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Incretin-based therapeutics for the treatment of neurodegenerative diseases

Nature Metabolism volume 7, pages 679–696 (2025)Cite this article

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Abstract

Neurodegenerative diseases (NDDs) represent a heterogeneous group of disorders characterized by progressive neuronal loss, which results in significant deficits in memory, cognition, motor skills, and sensory functions. As the prevalence of NDDs rises, there is an urgent unmet need for effective therapies. Current drug development approaches primarily target single pathological features of the disease, which could explain the limited efficacy observed in late-stage clinical trials. Originally developed for the treatment of obesity and diabetes, incretin-based therapies, particularly long-acting GLP-1 receptor (GLP-1R) agonists and GLP-1R–gastric inhibitory polypeptide receptor (GIPR) dual agonists, are emerging as promising treatments for NDDs. Despite limited conclusive preclinical evidence, their pleiotropic ability to reduce neuroinflammation, enhance neuronal energy metabolism and promote synaptic plasticity positions them as potential disease-modifying NDD interventions. In anticipation of results from larger clinical trials, continued advances in next-generation incretin mimetics offer the potential for improved brain access and enhanced neuroprotection, paving the way for incretin-based therapies as a future cornerstone in the management of NDDs.

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Fig. 1: Common hallmarks of neurodegenerative diseases offer therapeutic opportunities.
Fig. 2: Overview of established and potential disease-modifying effects of GLP-1R agonists.
Fig. 3: Expression of GLP-1R in NDD-relevant brain regions.
Fig. 4: Mechanisms of action of incretin mimetics in the brain.
Fig. 5: Emerging incretin-based therapies for NDDs.

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Acknowledgements

We thank previous and current members of the Clemmensen Group for scientific discussions. This work was supported by the Novo Nordisk Foundation (NNF22OC0073778). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research centre, based at the University of Copenhagen, Denmark, and is partially funded by an unconditional donation from the Novo Nordisk Foundation (www.cbmr.ku.dk) (grant numbers NNF18CC0034900 and NNF23SA0084103).

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Authors and Affiliations

  1. Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

    Anika Vear & Christoffer Clemmensen

  2. Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg

    Michael T. Heneka

  3. Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany

    Michael T. Heneka

  4. Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA

    Michael T. Heneka

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  1. Anika Vear
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A.V. and C.C. drafted the manuscript and created the visual elements; M.T.H. critically revised the manuscript for important intellectual content. All authors provided input and approved the final version of the manuscript.

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Correspondence to Christoffer Clemmensen.

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Competing interests

C.C. is a cofounder of Ousia Pharma, a biotechnology company developing therapeutics for treatment of obesity. M.T.H. is a scientific advisory board member at Alector the Dementia Discovery Fund and Muna Therapeutics and has received honoraria for oral presentations from Pfizer, Novartis, Roche, Abbvie and Biogen. A.V. does not declare any competing interests.

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Nature Metabolism thanks Carol Troy, Stefan Trapp, Xu Chen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Christoph Schmitt, in collaboration with the Nature Metabolism editorial team.

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Vear, A., Heneka, M.T. & Clemmensen, C. Incretin-based therapeutics for the treatment of neurodegenerative diseases. Nat Metab 7, 679–696 (2025). https://doi.org/10.1038/s42255-025-01263-4

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