Introduction
As the prevalence of type 2 diabetes mellitus has grown worldwide, so has the need to understand related health implications such as the link between diabetes and cognitive function. Type 2 diabetes is associated with an increased risk of cognitive decline and dysfunction, including dementia [
1]. Diabetes-associated cognitive impairment is expected to become more prevalent as life expectancy for individuals with diabetes increases worldwide, highlighting a need to understand the reciprocal dynamic progression of type 2 diabetes and cognitive decline. The present study investigates the relationships between cognitive change and HbA
1c measurements, one of the most important risk metrics in type 2 diabetes.
Impaired glucose control, confirmed by HbA
1c measurement, is present in and predicts the development of type 2 diabetes, even though the syndrome may be asymptomatic and go undetected for years [
2]. High HbA
1c is also associated with cognitive decline in older populations, in both healthy individuals [
3] and those diagnosed with type 2 diabetes [
4,
5]. Additionally, HbA
1c levels are associated with micro- and macrovascular complications [
2,
6], reduction in brain volume [
7,
8], and dementia [
9]. The HbA
1c–cognitive function relationship could be causative: the toxic generation of free radicals which accompanies increased HbA
1c may cross over into the brain, affecting cognitive functions [
10].
Previous work on cognitive functioning and diabetes has focused on controlling for known risk factors such as vascular disease and the
APOE*
ε4 allele, as well as identifying independent risk factors such as glucose peaks [
11] and insulin resistance [
12] that could be linked to cognitive decline. However, whereas type 2 diabetes and high blood glucose are associated with poorer cognitive function later in life, evidence for reverse causation also exists, suggesting that lower prior cognitive function might contribute to type 2 diabetes aetiology [
13]. Many samples are unable to address these types of questions because they lack a longitudinal design that tracks relevant variables, cognitive and health-related, in the same individuals across discrete waves of assessment. HbA
1c is a useful marker for studying the development of diabetes in this way, as it has good specificity and sensitivity to detect type 2 diabetes and also measures the severity of the disease [
6,
14‐
16].
This study’s aim was to characterise, across the eighth decade of life, parallel changes in cognitive functions and high blood glucose (measured by HbA
1c), and to investigate associations between baseline levels and change in these measures over time. Our study used four waves of data from the Lothian Birth Cohort of 1936 (LBC1936), a narrow age cohort of over 1000 community-dwelling people tested in four waves from age 70 to 79 years. LBC1936 also provides cognitive function data from age 11, as well as other control variables. This sample allowed us to assess two non-mutually exclusive hypotheses: higher HbA
1c at age 70 is associated with relatively greater cognitive decline from age 70 to 79 [
17‐
19]; and the reverse causative hypothesis, i.e. that lower initial cognitive function and relatively greater cognitive decline are associated with subsequently higher HbA
1c levels [
13,
20].
Discussion
The results show that in an older narrow age cohort, tested on four occasions between 70 and 79 years, lower cognitive function at 70 is associated with increases in HbA
1c over the following decade. Cognitive function level is negatively correlated with the slope of HbA
1c, and this effect is robust to the inclusion of all covariates, including age 11 cognitive function. Age 11 cognitive function itself is consistently and negatively related to HbA
1c level, which is consistent with previous reports of this sample [
20,
39]. Together, these results suggest that cognitive function consistently predicts blood glucose later in life.
Other associations between slope and level estimates of cognitive functions and HbA
1c were generally small and were inconsistent when different covariates were added. We found no consistent relationships between HbA
1c level and cognitive function slope, which represents cognitive decline. If HbA
1c had a causative, negative effect on cognitive function, we would expect to find this, but the largest association was 0.018 and in the opposite direction from what we would expect. The associations discussed thus far are visible in Fig.
2, where one can see that the initial level of cognitive function is lower in individuals with type 2 diabetes, though the rate of decline is not obviously different.
We found a significant association between age 11 cognitive function and HbA1c level starting at age 70 and cognitive function level at age 70, but we did not find any relationships between HbA1c level and age 70 cognitive function level or change in cognitive function from ages 11 and 70. This suggests that early life cognition, which is stable over the lifespan, drives the cross-sectional association between cognitive function and HbA1c at age 70. In 1947, there was no HbA1c measurement at age 11, so we cannot decide here whether early cognitive function is causal to worsening blood glucose across the life course to age 70, or whether cognitive functioning and blood glucose track each other through the life course.
