Type 2 Diabetes, Glycemia, and Brain Health: The Complexity of Causality.

Abstract

For several years, based on several large-scale cohort and twin studies of people well into older age, type 2 diabetes has been recognized to be strongly associated with a twofold increase in the risk of a “new” or incident dementia (1). The causality of this association and putative underlying pathways still remain uncertain. Several features such as hyperglycemia, insulin resistance, inflammation, and vascular endothelial dysfunction could theoretically mediate a causal link between type 2 diabetes and dementia (2), and their putative effects may also be influenced by several modifiers (Fig. 1). It is plausible that these pathways could lead to brain injury indirectly via cerebrovascular disease, or by directly affecting the neurons (gray matter) and their connections (white matter), or both. The attractiveness of this overall causal hypothesis lies in the potential to find targeted interventions to reduce the risk of future dementia. Thus, it is important to generate strong evidence either supporting or disproving causality in the associations of type 2 diabetes and its related features with measures of brain health. Figure 1 Potential causal pathways linking type 2 diabetes to dementia. In their article in this issue of Diabetes , Garfield et al. (3) attempt to further clarify causality in the relationship of type 2 diabetes (and specifically its primary feature glycemia) with indicators of dementia risk (cognitive function, brain MRI) and a diagnosis of Alzheimer dementia (AD). They adopted Mendelian randomization …