The findings point to potential neurological benefits of GLP-1RAs, which have already demonstrated cardiovascular benefits. Researchers investigated whether the effects of these medicines, as proxied by genetic variants, were associated with reduced risks of stroke and Alzheimer’s disease across populations of different ancestries. However, the extent to which these associations were consistent across ancestry groups had remained unclear.
To investigate the potential relationships, researchers conducted a two-sample Mendelian randomisation analysis using summary statistics from genome-wide association studies involving populations of European, East Asian and African ancestry. The datasets included participants with and without type 2 diabetes (T2D), stroke and Alzheimer’s disease, with sample sizes ranging from 3,026 to 1,812,017 individuals.
Mendelian randomisation uses genetic variation to investigate potential causal relationships between exposures and health outcomes. The approach can provide evidence to guide further experimental research and clinical studies, although it does not establish that a medication will produce the same effects when prescribed to patients.
Among participants of European ancestry, locus-based analyses identified protective associations between genetically proxied GLP-1RA effects and both any stroke and ischaemic stroke. These associations remained statistically significant after adjustment for multiple comparisons, meeting the false discovery rate threshold of pFDR<0.05. The association with Alzheimer’s disease reached nominal statistical significance (p<0.05), indicating that the evidence for this outcome was less robust in the European analysis alone.
The findings among participants of East Asian ancestry pointed in the same protective direction. The odds ratio (OR) was 0.81 for stroke and 0.67 for Alzheimer’s disease. However, neither association reached statistical significance. Exploratory analyses involving participants of African ancestry also indicated a potential protective trend, but the lack of statistical significance limited the conclusions that could be drawn from these ancestry-specific results.
A cross-ancestry meta-analysis provided stronger evidence of protective associations across four neurological outcomes. The analysis reported an odds ratio of 0.75 for any stroke, 0.72 for ischaemic stroke, 0.55 for cardioembolic stroke and 0.51 for Alzheimer’s disease. All four associations met the false discovery rate-adjusted significance threshold of pFDR<0.05.
These findings support further investigation into whether GLP-1RAs could help reduce the risk of neurological diseases. However, the researchers’ genetic analysis does not directly demonstrate that prescribing these medicines prevents stroke or Alzheimer’s disease. Experimental studies and clinical trials will be needed to establish whether treatment provides such protection and to clarify the mechanisms underlying the observed associations.
The study highlights potential links between GLP-1RA-related genetic effects and lower risks of stroke and Alzheimer’s disease across ancestry groups, while underscoring the need for further clinical evidence before these findings can be translated into treatment recommendations.
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