Unveiling the effect of diet-derived circulating antioxidants on brain cortical structure: New insights from Mendelian randomization.

The brain, which contains high levels of catecholamines and unsaturated lipids, is particularly susceptible to oxidative damage. Against this background, increasing antioxidant levels through diet seems to be a potential approach to the prevention of neurodegenerative diseases. A recent innovative study suggests that the shape of the brain itself, rather than just the neural pathways, can have a significant impact on our cognitive processes. Here, we investigated the causal relationship between diet-derived circulating antioxidants and surface area (SA) and thickness (TH) of brain cortical structure using Mendelian randomization (MR). Published studies were used to identify instrumental variables related to absolute levels of circulating antioxidants like lycopene, retinol, ascorbate, and β-carotene, as well as antioxidant metabolites such as ascorbate, retinol, α-tocopherol, and γ-tocopherol. Outcome data on brain cortical structure were obtained from the ENIGMA consortium, which included a total of 51,665 participants. Following the guidelines of the Desikan-Killiany atlas, the cortical structure was divided into 34 regions, resulting in 70 phenotypes covering both the global and regional aspects of SA and TH. Inverse variance weighted or Wald ratio was chosen as the main method for MR analysis based on the number of single nucleotide polymorphisms. Furthermore, we performed sensitivity analyses to confirm the reliability of the findings. At the global level, absolute circulating levels of ascorbate were found to increase SA of the full cortex (β = 2244.536 mm2, 95% CI: 921.172 mm2 to 3567.901 mm2, P = .001) but had no causal relationship with TH of the full cortex (β = -0.008 mm, 95% CI: -0.020 mm to 0.005 mm, P = .228). For the levels of functional parcellation analysis, we found that circulating ascorbate metabolite significantly reduced the SA of the inferior parietal (β = -110.917 mm2; 95% CI: -176.543 mm2 to -45.292 mm2; P = .00092) and absolute circulating retinol significantly reduced the TH of the precuneus (β = -0.045 mm; 95% CI: -0.073 mm to -0.017 mm; P = .00146). No heterogeneity, pleiotropy or outliers were found. MR estimates suggest that absolute circulating levels of ascorbate increase the SA of the whole cortex. There were also 2 significant negative correlations between circulating antioxidants and cortical structure. These results provide important insights into how circulating antioxidants influence structural changes within specific cortical areas and remind us of the potential adverse consequences of supplementation with circulating antioxidants.