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 glycaemia was mostly associated with a higher systemic inflammatory state in two of the three markers (e.g., HbA1c and interleukin-6: β = 0.05 [0.02. 0.01], p = 0.001 and glycoprotein A: β = 0.02 [=-0.01. 0.02], p = 0.001), we did not find a relationship between inflammation and our brain volume markers [whole brain, grey matter and white matter] (e.g. interleukin-6 and whole brain volume: β = -3.1 [=-7.7. 1.5], p = 0.2; interleukin-6 and grey matter: β = -0.3 [=-1.8. 1.2], p = 0.7), thus no mediated effect between the glycaemic markers and outcomes via the pathway of systematic inflammation. This raises the possibility alternative mechanistic pathway, to inflammation, playing a role in the relationship between hyperglycaemia and brain health outcomes.