Examining the causal mediating role of brain pathology on the relationship between diabetes and cognitive impairment: the Cardiovascular Health Study

Abstract

The paper examines whether diabetes mellitus leads to incident mild cognitive impairment and dementia through brain hypoperfusion and white matter disease. We performed inverse odds ratio weighted causal mediation analyses to decompose the effect of diabetes on cognitive impairment into direct and indirect effects, and we found that approximately a third of the total effect of diabetes is mediated through vascular-related brain pathology. Our findings lend support for a common aetiological hypothesis regarding incident cognitive impairment, which is that diabetes increases the risk of clinical cognitive impairment in part by impacting the vasculature of the brain.

Keywords: Alzheimer’s disease; Causal inference; Causal mediation analysis; Cognitive neuroscience; Public health.

Fig. 1.

Directed acyclic graph of our mediation model: the indirect effect of diabetes on MCI or dementia through brain hypoperfusion and white matter disease (paths 1 and 2) and the direct effect of diabetes on MCI or dementia (path 3) will be estimated as part of the analysis

Fig. 2.

Hypothetical observed data graph in which the assumption of no mediator–outcome confounder that is affected by the exposure holds (- - - →, absence of an arrow): the letters C and X represent confounders, whereas the letter A denotes a treatment, M denotes a mediator and Y denotes an outcome