The promise of GLP-1 receptor agonists for neurodegenerative diseases

Athauda D(1)(2), Greig NH(3), Meissner WG(4)(5)(6), Foltynie T(2), Gandhi
S(1)(2).

Author information:
(1)The Francis Crick Institute, London, United Kingdom.
(2)Department of Clinical and Movement Neurosciences, UCL Queen Square Institute
of Neurology, London, United Kingdom.
(3)Drug Design and Development Section, Translational Gerontology Branch,
Intramural Research Program, National Institute on Aging, NIH, Baltimore,
Maryland, USA.
(4)CHU Bordeaux, Service de Neurologie des Maladies Neurodégénératives, IMNc,
Bordeaux, France.
(5)University de Bordeaux, CNRS, IMN, UMR 5293, Bordeaux, France.
(6)Department of Medicine, University of Otago, Christchurch, and New Zealand
Brain Research Institute, Christchurch, New Zealand.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), established therapies for
type 2 diabetes and obesity, are increasingly recognized for their potential in
neurodegenerative diseases. Preclinical studies across diverse neurodegenerative
conditions consistently demonstrate neuroprotective effects of GLP-1RAs,
including reduced protein aggregation, enhanced autophagy, improved
mitochondrial function, suppression of neuroinflammation, and preservation of
synaptic integrity. Epidemiological analyses further suggest reduced incidence
of dementia, Parkinson disease, and multiple sclerosis among long-term GLP-1RA
users. Early human trials provide signals of target engagement, such as
preserved cerebral glucose metabolism, altered inflammatory biomarkers, and
slowed brain atrophy, although clinical outcomes to date remain mixed and trials
in rarer disorders are sparse. Translation is constrained by uncertainty around
optimal molecule choice, CNS penetrance, tolerability, adherence, and
heterogeneity of response. Furthermore, next-generation dual and triple agonists
may offer enhanced efficacy but remain untested in neurodegeneration.
Conceptually, GLP-1RAs share pleiotropic effects with exercise – one of the few
interventions with proven disease-modifying potential – by enhancing insulin
signaling, stabilizing mitochondria, reducing inflammation, and promoting
synaptic plasticity. This overlap highlights their promise as « pharmacological
analogues of exercise, » and underscores the need for biomarker-driven,
disease-specific trials to establish whether GLP-1RAs can deliver durable
disease modification across the spectrum of neurodegenerative diseases.

DOI: 10.1172/JCI194745
PMCID: PMC12904716
PMID: 41697753 [Indexed for MEDLINE]

Conflict of interest statement: Conflict of interest: TF has served on advisory
boards for Peptron, Abbvie, Eli Lilly, Bluerock, Bayer, and Bial. He has
received honoraria for talks sponsored by Bayer, Bial, Boston Scientific, and
Novo Nordisk. Outside the present manuscript, WGM has received consultancy fees
from Lundbeck, Inhibikase, Koneksa, Ferrer, TreeFrog, Takeda, and BioArctic. He
has also received fees for lecturing from Lundbeck.

Auteurs Bordeaux Neurocampus