The GLP-1-Brain Axis: From Metabolic Health to Cognitive Resilience

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are established treatments for type 2 diabetes (T2D) and obesity, and they have also attracted attention for their potential influence on brain health. Preclinical research suggests that GLP-1 signaling may impact hippocampal synaptic plasticity, neuronal survival, mitochondrial function, neuroinflammation, and neurovascular coupling. However, it is unclear whether these effects translate into clinically significant cognitive benefits and if such benefits arise from direct neural communication or broader metabolic improvements. This review examines the evolving understanding of the GLP-1–brain connection, exploring both direct central nervous system mechanisms and systemic pathways that link metabolic, vascular, immune, gut, and sleep physiology to cognitive function. Activation of GLP-1 receptors initiates cyclic adenosine monophosphate/protein kinase A, phosphoinositide 3-kinase/protein kinase B, and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling, providing a mechanistic basis for effects on synaptic plasticity and neuronal resilience. Systemically, improvements in insulin sensitivity, lipid profiles, inflammation, vascular function, and potentially gut-brain and sleep-related mechanisms may indirectly support brain health. Preclinical findings are generally promising, though memory enhancements do not consistently correlate with changes in Alzheimer's disease pathology. Human evidence is more varied: cognitive benefits have been observed in certain T2D populations, but studies in non-diabetic individuals have not yet demonstrated consistent advantages. These findings suggest that GLP-1RAs should be considered potential enhancers of cognitive resilience rather than proven cognitive treatments. Well-powered longitudinal studies incorporating cognitive, metabolic, immune, vascular, and neurobiological assessments are needed to distinguish direct neural effects from secondary metabolic benefits and to identify individuals most likely to respond.