The intersection of metabolic disease and neurodegeneration represents one of the most consequential frontiers in translational neuroscience. Converging epidemiological, mechanistic, and pharmacological evidence supports a bidirectional metabolic-brain axis in which systemic insulin resistance, obesity, and chronic metabolic inflammation are associated with and may contribute to alterations in neuronal survival, synaptic plasticity, and neuroimmune homeostasis. GLP-1 receptor agonists, originally developed for glycemic control and weight management, have therefore been investigated as potential disease-modifying therapies across Alzheimer's disease, Parkinson's disease, and related neurodegenerative conditions through mechanisms including neuronal PKA activation, microglial NLRP3 suppression, mitochondrial biogenesis, and restoration of AQP4 perivascular localization that may contribute to glymphatic waste clearance. Direct human evidence for these CNS mechanisms remains limited or absent, with current support derived primarily from preclinical models and indirect human data, as detailed in Table 1, warranting dedicated investigation in the context of GLP-1 receptor agonism. Importantly, the two pivotal phase 3 programs designed to test this hypothesis in humans - EVOKE/EVOKE+ in early Alzheimer's disease and Exenatide-PD3 in Parkinson's disease - have both now reported, and neither demonstrated a statistically significant benefit on its primary clinical endpoint, despite favorable biomarker and epidemiological signals preceding these results. This review synthesizes current knowledge on brain insulin signaling, GLP-1 neurobiology, obesity-driven neuroinflammation, and the translational evidence for metabolic therapeutics in neurodegeneration, and uses the dissociation between mechanistic plausibility, epidemiological association, and null confirmatory trial results to identify critical knowledge gaps and translational barriers related to CNS target engagement, optimal dosing, and disease-modifying efficacy of GLP-1 receptor agonists. The review is organized into four major themes: brain insulin signaling, central GLP-1 biology, obesity-associated neuroinflammation, and the translational evidence supporting metabolic therapies for neurodegenerative disease.
