Moderated mediation of cerebrospinal fluid fibroblast growth factor 21 and KLB rs17618244 genotype in the association between educational attainment and cognitive function

Behav Brain Res. 2026 Sep 5:116458. doi: 10.1016/j.bbr.2026.116458. Online ahead of print.

ABSTRACT

BACKGROUND: Although educational attainment influences both cognitive function and metabolic regulation, the biological mechanisms underlying this relationship remain unclear. This study investigated whether cerebrospinal fluid fibroblast growth factor 21 (CSF FGF21) mediates the association between educational attainment and cognitive function, and whether this pathway is moderated by the KLB rs17618244 genotype.

METHODS: A total of 186 participants were included in this cross-sectional study. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA), and CSF FGF21 levels were measured. Genotyping of the KLB rs17618244 variant was performed using MassARRAY single nucleotide polymorphism genotyping technology. Mediation and moderated mediation analyses were conducted using the PROCESS macro.

RESULTS: CSF FGF21 significantly mediated the association between educational attainment and cognitive function (β = 0.02, 95% CI: 0.0003 to 0.0526). Moderated mediation analysis further indicated that the KLB rs17618244 genotype significantly moderated this indirect pathway (Index = -0.05, 95% CI: -0.1219 to -0.0002). Specifically, the indirect protective effect of educational attainment on cognitive function through CSF FGF21 was significant only among AA/AG carriers (Effect = 0.05, 95% CI: 0.0060 to 0.1205), but not among GG carriers.

CONCLUSION: In this cross-sectional study, CSF FGF21 statistically accounted for part of the association between educational attainment and cognitive function, particularly among KLB rs17618244 AA/AG carriers.

PMID:42700933 | DOI:10.1016/j.bbr.2026.116458