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Accepted manuscript

The Effect of GLP-1 Receptor Agonists on Autophagy: Insights Gathered from Research Evaluating Neurodegenerative Disorders With These Agents

Published online by Cambridge University Press:  13 February 2026

Maria-Christina Sioufi ,
Isabela Heroiu ,
Sabrina Wong ,
Gia Han Le ,
Christine E. Dri ,
Yang Jing Zheng Open the ORCID record for Yang Jing Zheng [Opens in a new window] ,
Taeho Greg Rhee ,
Heidi Ka Ying Lo ,
Hernan F. Guillen-Burgos  and
Kayla M. Teopiz
...Show all authors
Maria-Christina Sioufi
Affiliation:
Brain and Cognition Discovery Foundation, Toronto, ON. Canada Department of Human Biology and Physiology, University of Toronto, ON. Canada
Isabela Heroiu
Affiliation:
Brain and Cognition Discovery Foundation, Toronto, ON. Canada
Sabrina Wong
Affiliation:
Brain and Cognition Discovery Foundation, Toronto, ON. Canada Department of Pharmacology and Toxicology, University of Toronto, ON. Canada
Gia Han Le
Affiliation:
Brain and Cognition Discovery Foundation, Toronto, ON. Canada Institute of Medical Science, University of Toronto, ON. Canada Poul Hansen Family Centre for Depression, University Health Network, Toronto, ON, Canada
Christine E. Dri
Affiliation:
Brain and Cognition Discovery Foundation, Toronto, ON. Canada
Yang Jing Zheng
Affiliation:
Brain and Cognition Discovery Foundation, Toronto, ON. Canada Institute of Medical Science, University of Toronto, ON. Canada
Taeho Greg Rhee
Affiliation:
Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA Department of Public Health Sciences, University of Connecticut School of Medicine, Farmington, CT, USA
Heidi Ka Ying Lo
Affiliation:
Department of Public Health Sciences, University of Connecticut School of Medicine, Farmington, CT, USA Department of Psychiatry, School of Clinical Medicine, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong
Hernan F. Guillen-Burgos
Affiliation:
Pontificia Universidad Javeriana, Department of Psychiatry and Mental Health, Bogota DC, Colombia Universidad Simon Bolivar, Center for Clinical and Translational Research, Barranquilla, Colombia Center for Clinical and Translational Research, Bogota DC, Colombia
Kayla M. Teopiz
Affiliation:
Brain and Cognition Discovery Foundation, Toronto, ON. Canada Institute of Medical Science, University of Toronto, ON. Canada
Roger S. McIntyre*
Affiliation:
Department of Psychiatry, University of Toronto, ON. Canada Department of Pharmacology and Toxicology, University of Toronto, ON. Canada
*
* Email: roger.mcintyre@bcdf.org
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Abstract

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Objective:

Impaired autophagy has been implicated in the pathophysiology of neurodegenerative disorders, such as Alzheimer’s Disease (AD) and Parkinson’s Disease (PD). Consistent and replicated evidence indicate that Glucagon-like Peptide-1 Receptor Agonists (GLP-1RAs) exert treatment and preventative effects across disparate neurologic and mental disorders, potentially through mechanisms involving autophagy. This systematic review examined the effects of GLP-1RAs on autophagy in cell and animal models of AD and PD, as a proof of concept, to determine if these agents can be repurposed for the prevention and treatment of neurodegenerative and other mental disorders.

Methods:

A systematic search on PubMed, Web of Science, and OVID (Medline, Embase, and APA PsycInfo databases) was conducted from inception to June 17, 2025. Screening was performed independently by two reviewers (MCS and IH) using predefined inclusion and exclusion criteria. Subsequently, a quality assessment was conducted.

Results:

The search yielded 142 studies, of which 14 were included. Across studies, GLP-1RAs (e.g., liraglutide, semaglutide, and exendin-4) autophagy-specific markers, including beclin-1, LC3-II/LC3-I, ATG7, ATG3, and LAMP1, while normalizing p62 levels.

Discussion:

In addition to promoting neurogenesis, neuroplasticity, and reducing inflammation, GLP-1RAs appear to modulate molecular and cellular systems contributing to autophagy, potentially mediating their broad therapeutic effects. Collectively, these studies present promising findings of GLP-1RAs for neurodegenerative and mental disorders; however, further studies are required to establish their translatability to human populations.

Keywords

AutophagyGlucagon-Like Peptide-1Alzheimer’s diseaseParkinson’s diseaseGLP-1 Receptor AgonistsLiraglutideSemaglutideExendin-4Major DepressionBipolar DisorderDementiaDiabetes MellitusObesityMetabolic Syndrome

Information

Type
Review Article
Information
Acta Neuropsychiatrica , Accepted manuscript , pp. 1 - 36
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.
Copyright
© The Author(s), 2026. Published by Cambridge University Press on behalf of Scandinavian College of Neuropsychopharmacology