Role of Glucagon-Like Peptide-1 on Amyloid, Tau, and α-Synuclein: Target Engagement and Rationale for the Development in Neurodegenerative Disorders

INTRODUCTION: Glucagon-like Peptide-1 (GLP-1) and Glucagon-Like Peptide-1 receptor agonist (GLP-1 RA) administration has been associated with neuroprotective effects in neurodegenerative disorders. We conducted a comprehensive synthesis of known effects of GLP-1 and GLP-1 RAs on the cognitive, cellular, and molecular changes in neurodegenerative diseases. METHODS: We examined preclinical and clinical paradigms that investigated changes in neurodegenerative disease pathology following administration of GLP-1 and GLP-1 RAs. Relevant articles were retrieved through OVID (MedLine, Embase, AMED, PsychINFO, JBI EBP Database), PubMed, and Web of Science from database inception to September 27th, 2024. Primary studies investigating the aforementioned changes following GLP-1 and GLP-1 RA administration were retrieved for analysis (n = 62). RESULTS: GLP-1 and GLP-1 RAs (i.e. dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, and tirzepatide) improved cognitive and motor function in neurodegenerative diseases in preclinical and clinical paradigms. Additionally, GLP-1 and GLP-1 RAs were associated with modulating changes in neuroinflammation, oxidative stress, and proliferative pathways. DISCUSSION: We observed that GLP-1 and GLP-1 RAs modulate molecular and cellular changes known to govern the phenomenology of neurodegenerative diseases. Future research should examine the interaction between signaling molecules, neuronal subpopulations, and cognitive effects affected by GLP-1 and GLP-1 RA administration.