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High Glucose Levels Associated with Increased Risk for Dementia

Fitzgerald, Susan

doi: 10.1097/01.NT.0000435584.63041.f1
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Investigators reported an elevated risk for dementia in people with high glucose levels, as well as in individuals with levels below those associated with diabetes or even prediabetes.

Higher glucose levels are associated with an increased risk for dementia even when diabetes is not present, according to a study that followed more than 2,000 persons age 65 or older.

While some previous research has found an association between diabetes and dementia, this study found an elevated risk for dementia even when blood sugar levels were far into the normal range, well below levels associated with diabetes or even prediabetes. Non-fasting glucose values of 100 mg/dL were associated with a higher risk for dementia than non-fasting glucose values of 90 mg/dL.

“In this prospective, community-based cohort study, we found that higher glucose levels were associated with an increased risk of dementia in populations without and with diabetes,” the researchers concluded in the study, published in the Aug. 8 edition of the New England Journal of Medicine. “The data suggest that higher levels of glucose may have deleterious effects on the aging brain.”

The analysis was based on 2,067 patients who were evaluated every two years for dementia, for a median follow-up time of 6.8 years. Researchers then analyzed multiple blood glucose tests taken by the patients during that time to see if there was any correlation between average blood glucose levels and the risk for dementia.

Paul K. Crane, MD, the study's lead author and associate professor of internal medicine at the University of Washington, told Neurology Today that “there have been a lot of studies that looked at diabetes as a potential risk factor for dementia, but there has not been much research looking at people who do not have diabetes, which is a lot of people.”

His study did not find that any particular “threshold” of blood glucose level divided low risk and high risk for dementia. In fact, the analysis found that risk for dementia steadily increased along with an increase of average sugar levels within the range of 90 to 120 mg/dL.

Among people with diabetes, the risk for diabetes was especially prominent with higher blood glucose levels, with steadily increasing risk at average blood glucose levels higher than 160 mg/dL.

Dr. Crane said it was premature to say whether clinicians should adjust their thinking on what is considered an acceptable blood glucose level. Still, “this study, along with studies on other organ systems, suggests yet another reason why controlling blood sugar might be beneficial.”

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The new study used data collected for the Adult Changes in Thought (ACT) study, which initially included 2,581 randomly selected, dementia-free members of the Group Health Cooperative in Washington State. Participants were 65 or older when they were enrolled from 1994 through 1998. An additional 811 participants were enrolled between 2000 and 2002. Participants were evaluated every two years using the Cognitive Abilities Screening Instrument.

This latest research involved 2,067 (839 men and 1,228 women; 232 people with diabetes and 1,835 without) persons from the original cohort who had at least one follow-up visit, been enrolled in Group Health for at least five years before the study began, and had at last five measurements of glucose or glycated hemoglobin over the course of at least two years before study entry. The blood tests were done as part of normal health care, and patients on average had 22 different test results related to blood sugar, Dr. Crane said.



The researchers then analyzed whether there was an association between developing dementia and average blood sugar levels over time. They looked at the risk for the most recent five-year period and also for the period of five to eight years back. During the follow-up period, dementia developed in 524 participants, 74 with diabetes and 450 without.

“Among participants without diabetes, higher average glucose levels within the preceding 5 years were related to an increased risk of dementia,” the researchers concluded. An average glucose level of 115 mg/dL was associated with an 18-percent increased risk for developing dementia compared with individuals with an average glucose level of 100 mg/dL.

“We found a monotonically increasing association between the glucose level and the risk of dementia among people without diabetes, which suggests that any incremental increase in glucose levels is associated with an increased risk for dementia,” the researchers said.

In addition, “we found the same relationship between glycemia and risk of dementia among people with diabetes at the higher end of the range of glucose levels,” they reported. An average blood level of 190 mg/dL was associated with a 40-percent increased risk for dementia compared to individuals with an average glucose level of 160 mg/dL.

Dr. Crane said the fact that higher average blood sugar levels in the more recent five-year period, as opposed to the more distant past, were especially associated with dementia risk suggests “there may be some reversibility associated with whatever mechanism is responsible for the association.”

“This means that there may be an opportunity to intervene, once we learn what is causing this association,” he said. Intervention was not tested in this study.

Dr. Crane said there are any number theories on how elevated blood sugar could be associated with higher dementia risk. Glucose could have a direct toxic effect on the brain, could be associated with insulin resistance, or could be an indicator of some other process such as inflammation that that has a deleterious effect on the brain. There could be some other relationship that is not yet understood, Dr. Crane said.

Dr. Crane and his team are continuing their research looking at related questions, such as the relation between blood glucose and cognition over time. He said 30 percent of study participants have agreed to donate their brains, which will yield even more information on the connection between glucose levels and dementia.

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James Mortimer, PhD, a professor of epidemiology at the University of South Florida who has studied the connection between exercise, blood glucose, and dementia, said the latest study was “a very interesting paper because it was based on a large sample of people who were followed prospectively over time.” He was particularly curious about why the risk for dementia took off in the low range of normal.

“The question is: 'Are there really subtle things going on in the range of 90 to 100?'” Dr. Mortimer said. Two different mechanisms could be at work — factors related to insulin-resistance could be causing deleterious effects at the pre-diabetes stage, while very high blood sugar levels in diabetics may lead to vascular problems associated with dementia.

While this new study suggests that lower blood sugar levels help minimize the risk off dementia, too low of a level can be harmful, he said.

Rachel Whitmer, PhD, led a study published in 2009 in the Journal of the American Medical Association that found that in older persons with type II diabetes, a history of severe hypoglycemic episodes was associated with a higher risk of dementia. Very tight glycemic control in persons with diabetes has also been associated with an increased risk of death, she said.



“Being too high is bad and being too low is bad,” Dr. Whitmer, an epidemiologist and senior research scientist at Kaiser Permanente Division of Research, told Neurology Today. “We need to better understand what is the best level of glycemic control.”

Dr. Whitmer and colleagues just published in the inaugural edition of The Lancet Diabetes & Endocrinology the details of a risk-assessment scale they developed to predict whether a person with diabetes is likely to develop dementia.

A fasting blood glucose level of 126 mg/dL is used to diagnosis diabetes, while a fasting glucose level of 100 to 125 mg/dL is considered “prediabetes,” a status that typically prompts doctors to advise patients to exercise more, watch their weight, and cut down on sweets. These thresholds are for fasting glucose levels, which are always below the average daily glucose levels characterized in the New England Journal of Medicine study, typically by 30–40 mg/dL, Dr. Crane said.

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•. Crane PK, Walker R, Hubbard RA, et al. Glucose levels and risk of dementia. N Engl J Med 2013;369:540–548.
    •. Neurology Today archive on metabolic syndrome and cognition:
      •. Neurology archive on metabolic syndrome and cognition:
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