Genetic evidence supports a cortical neuroprotective role of GLP-1 receptor activation in Alzheimer's disease: A drug-target Mendelian randomization study

INTRODUCTION: Whether glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation lowers Alzheimer's disease (AD) risk via peripheral metabolic improvement or direct neuroprotection remains unclear. METHODS: Using blood and brain-cortex cis-acting expression quantitative trait loci (cis-eQTLs) for GLP-1R as instruments, we performed cis-Mendelian randomization (cis-MR) for AD and seven biomarkers. Mendelian randomization Bayesian model averaging (MR-BMA), cis-multivariable Mendelian randomization (cis-MVMR), and two-step cis-MR assessed 11 metabolic and inflammatory mediators, and tissue-specific cis-MVMR identified the causal tissue. RESULTS: GLP-1R expression was associated with lower AD risk and cerebrospinal fluid phosphorylated tau (p-tau) levels. The cis-MVMR identified systolic blood pressure as the only independent mediator, whereas GLP-1R retained a direct protective effect on AD. Tissue-specific cis-MVMR attributed the effect predominantly to cortical (posterior inclusion probability [PIP] = 0.998) rather than blood GLP-1R expression (PIP = 0.002). CONCLUSION: Genetic evidence supports GLP-1R as a potential target in AD, with a protective effect not fully explained by peripheral metabolic improvement and possibly involving cortical neuroprotection, supporting further investigation of brain-penetrant agents at preclinical or prodromal stages. © 2026 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.