Diabetes Not Linked to Dementia

Pauline Anderson

July 30, 2013

In contrast to some previous research suggesting a link between diabetes and increased risk for dementia and Alzheimer's disease (AD), a new study shows no significant association between glucose intolerance, diabetes, or insulin resistance and AD or amyloid-β (Aβ) accumulation in the brain.

Along with other recent published papers, the new study "pretty definitively" indicates that long- term glucose problems do not alter Alzheimer's pathology in the brain, said study author Richard J. O'Brien, MD, PhD, professor of neurology, and chair, Department of Neurology, Johns Hopkins Bayview Medical Center, Baltimore, Maryland.

However, he said, "it's perfectly reasonable" to conclude that out-of-control diabetes, strokes, and myocardial infarctions can increase the risk for dementia.

"A lot of older folks are demented because there are several different pathologies going on in their head; they have Alzheimer's pathology; they have a couple of strokes; and they may have a lot of atherosclerosis," said Dr. O'Brien. "In many cases, it's the combination that tips them over; just the Alzheimer's by itself isn't enough."

The study was published online July 29 in JAMA Neurology.

Dr. Richard J. O'Brien

Autopsy and Imaging Data

Researchers used an autopsy study and a neuroimaging study that were embedded within the Baltimore Longitudinal Study of Aging, which assesses the effects of aging, including the effects on cognition and dementia.

The analysis included 197 participants from the brain autopsy study who had at least 2 oral glucose tolerance tests (OGTTs), all of whom were cognitively and neurologically normal at study entry.

It also included 53 participants from the imaging study, also with at least 2 OGTTs, who underwent in vivo assessment of fibrillary Aβ levels using carbon 11–labeled Pittsburgh compound (C-PIB).

After adjustment for sex and age at death, there was no significant association between AD pathology, calculated by using CERAD (Consortium to Establish a Registry for Alzheimer's Disease) and Braak criteria, and any measure of glucose or insulin homeostasis in the autopsy group.

When dividing these patients into those with dementia (n = 101) and those without dementia (n = 96), the researchers didn't detect significant differences in fasting glucose (100 mg/dL for nondemented vs 98 mg/dL for demented), fasting insulin (9.6 μIU/mL vs 9.0 μIU/mL), fasting Homeostasis Model Assessment (HOMA) (2.4 vs 2.2), and other tests.

In the imaging cohort, the researchers found no significant difference in mean cortical C-PIB retention between those with low and high lifetime fasting or 120-minute measures of glucose, insulin, or insulin resistance . There was also no significant difference between those with the top third of mean cortical C-PIB scores and those with the bottom third.

To assess whether the negative results were skewed by values later in life, the researchers analyzed the relationships using only values obtained at the baseline OGTT, or before age 70 years of age.

Again, there was no significant relationship with AD pathology or C-PIB retention. The imaging cohort had their initial OGTT at a relatively young mean age of about 53 years.

According to the authors, this suggests that "glucose intolerance does not affect AD pathology, even at its earliest stages."

The results appeared to be similar, whether or not the patients were taking medications to treat diabetes.

Focus on Cardiovascular Risk

The study results seem to indicate that there's no direct relationship between diabetes and dementia.

"The majority of older people get demented because they have more than one thing wrong with their brain," including both Alzheimer's pathology and strokes, said Dr. O'Brien. "That's not the same thing as saying diabetes causes AD."

For people with diabetes, "it's far more important that they worry about their cardiovascular risk factors that accompany diabetes, because every study in the world has shown that if you have strokes in addition to Alzheimer's pathology, that's a disaster," Dr. O'Brien added.

The current paper's findings don't necessarily conflict with suggestions from an earlier study that the administration of intranasal insulin may have a therapeutic benefit for adults with amnestic mild cognitive impairment or AD (Arch Neurol. 2012;69:29-38).

That study found that compared with participants taking placebo, those treated with intranasal insulin showed improved delayed memory and preserved ability to perform daily functions.

"It could be that insulin has an effect that's good for the brain that has nothing to do with Aβ or amyloid or any of that, so insulin could still be a perfectly good treatment for dementia, but that has nothing to do with what the glucosein your blood stream is," said Dr. O'Brien.

Dr. O'Brien is keen to stress this message, especially when the lay press has started to liken diabetes to "type 3 diabetes." "Things have gone way too far," he said, adding that he believes the current study "goes a long way" in tossing that theory out the window.

"There is some wiggle room left for the group with sugars that are just wacky or out of control," he said.

Such patients were not included in the study, which was one of its limitations. The participants had access to high quality of care and were unlikely to have experienced long periods of severe hyperglycemia.

"These are not the kind of patients we see in the hospital who are admitted all the time because their glucose is wildly out of control," he added.

For the most part, study participants were also highly educated and mostly white and so not an epidemiologically representative group.

This study was supported by grants from the National Institute on Aging (NIA), by the Burroughs Wellcome Fund for Translational Research, and by the Intramural Research Program, NIA, National Institutes of Health. The authors have disclosed no relevant financial relationships.

JAMA Neurol. Published online July 29, 2013. Abstract

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