GLP-1 receptor agonists as potential disease-modifying agents in Parkinson's and Alzheimer's disease: mechanisms, clinical trial evidence, and the neuroprotection horizon.
7 affiliations
- 1College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
- 2College of Medicine, Sulaiman Alrajhi University, Al Bukayriyah, Saudi Arabia.
- 3College of Medicine, Vision Colleges, Riyadh, Saudi Arabia.
- 4College of Medicine, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia.
- 5Faculty of Medicine, University of Bahri, Khartoum, Sudan.
- 6College of Medicine, AlMaarefa University, Riyadh, Saudi Arabia.
- 7Faculty of Medicine, Al Azhar University, Cairo, Egypt.
Abstract
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.
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BibTeX
@article{alsharif2026glp1,
title = {{GLP-1 receptor agonists as potential disease-modifying agents in Parkinson's and Alzheimer's disease: mechanisms, clinical trial evidence, and the neuroprotection horizon.}},
author = {Mohamed Alsharif and Omran Shrebaty and Mohammad Ammar Aloudah and Mayar Alqahtani and Raghad Saud Aloubili and Marafi Jammaa Ahmed and Bana Albani and Ahmad El Bana},
journal = {Frontiers in aging neuroscience},
year = {2026},
month = oct,
doi = {10.3389/fnagi.2026.1969490},
url = {https://europepmc.org/article/MED/42997320},
note = {CC BY},
}
RIS
TY - JOUR
TI - GLP-1 receptor agonists as potential disease-modifying agents in Parkinson's and Alzheimer's disease: mechanisms, clinical trial evidence, and the neuroprotection horizon.
AU - Mohamed Alsharif
AU - Omran Shrebaty
AU - Mohammad Ammar Aloudah
AU - Mayar Alqahtani
AU - Raghad Saud Aloubili
AU - Marafi Jammaa Ahmed
AU - Bana Albani
AU - Ahmad El Bana
PY - 2026
DA - 2026/10/07
JO - Frontiers in aging neuroscience
DO - 10.3389/fnagi.2026.1969490
UR - https://europepmc.org/article/MED/42997320
AB - 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.
SN - 1663-4365
ER -