GLP-1 receptor agonists as potential disease-modifying agents in Parkinson’s and Alzheimer’s disease: mechanisms, clinical trial evidence, and the neuroprotection horizon

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed as antidiabetic agents, have emerged as candidate disease-modifying therapies for Parkinson’s disease (PD) and Alzheimer’s disease (AD), reflecting the widespread expression of GLP-1 receptors across neurons, glia, and the cerebral vasculature. This narrative review synthesizes mechanistic, clinical trial, and biomarker evidence for GLP-1 RAs in PD and AD, based on a literature search of PubMed, Embase, Scopus, and Web of Science, with ClinicalTrials.gov searched separately for trial protocols and results, through May 2026. Preclinical data implicate GLP-1 receptor agonism in anti-neuroinflammatory signaling, mitochondrial preservation, autophagy and proteostasis enhancement, anti-apoptotic effects, synaptic plasticity, cerebrovascular protection, and glymphatic clearance. Clinical evidence in PD is mixed and agent- and formulation-dependent: the phase II Exenatide-PD trial reported a motor benefit that persisted after washout (∼3.5-point between-group difference in MDS-UPDRS Part III), and the phase II LIXIPARK trial (lixisenatide) reported a significant 3.08-point between-group difference (95% CI 0.86–5.30; p = 0.007) favoring lixisenatide, whereas the larger, longer phase III Exenatide-PD3 trial, using an extended-release weekly formulation, found no significant effect on the same endpoint (adjusted coefficient 0.92; 95% CI −1.56 to 3.39; p = 0.47); oral semaglutide is under investigation in the ongoing phase II MOST-ABLE trial. In AD, the phase IIb liraglutide (ELAD) trial did not achieve statistical benefit on either its primary imaging endpoint (cerebral glucose metabolic rate; p = 0.14) or on most secondary cognitive measures, and the phase III semaglutide trials EVOKE and EVOKE+ did not meet their primary CDR-SB endpoint (estimated difference −0.08, 95% CI −0.35 to 0.20, p = 0.57 in EVOKE; 0.10, 95% CI −0.17 to 0.38, p = 0.46 in EVOKE+), despite biomarker signals including reductions in cerebrospinal fluid tau species and inflammatory markers. Comparative pharmacology reveals substantial heterogeneity in central nervous system penetration, receptor engagement, and systemic bioavailability across exenatide, liraglutide, semaglutide, and the imbalanced GLP-1/GIP co-agonist tirzepatide, complicating cross-agent extrapolation. Persistent challenges include separating direct neuroprotection from indirect metabolic and cardiovascular benefit, limited characterization of brain drug exposure, trial durations that may be short relative to the expected latency of a disease-modifying effect, and the absence of validated response biomarkers. We conclude that although the mechanistic and epidemiological rationale for GLP-1 RAs in neurodegeneration remains biologically plausible, current trial evidence does not yet support their use outside clinical trials, irrespective of comorbid diabetes status; future studies should prioritize earlier intervention, biomarker-guided patient selection, adequately powered subgroup analyses, and brain-penetrant formulations.