Modulator Induces Soluble RAGE to Reduce BACE1 Expression in Alzheimer's Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Alzheimer's Disease: Models and Molecular Mechanisms Informing Disease and Treatments.Bioengineering (Basel, Switzerland) · 2024Review
- Discovery of a Small-Molecule Modulator of the Autophagy-Lysosome Pathway That Targets Lamin A/C and LAMP1, Induces Autophagic Flux, and Affects Lysosome Positioning in Neurons.ACS chemical neuroscience · 2023Article
- Chronic basal forebrain activation improves spatial memory, boosts neurotrophin receptor expression, and lowers BACE1 and Aβ42 levels in the cerebral cortex in mice.Cerebral cortex (New York, N.Y. : 1991) · 2023Article
- The emerging role of furin in neurodegenerative and neuropsychiatric diseases.Translational neurodegeneration · 2022Review
- Symptomatic and Disease-Modifying Therapy Pipeline for Alzheimer's Disease: Towards a Personalized Polypharmacology Patient-Centered Approach.International journal of molecular sciences · 2022Review
- Physiological Roles of Monomeric Amyloid-β and Implications for Alzheimer's Disease Therapeutics.Experimental neurobiology · 2022Review
- Effects of microRNA-298 on APP and BACE1 translation differ according to cell type and 3'-UTR variation.Scientific reports · 2022Article
- Human microRNA (miR-20b-5p) modulates Alzheimer's disease pathways and neuronal function, and a specific polymorphism close to the MIR20B gene influences Alzheimer's biomarkers.Molecular psychiatry · 2022Article
- Structural biology of cell surface receptors implicated in Alzheimer's disease.Biophysical reviews · 2022Review
- MicroRNA-298 reduces levels of human amyloid-β precursor protein (APP), β-site APP-converting enzyme 1 (BACE1) and specific tau protein moieties.Molecular psychiatry · 2021Article
- Critical thinking on amyloid-beta-targeted therapy: challenges and perspectives.Science China. Life sciences · 2021Review
- Cyclin-Dependent Kinases (CDK) and Their Role in Diseases Development-Review.International journal of molecular sciences · 2021Review
- Repeated electromagnetic field stimulation lowers amyloid-β peptide levels in primary human mixed brain tissue cultures.Scientific reports · 2021Article
- Is It the Twilight of BACE1 Inhibitors?Current neuropharmacology · 2021Article
- Article
- Partial reduction of amyloid β production by β-secretase inhibitors does not decrease synaptic transmission.Alzheimer's research & therapy · 2020Article
- Clinical Trials in Alzheimer's Disease: A Hurdle in the Path of Remedy.International journal of Alzheimer's disease · 2020Review
- Novel Anti-Alzheimer's Therapeutic Molecules Targeting Amyloid Precursor Protein Processing.Oxidative medicine and cellular longevity · 2020Review
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
Alzheimer's disease (AD) is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-β peptide (Aβ). The rate-limiting step in the production of Aβ is the processing of Aβ precursor protein (APP) by β-site APP-cleaving enzyme (BACE1). Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Aβ within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of BACE1 was suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study's team, particularly since BACE1 knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-BACE1 activity. We offer an alternative hypothesis, whereby anti-BACE1 activity may induce apparent hepatotoxicity through inhibiting BACE1's processing of β-galactoside α-2,6-sialyltransferase I (STGal6 I). In knockout mice, paralogues, such as BACE2 or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic BACE1 activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future.
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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.