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Genetically Simulated GLP-1 Receptor Agonism and Cerebral Small Vessel Disease

Panagiotis Zangas1, Murad Omarov1, Marios K Georgakis1,2,3

  • 1Institute for Stroke and Dementia Research (ISD), LMU University Hospital, LMU Munich, Germany.

Neurology. Genetics
|March 3, 2026
PubMed
Abstract

Insights

Genetic variants mimicking Glucagon-like peptide-1 receptor (GLP-1R) agonists were linked to reduced risk of small vessel stroke and white matter hyperintensity. This suggests GLP-1R agonism may offer a new therapeutic avenue for cerebral small vessel disease (cSVD).

Area of Science:

  • Neuroscience
  • Genetics
  • Pharmacology

Background:

  • Cerebral small vessel disease (cSVD) is a major cause of stroke and dementia with no effective treatments.
  • Glucagon-like peptide-1 receptor (GLP-1R) agonists are established treatments for diabetes and obesity, with known cardiovascular benefits.

Purpose of the Study:

  • To investigate the association between genetic variants mimicking GLP-1R agonist action and cSVD phenotypes.
  • To explore the potential of GLP-1R agonism in mitigating cSVD burden.

Main Methods:

  • A drug target Mendelian Randomization (MR) analysis was conducted using single-nucleotide polymorphisms (SNPs) near the GLP1R gene.
  • Primary outcomes included small vessel stroke and white matter hyperintensity (WMH) volume, analyzed using inverse variance-weighted MR.

Main Results:

  • Genetic mimicry of GLP-1R agonism via reduced HbA1c was associated with significantly lower odds of small vessel stroke and reduced WMH volume.
  • Similar protective associations were observed for genetically proxied GLP-1R-driven BMI reduction.

Conclusions:

  • Genetically proxied GLP-1 receptor agonism is associated with a lower burden of both clinical and imaging cSVD outcomes.
  • These findings support the rationale for clinical trials investigating GLP-1 receptor agonists for cSVD prevention.

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