Plasma glial fibrillary acidic protein and neurological diseases: A bidirectional Mendelian randomization study

Background Increased glial fibrillary acidic protein (GFAP) in blood, a biomarker of reactive astrogliosis and astrocytic injury, was observed in a variety of neurological disorders. However, the causal relationship between plasma GFAP and neurological disorders remains unclear. Objective We aim to investigate causal association between plasma GFAP levels and neurological disorders using bidirectional Mendelian randomization (MR). Methods The genome-wide association studies for neurological disorders, including neurodegenerative diseases, neuroimmune disorders, cerebrovascular diseases, and epilepsy, were collected. Genetic variables associated with plasma GFAP levels were obtained from the UK Biobank Pharma Proteomics Project. Inverse variance weighted or Wald ratio method was used as the main analysis to assess the causal association. Results Genetically predicted higher plasma GFAP levels were found to be associated with an increased risk of encephalitis (odds ratio [OR] = 2.52; 95% confidence interval [CI] = 1.67–3.47; p = 1.22 × 10 –5 ). Furthermore, we found that Alzheimer's disease (β = 0.05; standard error [SE] = 0.01; p = 6.63 × 10 –8 ), frontotemporal dementia (β = 0.12; SE = 0.01; p = 5.10 × 10 –16 ), and dementia with Lewy bodies (β = 0.08; SE = 0.02; p = 5.45 × 10 –5 ) were causally linked to an increase in plasma GFAP levels. Even after controlling for the influence of aging, these associations remained significant. Conclusions Our study found that higher plasma GFAP levels may increase the risk of encephalitis, while neurodegenerative dementia may enhance the plasma GFAP levels, supporting the clinical utility of blood GFAP as a reliable biomarker in neurological diseases.