Meta-analysis of Mendelian randomization suggests GLP-1 receptor agonism lowers vascular dementia risk

SUMMARY Background GLP-1 receptor agonists (GLP-1 RAs) are widely used for treatment of type 2 diabetes and obesity and have demonstrated cardiovascular benefits, but their effect on dementia risk is uncertain. We used a drug-target Mendelian randomisation (MR) framework to estimate the causal effect of GLP-1 receptor (GLP-1R) agonism on dementia risk and brain structure. Methods We used single nucleotide polymorphisms (SNPs) in GLP1R to recapitulate the effect of GLP1-RAs against circulating markers of glucose, glycated haemoglobin and outcomes of type 2 diabetes and obesity, to understand if we can reliably proxy agonism at GLP1R using gene variants. We then considered clinical outcomes, including all-cause dementia, vascular dementia, Alzheimer's disease, and neuroimaging outcomes. Analyses were conducted in UK Biobank and replicated in FinnGen and All of Us and results were combined using meta-analysis. Findings Genetically proxied GLP-1R agonism was associated with a 17% lower risk of vascular dementia, with directional consistency across the two largest cohorts. No consistent association was observed for all-cause dementia. An elevated risk of Alzheimer's disease was observed in UK Biobank but was not replicated in FinnGen or All of Us, and the pooled estimate across cohorts was null. There was no consistent evidence of an effect on neuroimaging outcomes, though higher GLP-1R agonism was associated with greater total brain volume. Interpretation Genetic evidence supports a potential protective effect of GLP-1R agonism on vascular dementia, consistent with the established cardio-metabolic benefits of this drug class. The null pooled finding for Alzheimer's disease suggests that GLP-1R agonism does not meaningfully modify neurodegenerative pathways specific to this disease, though results from ongoing clinical trials are awaited. These findings highlight the importance of distinguishing between dementia subtypes when evaluating the cognitive effects of cardiometabolic therapies.