High Glucose Linked to Poorer Memory, Even in People Without Diabetes

Pauline Anderson

October 23, 2013

Higher levels of both short-term and long-term blood glucose markers are significantly associated with poorer memory and with decreased volume and microstructure of the hippocampus in persons without diabetes or impaired glucose tolerance (IGT), according to a new study.

The results imply that lowering blood glucose levels, possibly even to relatively low levels, might help preserve cognition, study author Agnes Flöel, MD, Department of Neurology and Center for Stroke Research Berlin, Charite-University Medicine, Berlin, Germany, told Medscape Medical News.

Strategies that help lower blood glucose levels include a healthy Mediterranean-type diet and regular physical activity, she added.

The study is published online October 23 in Neurology.

Direct Relationship

The cross-sectional study included 141 healthy persons (mean age, 63.1 years) who were recruited through advertising. Persons with diabetes, IGT, or neurologic disorders and those taking antidepressants were excluded.

Dr. Agnes Flöel

Researchers obtained blood measurements, including glycosylated hemoglobin (HbA1c), which reflects peripheral glucose levels of the preceding 8 to 12 weeks; fasting glucose; and insulin. They also carried out apolipoprotein E (APOE) genotyping.

Participants underwent cognitive testing using the German version of the Rey Auditory Verbal Learning Test. Researchers calculated hippocampal volume from MRI scans and assessed hippocampal microstructure by mean diffusivity (MD) estimated by using diffusion tensor imaging.

According to Dr. Flöel, this was the first time that this MD method provided data on the association between hippocampal microstructure and glucose metabolism.

The investigators found that lower performance on 3 memory tasks (delayed recall, learning ability, and consolidation) was associated with higher levels of both the long-term marker of glucose control (HbA1c) and the short-term glucose marker (all P ≤ .01).

For insulin, there was a "general trend going in the same direction" but correlations were less clear, and without the same direct relationship, said Dr. Flöel.

Potential Mechanisms

Memory performance was correlated with hippocampal volume (P = .001) and lower MD (P = .01), lower age, and, in part, lower blood pressure and female sex. Researchers did not find a statistically significant association between memory performance and APOE genotype, body mass index, Beck Depression Inventory score, physical activity, or smoking.

Lower levels of HbA1c were associated with larger hippocampal volume (nonsignificant trend; P = .06). The associations between lower fasting glucose levels and higher hippocampal volume did reach significance (P = .01). There was no significant relationship between hippocampal volume and insulin.

As for hippocampal microstructure, the researchers noted that lower levels of all 3 markers of glucose metabolism significantly correlated with lower MD within the hippocampus.

There was no significant association between glucose markers and volume or MD in brain areas other than the hippocampus (eg, gray matter and thalamus).

The hippocampus is particularly vulnerable to disturbances in metabolic supply, including glucose, said Dr. Flöel.

"Elevated blood sugar levels may damage the outer membrane of the cells, or decrease neurotransmitter levels, which would disturb signaling within and between hippocampal cells. Information transfer between cells, which is indispensable for memory encoding, storage and retrieval, would then be compromised."

Elevated blood sugar levels may also damage small and large vessels in the brain, leading to decreased blood and nutrient flow to brain cells or even brain infarcts, and this may further damage memory-relevant brain structures, added Dr. Flöel.

The current findings are in line with studies of patients with type 2 diabetes mellitus and IGT, but earlier research was unable to confirm the deleterious effects of nondiabetic glucose levels on cognition. This, said the authors, may be because of different methods for classifying glucose levels and varying cognitive tests used.

Prevention Research

The authors also pointed out that the current study used MRI with higher magnetic field strength, which offers a higher sensitivity of hippocampal volumetry and greater statistical power to observe significant associations.

Following a diet high in lean protein and complex carbohydrates (such as whole grains, vegetables, fruits, and fiber) and low in heavily refined foods will help lower blood glucose, said Dr. Flöel. Another important lifestyle strategy is regular physical activity.

How low is it safe to go in terms of blood glucose levels? According to Dr. Flöel, that depends in part on lifestyle. "If you're used to low blood sugar levels, you can go quite low," she said.

She likened this to the situation with blood pressure. "At one time, it was assumed that you needed a certain level to function, but that actually is not true. You can go very low and still maintain normal function, and it might actually be better in the long run."

Although the study uncovers the protective potential of lower blood glucose levels, the relationship between high blood glucose and poor memory "seems to be more linear" and changing recommended cutoffs may not make much of a difference, said Dr. Flöel.

On the other hand, what could be key is prevention, she said.

"There have been some initiatives to put prevention more on the agenda of dementia research," she said. "There has been so much money spent on treatment of Alzheimer's disease and it has already been established that this is not very successful. "

Dementia prevention strategies could include taking measures at an earlier stage to encourage physical fitness and control hypertension, blood lipids (including cholesterol and triglycerides), and now, possibly, blood glucose levels, she said.

Patients should have their fasting glucose and HbA1c levels measured as part of a regular medical check-up starting at age 55 years, unless there's a personal or family history of diabetes or the patient is obese, in which case the family doctor may opt for earlier and more intense monitoring, said Dr. Flöel. She pointed out that such tests are easy to do and are already carried out regularly in pregnant women.

Fresh Eyes

Commenting on the findings for Medscape Medical News, Marwan N. Sabbagh, director, Banner Sun Health Research Institute, Sun City, Arizona, said that the study looks at the link between glucose metabolism and cognition with fresh eyes.

"This is saying that immediate learning and A1c levels, and potentially even blood sugars, interact even in people who are nondemented, and I don't think anyone has looked at it that way before," said Dr. Sabbagh.

"The idea is that the lower the A1c the better your brain function. This is a very exciting development and clearly helps put a frame around the Alzheimer's discussion, but more importantly, it talks about how blood sugar metabolism and cognitive function directly interact."

The study opens "a whole new territory" because until now, HbA1c and blood glucose have been looked at only in the context of diabetes and the risk for diabetes, added Dr. Sabbagh. "Maybe we need to rethink our normalization of glucose with an eye toward cognition and not simply a diabetes risk."

The authors have disclosed no relevant financial relationships.

Neurology. Published online October 23, 2013.

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