Higher glucose levels were associated with an elevated risk of dementia in a community-based cohort study reported Aug. 8 in the New England Journal of Medicine.
High glucose levels were linked to this adverse effect both in people who had diabetes and in people who did not. "These data suggest that higher levels of glucose may have deleterious effects on the aging brain," said Dr. Paul K. Crane of the University of Washington, Seattle, and his associates.
In addition, "our findings underscore the potential consequences of temporal trends in obesity and diabetes, and suggest the need for interventions that reduce glucose levels," they said.
Dr. Crane and his colleagues analyzed data from a prospective, longitudinal study in which participants were followed every 2 years to identify incident cases of dementia. The study involved 2,067 randomly sampled older men and women who underwent numerous glucose tests as part of their biennial work-ups, beginning in the 1990s.
"The extensive clinical laboratory data available and the long-term follow-up of the cohort, in which there were hundreds of cases of dementia, afforded us the opportunity ... to evaluate risk across the entire spectrum of observed glucose levels."
The researchers described this as the first study among those investigating associations between glucose metabolism and the risk of dementia to evaluate glucose levels as a time-varying phenomenon. They used a hierarchical Bayesian statistical model that allowed them to incorporate multiple measurements taken over the course of several years – including random blood glucose tests, fasting blood glucose tests, and glycated hemoglobin tests – into a single composite estimate of glucose exposure for each study subject.
Each participant underwent an average of 17 measurements of blood glucose and 5 of glycated hemoglobin. This yielded a total of 35,264 values for fasting and random glucose levels and 10,208 values for glycated hemoglobin levels.
"The extensive clinical laboratory data available and the long-term follow-up of the cohort, in which there were hundreds of cases of dementia, afforded us the opportunity ... to evaluate risk across the entire spectrum of observed glucose levels," the investigators noted.
Overall, 524 (25.4%) of the study subjects developed dementia during a median follow-up period of 6.8 years. This included 21.6% of the subjects who had diabetes and 26.1% of those who didn’t have diabetes. Most of the patients with dementia had probable or possible Alzheimer’s disease (403), followed by dementia from vascular disease (55) and dementia from other causes (66).
In the subjects with diabetes, those who had the highest glucose levels were at increased risk of dementia, compared with those who had lower glucose levels. "For an average glucose level of 190 mg/dL [in the preceding 5 years], as compared with 160 mg/dL, the adjusted hazard ratio for dementia was 1.40," Dr. Crane and his associates wrote (N. Engl. J. Med. 2013 Aug. 8 [doi:10.1056/NEJMoa1215740]).
More surprisingly, in the subjects without diabetes, those who had the highest but still normal glucose levels were at increased risk of dementia, compared with those who had lower glucose levels. "For an average glucose level of 115 mg/dL [in the preceding 5 years], as compared with 100 mg/dL, the adjusted hazard ratio for dementia was 1.18," the researchers reported.
These associations remained significant in several sensitivity analyses, regardless of the subjects’ age or sex, and were independent of apolipoprotein E epsilon-4 allele status.
The mechanism(s) by which higher glucose levels may contribute to dementia risk have not yet been elucidated, but both acute and chronic hyperglycemia, insulin resistance, and microvascular disease of the CNS could all play a role, according to the researchers.
This study was supported in part by the National Institutes of Health. Dr. Crane reported no financial conflicts of interest; four other authors reported ties to industry sources.