The promise of GLP-1 receptor agonists for neurodegenerative diseases.

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.