Glucagon-Like Peptide-1 Signaling in Learning and Memory: Evidence, Mechanisms, and Therapeutic Implications.

Glucagon-like peptide-1 (GLP-1) is primarily known for its role in glucose homeostasis and food intake control, and GLP-1 analogs (either as monotherapy or dual agonists) are commonly used for type 2 diabetes and obesity treatment in humans. Beyond these functions, the GLP-1 receptor (GLP-1R) is widely expressed throughout the brain, including in the hippocampus (HPC) and interconnected regions that contribute to learning and memory processes. Here we review emerging evidence supporting a role for GLP-1 signaling in promoting learning and memory function, particularly in dementia and other conditions that manifest with HPC dysfunction. Evidence is synthesized from preclinical rodent models revealing that GLP-1 analog treatment improves deficits in memory function and HPC neuronal signaling processes in various models of dementia, aging, and metabolic disruption. While findings from human clinical trials and meta-analyses also show promise for GLP-1 analog-based treatment for memory disorders, results thus far are mixed, with many studies underpowered and/or lacking comprehensive memory evaluation. We describe several distinct yet non-mutually exclusive neurobiological mechanisms by which GLP-1R signaling can enhance memory, including blood-brain barrier penetration and direct action on HPC GLP-1Rs, improved peripheral and central insulin sensitivity, vagus nerve GLP-1R activation, and peripheral metabolic and inflammatory improvements. We conclude by emphasizing important considerations for future clinical trials for GLP-1 analogs in the treatment of Alzheimer's disease and other memory disorders, including focusing on metabolically vulnerable individuals, stratifying results by cardiovascular and metabolic status, and leveraging existing GLP-1 analogs and drug delivery approaches toward maximizing bioavailability and brain penetrance.