Hyperglycemia Tied To Cognitive Decline, Vascular Dementia

Elevated HbA1c is associated with increased risk of vascular dementia, cognitive decline and structural brain changes, an analysis of data from the UK Biobank study suggests.

The study included 210,309 participants in the UK Biobank who had low HbA1c levels (less than 35 mmol/mol); 198,969 people who were normoglycemic (35 - 42 mmol/mol); 15,229 participants with prediabetes (42 - 48 mmol/mol); 3,279 individuals with undiagnosed diabetes (48 mmol/mol or more); and 22,187 people with a known diabetes diagnosis based on primary care records or prescription data.

Compared to normoglycemic individuals, people with pre-diabetic HbA1c levels had a significantly higher risk of developing vascular dementia (adjusted hazard ratio 1.54) and cognitive decline (odds ratio 1.42), the analysis found.

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Known diabetes carried a significantly higher risk of vascular dementia (aHR 2.97) and cognitive decline (OR 1.39), as well as all-cause dementia (aHR 1.91) and Alzheimer's disease (aHR 1.84).

In addition, researchers found higher white matter hyperintensity volumes with prediabetes (3%), undiagnosed diabetes (22%) and known diabetes (7%) than with normoglycemia, and lower hippocampal volumes. By contrast, individuals with low HbA1c had 1% lower level of white matter hyperintensity volumes than those with normoglycemia and larger hippocampal volumes.

"Associations appeared to be somewhat driven by antihypertensive medication, which implies that certain cardiovascular drugs may ameliorate some of the excess risk," the study team notes in Diabetes, Metabolism and Obesity.

"While the results for diagnosed diabetes were less surprising, the particularly strong associations of prediabetes and worse brain health outcomes are novel," said lead study author Victoria Garfield of the Institute of Cardiovascular Science at University College London.

"We are the first to find that blood sugar levels that are somewhat high, but preclude a diabetes diagnosis, may negatively affect our brain health," Garfield said by email. "However, we still have a very incomplete picture when it comes to the underlying biological mechanisms of exactly how long-term elevated blood sugar affects associates with worse brain health."

One limitation of the study is that validated algorithms to define diabetes and dementia can still lead some individuals to be misclassified, the authors write.

Not everyone with prediabetes or diagnosed diabetes will go on to develop dementia, noted Barbara Bendlin of the University of Wisconsin-Madison School of Medicine and Public Health and the Wisconsin Alzheimer's Disease Research Center.

"For many people who have elevated blood sugar levels in the pre-diabetic range, it's very likely that lifestyle changes could ameliorate their blood sugar levels and confer health benefits, preventing or delaying the development of diabetes and associated health risks," Bendlin, who wasn't involved in the study, said by email.

However, the study offers fresh evidence that prediabetes and diabetes are both risk factors for vascular disease in general and for small vessel disease in the brain, said Dr. David Tanne, director of the Stroke and Cognition Institute at Rambam Health Care Campus in Haifa, Israel.

"Prediabetes itself may impair brain health and cause harm, and there is a higher risk of accelerated cognitive decline and vascular dementia already in people having prediabetes," Dr. Tanne, who wasn't involved in the study, said by email. "Healthy lifestyle, normal weight and regular exercise benefit your brain and are key for preserving brain health."

—Lisa Rapaport

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