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

Abstract 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.