Diabetes in midlife is associated with an increased rate of cognitive decline over a 20-year follow-up, a new study shows.

And while patients with diabetes at midlife had a steeper cognitive decline than patients without diabetes, greater loss of cognitive function was also seen for patients who had prediabetes with only modestly raised blood glucose levels.

“These data suggest that primary prevention of diabetes or glucose control in midlife may protect against later-life cognitive decline,” the authors conclude.

The effect was greater for patients with a longer duration of diabetes, highlighting the importance of intervention as early as possible.
“The implication is that we have seen over a 20-year period what happens before the development of dementia,” coauthor A. Richey Sharrett, MD, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, commented to Medscape Medical News. “This gives patients and care providers a window of opportunity to do something about it.”

Diabetes can be prevented in some cases or at least delayed by lifestyle improvements, and when diabetes has already occurred, it can be controlled, he added. “Our results give additional reasons to do this. People dread dementia more than anything else. The idea that dementia can be delayed or reduced is a strong motivator. This is a pretty good reason to keep blood sugar in control.”

The findings are published online December 2 in Annals of Internal Medicine.

A “Window of Opportunity”

The study, lead by Andreea M. Rawlings, MS, also at Johns Hopkins, analyzed data from the Atherosclerosis Risk in Communities (ARIC) study, which prospectively followed 15,792 middle-aged adults from 1987 to 2013.
The current analysis is based on 13,351 participants (mean age at baseline, 57 years); 56% were female, 24% were black, and 13.3% had diabetes.

Cognitive testing was performed at visit 2 (1990 to 1992), visit 4 (1996 to 1998), and visit 5 (2011 to 2013) and involved three tests: the Delayed Word Recall Test, the Digit Symbol Substitution Test of the Wechsler Adult Intelligence Scale-Revised, and the Word Fluency Test. From these, a global cognitive Z score was calculated.

Blood glucose levels were calculated as hemoglobin A1c (HbA1c) values from stored whole blood samples.

Of the initial cohort, 17% did not attend any follow-up visits, leaving 10,720 individuals who attended visit 4 and 5987 who attended visit 5. The median duration of follow-up was 19.3 years.

Results showed that individuals with diabetes had a 19% greater decline in global cognitive Z score: a decline of 0.92 vs 0.78 for persons without diabetes (a difference of 0.15).

The authors estimate that this difference in Z score is equivalent to an age difference of 4.9 years older or the difference in cognitive performance of a 60-year-old person vs a 55-year-old person if they are otherwise similar.

Persons without diagnosed diabetes but with an HbA1c level of 5.7% to 6.4% at baseline also had significantly more cognitive decline over 20 years (adjusted difference in global cognitive Z score of –0.07) than persons with an HbA1c level less than 5.7%.

The greatest decline was found in patients with poorly controlled diabetes, defined as an HbA1c level of at least 7.0%, who had a larger decline than those with better controlled diabetes with an HbA1c level less than 7.0% (adjusted global Z score difference, –0.16; P = .071).

Diabetes duration seemed to be a factor, with a greater cognitive decline late in life for participants with longer-duration diabetes.

“Critical Aspect of Successful Aging”

“Maintaining cognitive function is a critical aspect of successful aging and ensuring a high quality of life,” the authors write. “Diabetes and glucose control are potentially modifiable and may offer an important opportunity for the prevention of cognitive decline, thus delaying progression to dementia. At the population level, delaying the onset of dementia by even a couple of years could reduce its prevalence by more than 20% over the next 30 years.”

Dr Sharrett explained to Medscape Medical News that other studies have linked diabetes to dementia but that this is the largest, with the longest follow-up.

“But what really sets it apart from other studies is that we measured change in cognition over time in diabetics and nondiabetics using the same tests in a standardized way,” he said. “This gives us assurance that our findings are real. In fact, I would say we are sure they are conservative.”

The study did not address possible mechanisms, although exclusion of persons who had a stroke after baseline attenuated the results slightly, suggesting that stroke partially mediates the association.

Dr Sharrett suggested that elevated blood glucose could affect cognition in different ways. While there is obviously a link between diabetes and vascular disease that could lead to vascular dementia, he believes that raised blood glucose levels may also affect the Alzheimer’s type of dementia.

“There is substantial controversy as to whether diabetes affects β-amyloid deposits or tangles that are the classical hallmarks of Alzheimer’s dementia,” he commented.

“It is difficult to ascertain what the cause of dementia is,” he added. “Postmortem studies have shown that both Alzheimer’s and vascular pathology can often be present. While it is often thought that most dementia is related to Alzheimer’s disease and there has been disappointment that we haven’t been able to delay or prevent this yet, there is a sizable portion of dementia that is related to the vasculature and we can do something about that.”

“Our observations that diabetes duration and even prediabetes [are] associated with faster cognitive decline emphasize the importance of adopting a healthy lifestyle as soon as possible,” he concluded.