GENETIC evidence has suggested that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may protect against Alzheimer’s disease and stroke, particularly ischaemic and cardioembolic subtypes, according to a new Mendelian randomisation study examining associations across multiple ancestry groups.
Potential Benefits for Brain Health
GLP-1RAs are widely used to treat type 2 diabetes (T2D) and obesity and have demonstrated cardiovascular benefits. Growing interest in their potential effects on brain health has prompted researchers to investigate whether these benefits could extend to neurological conditions. However, whether genetically proxied GLP-1RA effects are associated with a lower risk of stroke and Alzheimer’s disease across different ancestries has remained unclear.
Mendelian Randomisation Across Ancestries
To explore this question, researchers conducted a two-sample Mendelian randomisation analysis using genome-wide association study summary statistics from populations of European, East Asian, and African ancestry. The datasets included participants with and without T2D, stroke, and Alzheimer’s disease, with sample sizes ranging from 3,026 to 1,812,017 individuals. This approach uses genetic variation to investigate potential causal relationships, providing evidence that can help guide further experimental and clinical research.
Protective Associations With Stroke and Alzheimer’s Disease
Among European participants, locus-based analyses identified protective associations with any stroke and ischaemic stroke that remained statistically significant after adjustment for multiple comparisons (pFDR<0.05). The association with Alzheimer’s disease reached nominal significance (p<0.05), indicating that the evidence for this outcome was less robust within the European analysis alone.
In East Asian participants, the findings pointed in the same protective direction for stroke (odds ratio [OR]: 0.81) and Alzheimer’s disease (OR: 0.67), although neither association was statistically significant. Exploratory analyses in participants of African ancestry also suggested a protective trend, but the absence of statistical significance limits the conclusions that can be drawn from these ancestry-specific findings.
When evidence was combined through cross-ancestry meta-analyses, protective associations were identified for any stroke (OR: 0.75), ischaemic stroke (OR: 0.72), cardioembolic stroke (OR: 0.55), and Alzheimer’s disease (OR: 0.51). All four associations met the false discovery rate-adjusted significance threshold of pFDR<0.05.
Further Research Needed to Confirm Clinical Benefits
The findings support further investigation of GLP-1RAs as potential treatments for reducing neurological disease risk. However, genetically proxied effects do not directly establish the benefits of prescribing these medicines. Experimental studies and clinical trials are needed to confirm whether treatment provides protection and to clarify the mechanisms underlying the observed associations.
Reference
Caro-Châtelier I et al. Genetic insights into protective effects of GLP-1 receptor agonists on stroke and alzheimer disease across ancestries. Neurology: Genetics. 2026;12(5):e200425.
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