Serum insulin-like growth factor-1 and its association with epilepsy risk and cognitive function

Insulin-like growth factor 1 (IGF-1) has neurotrophic and neuroprotective properties, but its relationship with epilepsy risk and cognitive outcomes remains unclear. We investigated whether serum IGF-1 was associated with incident epilepsy and cognitive performance in a large population-based cohort.

We performed a prospective analysis of the UK Biobank including 466,857 participants with baseline serum IGF-1 measurements. Incident epilepsy was identified from hospital records and self-report. Associations with epilepsy risk were assessed using prespecified Cox proportional hazards models, restricted cubic splines, and sensitivity analyses. Cross-sectional and longitudinal analyses were used to examine cognitive outcomes.

Over more than 15 years of follow-up, 4,532 participants developed incident epilepsy. Higher serum IGF-1 was consistently associated with a lower risk of incident epilepsy; in the primary model, each 1 nmol/L increase was associated with a lower hazard of incident epilepsy (HR = 0.978, 95% CI 0.973-0.984). The association was nonlinear and L-shaped, with a steeper increase in risk at lower IGF-1 concentrations and an apparent plateau above approximately 20 nmol/L. Per-standard-deviation, quartile-based, lagged, and alcohol-frequency sensitivity analyses showed similar results. In cross-sectional analyses of participants with epilepsy at baseline, higher IGF-1 was nominally associated with faster reaction time and better prospective memory, but neither association remained significant after false discovery rate correction. Exploratory longitudinal analyses in the epilepsy subgroup were limited by sample size and did not show significant cross-lagged associations. In the full cohort, higher baseline IGF-1 was associated with better subsequent performance in several cognitive domains, although these findings were not epilepsy-specific.

Lower serum IGF-1 was independently associated with a higher risk of incident epilepsy in this large population-based cohort. Evidence for cognitive associations was more limited, with only nominal cross-sectional findings in baseline epilepsy and exploratory, non-epilepsy-specific longitudinal signals. These results support further investigation of circulating IGF-1 as a candidate biomarker and biologically relevant pathway rather than as evidence of a causal or therapeutic target.