Association of a GSK-3β polymorphism with brain resting-state function in amnestic-type mild cognitive impairment

The glycogen synthase kinase-3β (GSK-3β) gene has been implicated in Alzheimer's disease (AD). Polymorphisms in this gene are plausible modulators of brain function. However, little is known about the potential role of the GSK-3β rs334558 polymorphism, which has been associated with amnestic mild cognitive impairment (aMCI), which is itself associated with a high risk of AD. In this study, 43 aMCI patients and 30 healthy controls underwent resting-state functional magnetic resonance imaging, and their GSK-3β rs334558 genotypes were evaluated to determine the effect of the risk variant on regional brain activity and functional networks in these subjects. Then, gene-brain-behavior relationships were examined. Compared with the controls, aMCI subjects with the higher risk T allele had more deficits in regional activation of the right superior frontal gyrus (rSFG), while a higher functional connectivity of the rSFG was observed in TT/CT carriers. Further correlative analyses revealed that the increase in rSFG connectivity was robustly positively correlated with non-memory performance in aMCI GSK-3β rs334558 TT/CT carriers. Our findings are the first to show that a clinically significant proportion of resting-state brain function variation in aMCI patients may be explained by genetic variation at the GSK-3βrs334558 locus in ways that are distinguishable from controls.