Blood neurofilament light chain as a biomarker for cognitive impairment in adults with epilepsy: Integrated evidence from clinical cohorts in Northeast China and European GWAS data

Abstract Objective Epilepsy treatment aims not only to control seizures but also to enhance quality of life. However, reliable blood‐based biomarkers for epilepsy‐related cognitive impairment are lacking. This study investigated the association between plasma neurofilament light chain (NfL) levels and cognitive function in epilepsy by integrating evidence from observational and Mendelian randomization (MR) analyses across different populations. Methods We conducted a cross‐sectional observational study at the First Hospital of Jilin University, enrolling 152 adults with epilepsy. Demographic and clinical information was collected, and cognitive status and psychological status were assessed using the Montreal Cognitive Assessment (MoCA), Mini‐Mental State Examination (MMSE), Memory and Executive Screening (MES) scale, Hamilton Anxiety Scale (HAMA), and Hamilton Depression Scale (HAMD). Plasma NfL levels were measured using enzyme‐linked immunosorbent assay (ELISA). Statistical analyses included logistic regression, linear regression, and receiver‐operating characteristic (ROC) curve analysis. In parallel, two‐sample MR was performed using genome‐wide association study (GWAS) summary statistics from European cohorts. Shared genetic variants between epilepsy and cognitive impairment were identified using multi‐trait analysis of GWAS (MTAG) and cross‐phenotype association (CPASSOC), and served as instrumental variables to estimate the causal effect on plasma NfL levels. Results Plasma NfL levels were significantly higher in the cognitively impaired group. After adjusting for confounders, elevated NfL levels remained independently associated with increased risk of cognitive impairment and inversely correlated with cognitive scores. ROC curve analysis showed high diagnostic accuracy of plasma NfL. MR analysis confirmed a positive causal relationship between epilepsy‐related cognitive impairment and plasma NfL levels. Significance Plasma NfL is associated with cognitive impairment in epilepsy and may serve as an early blood‐based biomarker for identifying cognitive dysfunction in this population.