It is notable that age 11 cognitive function was not associated with HbA1c slope, but cognitive function level at age 70 was. This was surprising, given that cognitive function level at age 70 was not reliably related to HbA1c level starting at the same age. However, these findings are consistent with a lead-lag effect: better cognitive functioning earlier in life predicts lower blood glucose, but only later in life.
Early cognitive function is a major life course variable that influences blood glucose and type 2 diabetes progression. In this sample, sex had few effects on level and slope outcomes. The strongest was with cognitive function level—men tended to have higher cognitive function level in this sample. Years of education display similar relationships: very small effects on all level and slope estimates other than cognitive function level, with which education showed positive relationships (β > 0.12).
When introduced in model B, disease variables including
APOE*ε
4 and hypertension and CVD history greatly reduced the effect of cognitive function on HbA
1c slope. Smoking history, for example, had a notable effect on HbA
1c level, indicating that smokers were more likely to have higher HbA
1c at age 70. The impact of these variables suggests that the association between cognitive function and later measurements of HbA
1c is related to health behaviours. One interpretation of the results is that individuals with higher cognitive function take better care of themselves: they smoke less, are more active and have a healthier diet [
40]. These associations between cognitive function and health later in life have been extensively investigated [
41‐
43], including through diabetes epidemiology [
13,
20]. However, our post hoc analyses demonstrated that the relationship between cognitive function and HbA
1c could not be explained by participants with higher cognitive function altering their behaviour more than those with lower cognitive function when these participants become aware of their type 2 diabetes diagnosis.
The extensive clinical and cognitive data that were available across all four waves, over a decade, are clear strengths of this study, as was the availability of a reliable cognitive function measure at an early age. Moreover, the broad range of validated cognitive tests allowed us to investigate both overall and domain level associations between cognitive function and blood glucose. As the LBC1936 is a narrow age cohort, neither cohort nor age effects could significantly bias our findings.
There were also limitations to this study that ought to be considered. First, our sample featured relatively few individuals diagnosed with type 2 diabetes, which limits the power of the statistical analyses. This issue was somewhat ameliorated by our use of HbA
1c as an outcome, which captures fine-grained information about diabetic and prediabetic status; nevertheless, comparatively few individuals had clinically elevated blood glucose. Second, and similarly, dropout (most likely due to mortality and frailty) was significant; almost half of the original sample did not return by the fourth wave. Whereas our models take existing and missing data into account, ultimately these missing data limit our statistical power and would particularly impact our analyses of slopes. For instance, we might not have possessed the statistical power to detect small changes in cognitive function that could have been driven by high HbA
1c. Third, we did not have any HbA
1c measurements from earlier in life, so we could not control for the influence of type 2 diabetes precursors that might have existed earlier in life. However, the prevalence of type 2 diabetes in children and young adults is low [
44] and would be lower still in a cohort born in 1936 [
20].
HbA
1c not only predicts type 2 diabetes but is also associated with vascular complications [
2,
6] and declines in both cognitive function [
3,
4,
9] and brain volume [
7,
8]. However, some prior findings are counterintuitive. For example, total brain volume was increased in a group receiving targeted glycaemic control therapy, but in spite of this no differences were found in cognitive outcomes [
7]. In general, it is difficult to determine the direction of causality in the association between type 2 diabetes and cognitive decline, but the current literature suggests that having type 2 diabetes causes greater cognitive decline [
11,
12,
19,
45,
46].
Our results support an alternative hypothesis, i.e. that cognitive function predicts high blood glucose; however, we stress that the two hypotheses are not mutually exclusive. The best explanation for our results and the wider body of research is that early life cognitive function contributes to impairment of glucose tolerance and onset of type 2 diabetes. Once an individual has developed diabetes, complication of the disease could lead to later impairment in cognitive function. Our results also suggest that good cognitive function continues to protect an individual from developing high blood glucose, emphasising its possible importance in ameliorating type 2 diabetes progression throughout the lifespan. Further research into the mechanisms whereby cognitive function impacts and is impacted by elevated blood glucose is warranted in the pursuit of underused strategies for identifying at-risk older individuals and protecting them from cognitive decline and type 2 diabetes.