Frontoparietal cortical thickness mediates the effect of COMT Val¹⁵⁸Met polymorphism on age-associated executive...

Proper dopamine (DA) signaling is likely necessary for maintaining optimal cognitive performance as we age, particularly in prefrontal-parietal networks and in fronto-striatal networks. Thus, reduced DA availability is a salient risk factor for accelerated cognitive aging. A common polymorphism that affects DA D1 receptor dopamine availability, COMT Val¹⁵⁸Met (rs4680), influences enzymatic breakdown of DA, with COMT Val carriers having a 3- to 4-fold reduction in synaptic DA compared to COMT Met carriers. Furthermore, dopamine receptors and postsynaptic availability are drastically reduced with aging, as is executive function performance that ostensibly relies on these pathways. Here, we investigated in 176 individuals aged 20-94 years whether: (1) COMT Val carriers differ from their Met counterparts in thickness of regional cortices receiving D1 receptor pathways: prefrontal, parietal, cingulate cortices; (2) this gene-brain association differs across the adult lifespan; and (3) COMT-related regional thinning evidences cognitive consequences. We found that COMT Val carriers evidenced thinner cortex in prefrontal, parietal, and posterior cingulate cortices than COMT Met carriers and this effect was not age-dependent. Further, we demonstrate that thickness of these regions significantly mediates the effect of COMT genotype on an executive function composite measure. These results suggest that poorer executive function performance is due partly to thinner association cortex in dopaminergic-rich regions, and particularly so in individuals who are genetically predisposed to lower postsynaptic dopamine availability, regardless of age.