Neuroprotective Potential of GLP-1 Receptor Agonists in Neurodegenerative Diseases: Narrative Review

Abstract

Abstract Background Neurodegenerative disorders, particularly Alzheimer’s disease (AD) and Parkinson’s disease (PD), present substantial global health challenges due to a lack of disease-modifying therapies. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), traditionally used in type 2 diabetes management, have emerged as promising candidates for neuroprotection due to their ability to cross the blood-brain barrier, suppress neuroinflammation, and support neuronal survival. Objective This narrative review aims to analyze the clinical efficacy of GLP-1 RAs in mitigating cognitive and motor deficits in patients with AD and PD. Materials and Methods A narrative literature review was conducted, encompassing large-scale observational cohort studies, nationwide registry analyses, randomized controlled trials (RCTs), and systematic reviews with meta-analyses evaluating the clinical efficacy and safety of GLP-1 receptor agonists in patients with Alzheimer’s disease and Parkinson’s disease. Additionally, preclinical in vivo and in vitro evidence was integrated to elucidate the underlying neuroprotective pathways, focusing on brain-derived neurotrophic factor (BDNF) expression, autophagy regulation, neuroinflammation, and blood-brain barrier integrity. Results In Alzheimer’s disease (AD), observational data associate GLP-1 RA therapy with up to a 63% reduction in dementia risk (RR = 0.37) in diabetic populations; however, randomized controlled trials (RCTs) point to cognitive stabilization and metabolic preservation rather than disease reversal. In Parkinson’s disease (PD), observational studies suggest a 30% lower risk of disease onset (HR = 0.70). Symptomatically, outcomes are highly dependent on drug kinetics: only short-acting formulations (such as exenatide) show statistically significant motor improvements in trials (MD = −2.93 on the MDS-UPDRS Part III). Nevertheless, clinical translation remains constrained by high study heterogeneity, short follow-up periods, and a substantial risk of patient dropout due to gastrointestinal side effects. Conclusions GLP-1 RAs demonstrate promising neuroprotective properties in preclinical and observational studies, though a clinical dualism exists where motor benefits in PD appear highly dependent on formulation kinetics. However, robust evidence of true disease-modifying efficacy in humans remains to be established through ongoing Phase III clinical trials.