This analysis of ~3,000 individuals with established type 2 diabetes demonstrates a clear age-adjusted inverse relationship between cognitive function and the degree of chronic hyperglycemia as measured by the A1C level. The observed effect of a 1% change in A1C on tests scores is clearly small; nevertheless, such an effect may be clinically important. For example, in the same sample every 1-year increase in age was associated with a 0.7-point decrease in DSST score (data not shown). Therefore, the 1- to 1.5-point difference in DSST per 1% higher A1C corresponds to an age difference of up to 2 years. Moreover, several recent studies demonstrated the clinical importance of this difference. Thus, a cross-sectional study in older healthy individuals reported that a 3-point difference in DSST score was associated with lower scores on physical performance tests (16
), and in a 3-year follow-up study a 1-point difference in baseline DSST score significantly increased the risk for the development of Alzheimer's disease among individuals with minimal cognitive impairment (19
). Finally, during a mean follow-up of 3.3 years, a 1-point difference in baseline DSST score was associated with a 3% increase in the risk for dementia in community dwellers aged >70 years (20
The relationship between the A1C level and cognition was attenuated after adjustment for other factors associated with cognitive function in some of the models but remained significant for the DSST score in every adjusted model. These findings suggest that much, but not all, of the relationship between A1C and cognitive function may be explained by risk factors other than A1C. Thus, the small increment in the R2 value () attributable to addition of the A1C term to the multivariable models (which reflects the degree to which the model accounts for the cognitive test score) suggests that A1C is not the crucial determinant of cognitive score after consideration of these other factors and particularly those related to ethnicity/language. However, these other factors are mostly not modifiable, whereas A1C levels can be changed with therapy. This evidence for a small additional significant effect of A1C on cognitive test scores therefore supports (but clearly does not prove) the hypothesis that lowering A1C may have an impact on these scores.
Taken together, these analyses extend previous reports of a link between cognitive decline and diabetes and are consistent with the hypothesis of a progressive relationship between the degree of chronic hyperglycemia and cognitive dysfunction.
The fact that optimal diabetes care requires affected patients to make therapeutic decisions based on information that they collect and process highlights the clinical significance of this finding. Finally, the absence of a clear relationship between FPG and these tests may be due to the fact that FPG is not as reliable as A1C as a measure of the underlying chronic glycemic status.
A number of possibilities may explain these findings. Because higher glucose levels are associated with a higher prevalence of cardiovascular risk factors and CVD, the relationship with cognitive dysfunction may be mediated through CVD. The fact that this relationship is not attenuated by adjusting for CVD reduces but does not completely eliminate this possibility. It is also possible that chronic exposure of the brain to high levels of glucose may accelerate cognitive decline. Indeed, postmortem studies of senile plaques from the brains of individuals with Alzheimer's disease demonstrate metabolic oxidation products associated with hyperglycemia (21
A third possibility is related to the fact that higher A1C levels imply insufficient action or effect of insulin due to insufficient secretion, activity, or both. There are many insulin receptors in the brain. Some have a role in glucose transport, but many are thought to have a function in cognitive processes. Several observations suggest that cognitive decline is a consequence of reduced insulin action in the brain. In individuals without diabetes, worse glucoregulation (as measured by a glucose tolerance test) was associated with worse outcomes on cognitive assessment, especially in elderly individuals. Individuals with Alzheimer's disease also have less efficient glucoregulation than unaffected individuals (23
), and exposure of individuals with Alzheimer's disease to a euglycemic-hyperinsulinemic clamp improved cognitive function, whereas exposure to a euinsulinemic-hyperglycemic clamp had no effect (23
There are limitations to this study. First, because the analyses were cross-sectional, it is not possible to make any temporal or causal inferences regarding relationships. Second, cognitive tests were administered to individuals of several ethnic groups and in two languages, thus increasing the variability of the measurement. Third, the ACCORD trial excluded individuals whose most recent A1C was <7.5% or >11% and those who were deemed unable to participate in their diabetes management; these results may therefore not apply to individuals with lower or higher A1C levels or significant cognitive impairment. Fourth, exclusion of individuals with lower A1C levels means that the relationship between A1C and cognition is studied over a narrow range of A1C levels. This reduces the ability to detect a relationship, and thus the link between A1C and cognition may have been underestimated. However, this large sample of individuals with diabetes is well powered to study the association of A1C levels and cognition.
In summary, this cross-sectional analysis illustrates that chronic hyperglycemia appears to be independently associated with cognitive function in individuals with diabetes. It also raises the hypothesis that strategies to lower A1C levels or prevent their rise may favorably affect cognitive function. Such a hypothesis can only be tested in prospective studies, such as the ongoing ACCORD-MIND trial.