Genetic Predisposition for Inflammation Exacerbates Effects of Striatal Iron Content on Cognitive Switching Ability in Healthy Aging

Non-heme iron homeostasis interacts with inflammation bidirectionally, and both contribute to age-related decline in brain structure and function via oxidative stress. Thus, individuals with genetic predisposition for inflammation may be at greater risk for brain iron accumulation during aging and more vulnerable to cognitive decline. We examine this hypothesis in a lifespan sample of healthy adults (N = 183, age 20 - 94 years) who underwent R2*-weighted magnetic resonance imaging to estimate regional iron content and genotyping of interleukin-1beta (IL-1β), a pro-inflammatory cytokine for which the T allelle of the single nucleotide polymorphism increases risk for chronic neuroinflammation. Older age was associated with greater striatal iron content that in turn accounted for poorer cognitive switching performance. Heterozygote IL-1β T-carriers demonstrated poorer switching performance in relation to striatal iron content as compared to IL-1β C/C counterparts, despite the two groups being of similar age. With increasing genetic inflammation risk, homozygote IL-1β T/T carriers had lesser age-related variance in striatal iron content as compared to the other groups but showed a similar association of greater striatal iron content predicting poorer cognitive switching. Non-heme iron and inflammation, although necessary for normal neuronal function, both promote oxidative stress that when accumulated in excess, drives a complex mechanism of neural and cognitive decline in aging.