Treatment of Alzheimer's Disease with the GSK-3 Inhibitor Tideglusib: A Pilot Study
Abstract
This pilot, double-blind, placebo-controlled, randomized, escalating dose trial explored the safety and efficacy of tideglusib, an inhibitor of glycogen synthase kinase-3, in Alzheimer's disease (AD) patients. Thirty mild-moderate AD patients on cholinesterase inhibitor treatment were administered escalating doses (400, 600, 800, 1,000 mg) of tideglusib or placebo (ratio 2 : 1) for 4, 4, 6, and 6 weeks, respectively. The primary objective was to evaluate the safety and tolerability of tideglusib with strict criteria for drug escalation or withdrawal. Mini-Mental Status Examination (MMSE), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog+), word fluency, Geriatric Depression Scale (GDS), and a final Global Clinical Assessment (GCA) were assessed as secondary objectives. Treatment was well tolerated. Adverse events were as frequent in active and placebo groups, except for some moderate, asymptomatic, and fully reversible increases (>2.5 × ULN) of serum transaminases in 6 active cases (p = 0.001). Tideglusib produced positive trends in MMSE, ADAS-cog, GDS, and GCA without statistical significance in this small sample. Responders in MMSE were significantly higher in the active group (p = 0.05). Patients escalated up to 1000 mg/day had a benefit of 1.68 points in the MMSE and 4.72 points in the ADAS-cog+ when compared to placebo. This small pilot study provides valuable safety and efficacy estimates for the treatment of AD patients with tideglusib, currently being confirmed in a larger clinical trial. Due to escalating doses and the small sample size, this trial provides insufficient evidence to support or reject a benefit of tideglusib in AD.
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In a pilot clinical study, patients with AD who received 1,000 mg tideglusib daily showed significant improvements in cognition compared with placebo-treated patients.
“In a pilot clinical study120, patients with AD who received 1,000 mg tideglusib daily showed significant improvements in cognition compared with placebo-treated patients121.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [121]
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BackgroundElucidation of the GSK3α Structure Informs the Design of Novel, Paralog-Selective Inhibitors
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- Authors
- del Ser, T., Steinwachs, K. C., Gertz, H. J., Andrés, M. V., Gómez-Carrillo, B., Medina, M., Vericat, J. A., Redondo, P., Fleet, D., & León, T.
- Affiliations
- Medical Director, Medical Department, Noscira SA, Madrid, Tres Cantos, Spain
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Leipzig University (DE)
- Statistical Consultant, Data Magik Ltd., London, UK
- ORCID
- Medina, Miguel
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2012-12-03
- Volume
- 33
- Issue
- 1
- Pages
- 205-215
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W1513401887
- Cited by
- 329
- References
- 34
- Citations by year
- 2026: 10 · 2025: 25 · 2024: 23 · 2023: 20 · 2022: 22 · 2021: 30 · 2020: 44 · 2019: 21 · 2018: 24 · 2017: 33 · 2016: 16 · 2015: 18 · 2014: 26 · 2013: 15 · 2012: 2
- FWCI
- 13.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- 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
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- tideglusib, Alzheimer's disease
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Cholinesterase Inhibitors, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Pilot Projects, Thiadiazoles, Treatment Outcome, Glycogen Synthase Kinase 3, Protein Kinase Inhibitors
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