In this population-based case-control study, onset of diabetes before age 65 years, longer duration of diabetes, treatment of diabetes with insulin, and presence of diabetic complications were independently associated with MCI after accounting for age, sex, education, vascular risk factors, and depression. When we broadened the definition of diabetes to include subjects with a fasting blood glucose level that met criteria for diabetes, we observed marginally significant associations of MCI with diabetes overall. Our findings suggest that diabetes duration and severity, as measured by type of treatment and presence of diabetic complications, may be important in the pathophysiology of cognitive impairment in diabetics. In contrast, late onset of diabetes, short duration, or well-controlled diabetes, may have a lesser impact. Long duration of diabetes may be associated with greater cerebral macrovascular disease, clinical cerebral infarctions, and sub-clinical infarctions that may impair cognitive function.27,28
This is consistent with other studies in which vascular disease in mid-life predicted late life cognitive impairment or dementia.29
Severe diabetes is more likely to be associated with chronic hyperglycemia, which in turn, increases the likelihood of cerebral microvascular disease,30
and may contribute to neuronal damage, brain atrophy,31-33
and cognitive impairment. The 2-fold increased risk of MCI in subjects with diabetic retinopathy in the present study supports the potential effects of diabetes on cerebral microvascular disease and on the pathogenesis of MCI.
Alternative mechanisms besides vascular disease may be involved in the pathogenesis of cognitive impairment in diabetics. It has been hypothesized that defects in insulin action may increase β-amyloid aggregation.11,12,34
In type 2 diabetes, insulin therapy may inhibit synaptic activity in the brain,35
decrease insulin degrading enzyme production, promote the development of amyloid plaques,11,12
and may increase production of advanced glycation end-products associated with Alzheimer’s disease pathology.10-12
Recurrent or chronic hypoglycemia caused by treatment with insulin may also contribute to permanent cognitive impairment.36,37
In the present study, the association of diabetes with MCI persisted after adjustment for vascular risk factors; this supports the hypothesis that additional pathologic mechanisms independent of vascular disease contribute to MCI in diabetics.
Differences in the association of diabetes across MCI subtypes raise questions regarding the role of diabetes in the etiology and prognosis of MCI subtypes. When fasting blood sugars were taken into account, we observed a significant association of diabetes with na-MCI, but not with a-MCI. Other investigators have reported stronger associations between vascular risk factors and na-MCI, suggesting that vascular risk factors may increase the risk of na-MCI. Na-MCI may be a prodromal stage for vascular dementia38
or other non-degenerative dementias,39
whereas a-MCI may be a prodromal stage for neurodegenerative dementias such as Alzheimer’s disease. This hypothesis, however, is disputed by other studies that have found no difference in the association of vascular risk factors across MCI subtypes.40
We observed no significant interactions of diabetes with APOE ε4 genotype or with depression. However, in our stratified analyses, the ORs for diabetes were stronger in the strata of subjects exposed to variables that have been reported to be associated with cognitive impairment or dementia. We may not have had sufficient power to detect significant interactions in these stratified analyses.
There are several strengths of this study. Participants were randomly selected from the community, thus the potential for selection bias was reduced in comparison to studies performed among subjects seen in referral practices or memory clinics. Availability of fasting blood glucose levels enabled us to identify subjects with undiagnosed or unreported diabetes and thereby to reduce potential misclassification. In addition, using the medical records-linkage system of the Rochester Epidemiology Project we validated the self-report of diabetes and performed sensitivity analyses; these results confirmed our primary analyses.
There are also potential limitations of our study. A comparison of participants and non-participants showed lower participation in older men, subjects with lower education, and subjects with diabetes.18
This under-representation of subjects with diabetes may have precluded our ability to detect a significant association between diabetes overall and MCI. Active follow-up of participants by repeated interviews and examinations and passive follow-up of non-participants through the medical records-linkage system of the Rochester Epidemiology Project will enable us to determine whether these baseline differences are associated with differences in dementia incidence. Since MCI is typically not diagnosed in routine clinical practice, we may be unable to assess the impact on MCI incidence. Due to the cross-sectional design of the present study, we cannot be sure that diabetes preceded MCI. Finally, these findings were based on a primarily Caucasian sample representative of the Olmsted County community; therefore, extrapolation of findings to ethnic groups not represented in our study should be performed with caution.