Type 2 Diabetes Linked to Mild Cognitive Impairment

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April 12, 2007 — A study shows individuals with type 2 diabetes have a significantly increased risk of developing amnestic mild cognitive impairment (MCI), a condition widely acknowledged as a transitional state between normal cognitive functioning and Alzheimer's disease (AD).

In a longitudinal study appearing in the April issue of the Archives of Neurology, elderly individuals with type 2 diabetes were found to be at greater risk for MCI overall and for amnestic MCI impairment specifically compared with their counterparts without diabetes.

"In our analyses, diabetes was related to a higher risk of amnestic MCI even after adjusting for stroke and vascular risk factors, which suggests that the association between diabetes and amnestic MCI is independent of cerebrovascular disease," José A. Luchsinger, MD, from the Columbia University Medical Center in New York, and colleagues write.

Conversely, the authors note, the association between diabetes and nonamnestic MCI lessened and became nonsignificant after adjustment for stroke and vascular risk factors. This finding suggests cerebrovascular disease may mediate the relation between diabetes and nonamnestic MCI, the authors say.
Attenuated Risk

The study included 918 individuals aged 65 years or older without MCI or dementia at study entry who were residing in northern Manhattan.

Baseline data, which included an in-person interview about general health and function, followed by a standard assessment, medical history, physical and neurologic examinations, and neuropsychological testing, were gathered between 1992 and 1994.

With an average 6.1 years of follow-up, study participants were assessed every 18 months until 2003. During this period 334 individuals developed MCI: 160 amnestic cases and 174 nonamnestic cases.

Multivariate analyses revealed diabetes was related to a higher risk for all-cause MCI even after adjusting for age, sex, ethnic group, years of education, apolipoprotein E (APOE) ?4, hypertension, low-density lipoprotein cholesterol level, heart disease, stroke, and current smoking.

When only nonamnestic MCI was considered, type 2 diabetes became nonsignificant after adjusting for ethnic group, years of education, and APOE ?4, In addition, the risk was further attenuated after investigators adjusted for other vascular risk factors, heart disease, and stroke.

In contrast, adjusted analyses did not change the association between type 2 diabetes and amnestic MCI risk.

"The risk of MCI attributable to diabetes was 8.8% for the whole sample, 8.4% for African-American persons, 11.0% for Hispanic persons, and 4.6% for non-Hispanic white persons, reflecting the differences in diabetes prevalence by ethnic group," the authors write.
Possible Mechanisms

According to the investigators, there are several possible mechanisms at play that may explain the link between type 2 diabetes and amnestic MCI — among them, the hypothesis that diabetes may directly affect amyloid accumulation, the hallmark of AD.

"Hyperinsulinemia, which can precede and accompany diabetes, may disrupt brain amyloid ? clearance by means of the insulin degrading enzyme. Another potential mechanism is the generation of advanced products of glycosylation," Dr. Luchsinger and colleagues write.

It also is possible, the authors note, that diabetes may be a risk factor for nonamnestic forms of MCI and cognitive impairment via cerebrovascular disease.

"Our results provide further support to the potentially important independent role of diabetes in the pathogenesis of AD. Diabetes may also be a risk factor for non-amnestic forms of MCI and cognitive impairment, but our analyses need to be repeated in a larger sample."

The National Institutes of Health, the Charles S. Robertson Memorial Gift for Research on Alzheimer's Disease, the Blanchette Hooker Rockefeller Foundation, and the New York City Council Speaker's Fund for Public Health Research supported this study. The authors have disclosed no relevant financial relationships.

Arch Neurol. 2007;64:570-575.