GLP-1 Receptor Agonists as Neuroprotective Agents in Alzheimer’s Disease: Mechanisms and Therapeutic Potential

Abstract

Although Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used as a treatment for type 2 diabetes, and appear to be promising candidates for neuroprotection in Alzheimer's disease (AD). There has been an increase in evidence that suggests that GLP-1 signalling, beyond the metabolic regulation, seems to influence central nervous system function including synaptic plasticity and neuroinflammation. Preclinical studies have shown that GLP-1RAs can cross the blood-brain barrier and exert neuroprotective effects by reducing amyloid-β and tau accumulation, and reducing neuroinflammation. Additionally, GLP-1R activation enhances insulin signalling in the brain, addressing insulin resistance, a key feature implicated in AD pathogenesis. These mechanisms collectively contribute to an improved synaptic integrity and cognitive function in disease models. Data from emerging studies also suggest that GLP-1RAs may mitigate oxidative stress and support mitochondrial function, slowing neurodegenerative progression. However, conflicting evidence remains, as clinical findings demonstrate variable and often modest cognitive benefits depending on disease stage, treatment duration, and study design. Although most evidence remains preclinical and that continued research is still needed to establish their efficacy in large-scale clinical trials, GLP-1RAs represent a promising neuroprotective intervention for AD and other neurodegenerative diseases alike. Future research should prioritize large long‑term trials with standardized cognitive and biomarker outcomes to clarify the efficacy and optimal use of these agents. Combining semaglutide and liraglutide may also offer stage‑specific benefits in AD due to their distinct pharmacological profiles. Dual GLP‑1 agonists represent a promising emerging therapeutic strategy.