To add weight to the possible association between FGF21 and cognitive impairment in thalassemia patients, the in vivo results showed that there was an increase in plasma FGF21 and brain FGF21 levels with the reduced expression of brain FGF21 signaling in iron-overloaded thalassemic mice, suggesting a resistance of brain FGF21 might develop in cases of thalassemia with the iron-overload condition. The gene discussed is FGF21; the disease is thalassemia.