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Elevated Glucose A Risk for Cognitive Decline and Dementia

Glucose peaks tied to greater cognitive decline for those with diabetes and A1c ≥7.0 percent.

According to a study published online May 12 in Diabetes Care, hemoglobin A1c (HbA1c), a measure of average blood glucose level, is associated with the risk of dementia and cognitive impairment. However, the role of glycemic variability or glucose excursions in this association is unclear. They examined the association of glucose peaks in midlife and determined by the measurement of 1,5-anhydroglucitol (1,5-AG) level.

Andrea M. Rawlings, from the John Hopkins Bloomberg School of Public Health in Baltimore, and colleagues examined the correlation between glucose peaks in midlife with the risk of dementia and 20-year cognitive decline among nearly 13,000 participants from the Atherosclerosis Risk in Communities study. Glucose peaks were determined by measurement of 1,5-anhydroglucitol (1,5-AG) level, which was dichotomized at 10 µg/mL.

The researchers found that dementia developed in 1,105 participants over a median of 21 years. Each 5 µg/mL decrease in 1,5-AG correlated with increased estimated risk of dementia among persons with diabetes (hazard ratio, 1.16; P = 0.032). Compared to those without peaks, those with glucose peaks had a 0.19 greater z score decline over 20 years for cognitive decline among participants with diabetes and hemoglobin A1c (HbA1c) <7 percent (P = 0.162). Compared to those without glucose peaks, those with glucose peaks had a 0.38 greater z score decline among participants with diabetes and HbA1c ≥7 percent (P < 0.001). No significant correlation was seen for those without diabetes.

“Among participants with diabetes, glucose peaks are a risk factor for cognitive decline and dementia,” the authors write. “Targeting glucose peaks, in addition to average glycemia, may be an important avenue for prevention.”

In this community-based study, it was found that low levels of 1,5-AG, indicative of glycemic peaks, were associated with an increased risk of dementia and greater cognitive decline over 20 years. In persons with diabetes, each 5 mg/mL increase in 1,5-AG was associated with a 16% increase in the risk of dementia. Among persons with diabetes and HbA1c of 7% or above, (53 mmol/mol), those with more glucose peaks had greater cognitive decline over 20 years compared with persons without peaks. Although this value was not statistically significant (P = 0.162), the magnitude of this association was nearly as large as our previously reported association between diabetes and 20-year decline (z = 0.23 more decline in participants with diabetes compared with those without). 1,5-AG appeared to modify the association between diabetes status and cognitive decline. Although persons without glucose peaks had little cognitive decline, even if they had diabetes or an HbA1c level of 7% or above (53 mmol/mol), more research is needed to investigate this finding. 1,5-AG did not seem to provide additional information about incident dementia or 20-year decline in persons without diabetes.

The mechanisms by which diabetes leads to cognitive impairment are not well understood. It is thought that hyperglycemia, hypoglycemia, and oxidative stress, among other factors, play important roles, but less attention has been given to the role of glycemic variability, and debate on its usefulness in clinical practice is ongoing. At the cellular level, fluctuations in glycemia have been shown to more adversely affect endothelial function and induce oxidative stress compared with sustained hyperglycemia, potentially leading to greater cerebrovascular damage and cognitive decline. A few studies using continuous glucose monitors have found associations between measures of glycemic variability and cognitive impairment and brain atrophy independent of both mean levels of glycemia and hypoglycemic episodes. Studies using data from continuous glucose monitors have found moderate correlations between common measures of glycemic variability (e.g., mean amplitude of glycemic excursions and postprandial glucose excursions) and 1,5-AG. Glycemic variability is an aspect of glycemia that is not well captured by HbA1c, which is less sensitive to glycemic peaks compared with 1,5-AG. If glucose peaks in persons with diabetes contribute to long-term cognitive decline and dementia above and beyond average hyperglycemia, they may also offer additional targets for prevention. Lastly, glycemic peaks are common in older adults. A study of 3,200 participants with non–insulin-treated type 2 diabetes using in-home glucose readings over a 1-week period found that 84% of participants recorded at least one postprandial blood glucose concentration .160 mg/dL.

Even among persons with an HbA1c level of 7% or above (53 mmol/mol), 38% had a postprandial glucose concentration .160 mg/dL in .40% of the readings.

Practice Pearls:

  • Glucose peaks are a risk factor for cognitive decline and dementia.
  • Targeting glucose peaks, in addition to average glycemia, may be an important avenue for prevention.
  • Low levels of 1,5-AG, indicative of glycemic peaks, were associated with an increased risk of dementia and greater cognitive decline over 20 years.

Andreea M. Rawlings, A. Richey Sharrett, Thomas H. Mosley, Shoshana H. Ballew, Jennifer A. Deal and Elizabeth Selvin; Diabetes Care 2017 Apr; dc162203. https://doi.org/10.2337/dc16-2203