Serial measures of glucose and insulin homeostasis taken over 20 years’ time show no association with the development of Alzheimer’s disease symptoms or pathology, according to a report published July 29 in JAMA Neurology.
These findings, from a large, prospective, cohort study that included multiple physical and cognitive assessments during middle and old age as well as autopsy results, indicate that glucose intolerance and insulin resistance likely do not play a role in Alzheimer’s disease (AD) pathogenesis, said Dr. Madhav Thambisetty of the National Institute on Aging, Baltimore, and his associates.
"Our results concur with other studies that found no association between diabetes mellitus and AD pathology, and we extend these observations more broadly to include hyperglycemia and insulin resistance," they noted.
Dr. Madhav Thambisetty
Dr. Thambisetty and his colleagues used data from the Baltimore Longitudinal Study of Aging (BLSA) to examine the assertion that diabetes and glucose intolerance may be risk factors for AD. Some studies have reported excess cognitive impairment and lower cognitive performance in patients with metabolic derangements, as well as a doubling of the risk for AD in those with full-blown diabetes. Other studies have not confirmed any such links.
The BLSA is a longitudinal study involving older men and women who undergo periodic oral glucose tolerance testing (OGTT) as part of serial comprehensive physical examinations, as well as periodic neurologic examination and neuropsychological testing. The BLSA includes an autopsy substudy of subjects who agreed to postmortem brain examinations and a neuroimaging substudy of subjects who had periodic in-vivo assessment of fibrillar amyloid-beta levels using carbon-11-labeled Pittsburgh Compound B (C-PiB).
For their analysis, Dr. Thambisetty and his associates focused on 197 subjects who were cognitively and neurologically normal at study entry and were aged at least 69 years at the time of death (mean age at death was 88 years). During a mean follow-up period of 22 years, the participants underwent at least two OGTTs during follow-up, and 53 also underwent C-PiB brain imaging. All participants underwent brain autopsy that included quantification of beta-amyloid plaques. Overall, 95% of subjects in the study were white.
The study design, with its serial assessments over a long period of time, allowed the investigators "to determine the effect of prolonged burdens of hyperglycemia and insulin resistance on pathological findings in the brain." The study results indicate that these metabolic measures show no association with AD pathology even at its earliest stages, they said.
In the first analysis of the data, the 197 study subjects were divided into tertiles according to mean lifetime fasting or 120-minute glucose, insulin, or insulin resistance values. The investigators found no significant difference among these groups in any measure of AD pathology.
A further analysis of individual, rather than grouped glucose and insulin measures also found no significant association between any measure of AD pathology and any measure of glucose or insulin homeostasis after controlling for the effects of age and sex at death.
A third analysis that examined the rates of change in glucose and insulin values over the lifetime of each participant also showed no significant differences among subjects with low, medium, or high AD pathology scores, the investigators said (JAMA Neurol. 2013 July 29 [doi:10.1001/jamaneurol.2013.284]).
When the participants were categorized by the absence (96 subjects) or presence (101 subjects) of dementia, there were no significant differences in mean nondementia/dementia values for fasting glucose (100/98 mg per dL), fasting insulin (9.6/9.0 micro IU/mL), fasting homeostasis modeling assessment (HOMA, 2.4/2.2), 120-minute glucose (156/149 mg per dL), 120-minute insulin (63/57 micro IU/mL), and 120-minute HOMA (25/22).
In the subgroup of subjects who underwent periodic C-PiB brain scanning, no significant differences were found in beta-amyloid deposition between those with the highest and those with the lowest mean lifetime fasting or 120-minute glucose, insulin, or insulin resistance values.
In addition, there was no significant difference between subjects with the highest and those with the lowest levels of beta-amyloid deposition in glucose metabolism or insulin resistance. And there were no differences in metabolic measures when the analysis was restricted to beta-amyloid deposition in the posterior cingulate/precuneus and the medial temporal lobe, "two areas where fibrillar beta-amyloid is deposited early in the course of AD," Dr. Thambisetty and his colleagues wrote.
When the investigators limited their analyses to metabolic measures obtained at relatively younger ages (mean age of 53 years), they found no significant relationship between AD pathology and glucose, insulin, and insulin resistance.
In a final analysis, the researchers focused on the 30 subjects who had been taking diabetes medications at the time of death and who had undergone autopsy. "We found no significant difference in any measure of AD pathology, whether or not the participant was taking the medication," they wrote.