Examining the role of systemic inflammation as a mediator of the glycaemia-brain volume associations in women.

Previous studies have found that diabetes and its mechanistic factors (e.g., glycaemia) are associated with poorer cognitive and brain health. There is also growing evidence of sex differences in how diabetes manifests itself and impacts the brain. The mechanisms through which this association manifests itself are still poorly understood, but the possible role of inflammation has been proposed. This study aims to explore whether the relationship between mid-life glycaemia and brain volumes in later-life in women is mediated by systemic inflammation. The sample consisted of female participants from the National Survey of Health and Development (NSHD) who underwent neuroimaging as part of the Insight 46 sub-study. Path analysis models were then constructed between glycaemic markers (age 60-64) and brain health outcomes (age 69-71) with adjustments for social and metabolic confounders (age 60-64). Although fasting glucose was associated with higher GlycA levels (β = 0.05 [0.01, 0.10], p = 0.005), associations with CRP and IL-6 were weaker and not statistically significant (e.g., IL-6: β = 0.10 [-0.04, 0.30], p = 0.102). However, we did not find evidence that inflammatory markers were associated with brain volume outcomes (e.g., IL-6 and whole brain volume: β = -3.4 [-8.1, 1.3], p = 0.092; IL-6 and grey matter volume: β = -0.4 [-1.9, 1.0], p = 0.512). Consequently, indirect (mediated) effects via systemic inflammation were not observed. This suggests that alternative mechanisms beyond inflammation may contribute to the relationship between mid-life glycaemia and later-life brain health.