In this community-based population, we observed a significant trend for cognitive decline over a 10 year period among individuals aged ≥50 years with normoglycaemia, prediabetes or diabetes at baseline. Additionally, HbA 1c levels were linearly associated with subsequent cognitive decline in memory and executive function (but not orientation) irrespective of diabetes status at baseline.

To the best of our knowledge, this is the first prospective study of the association between diabetes (assessed using HbA 1c levels) and cognitive decline that analyses data from more than three cognitive assessments over time. From these data, we were able to generate a reliable and accurate trajectory of cognitive decline with which to investigate this association. Our results are compatible with prior studies exploring this association using clinical categories of HbA 1c levels [12, 13]. Two cohort studies, both conducted in middle-aged populations, reported significantly faster cognitive decline in participants with diabetes than in those with normoglycaemia, although the tests used to measure cognitive function were different from those used in our study [12, 13]. Regarding the relationship between prediabetes and cognitive decline, results are inconsistent between studies. In agreement with the present study, Tuligenga et al reported that cognitive decline was not significantly faster in people with prediabetes than in those with normoglycaemia [13]. Conversely, Rawlings et al reported that cognitive decline was significantly faster among people with prediabetes than among those with normal HbA 1c levels [12]. Given the similar trends of cognitive decline among participants with normoglycaemia, prediabetes and diabetes in all three of the aforementioned studies, it is possible that sample size is responsible for the controversial results. In particular, the significant result for cognitive decline in people with prediabetes vs those with normoglycaemia was obtained from a cohort of 2365 individuals with prediabetes [12], whereas the non-significant results were obtained from cohorts of only 648 and 1190 individuals with prediabetes in the study by Tuligenga et al [13] and the present study, respectively. Further studies with larger sample sizes are required to validate the association between prediabetes and cognitive decline.

According to recommendations of the American Diabetes Association, maintaining an HbA 1c level of less than 53.0 mmol/mol (7.0%) could help prevent diabetes-related microvascular complications [9]. Therefore, using HbA 1c levels as a marker of glucose management, we divided our diabetic participants into two groups to examine the effect of glucose management on subsequent cognitive decline. The results revealed that while both groups showed a significant trend towards cognitive decline, there was no significant difference between the two groups. This result agrees with that of a previous study reporting a greater but not statistically significant decline in diabetic participants with an HbA 1c level of at least 53.0 mmol/mol (7.0%) [12]. This finding might be attributable to diabetes treatment-related adverse events such as severe hypoglycaemia [20], which would result in fluctuations in blood glucose levels. Although the underlying mechanisms remain to be elucidated, it is suggested that both hyperglycaemia and hypoglycaemia play important roles in diabetes-related cognitive decline [21, 22]. Studies of cellular mechanisms suggest that, compared with sustained hyperglycaemia, glycaemic fluctuations may have a greater adverse effect on endothelial function and induce more oxidative stress, potentially leading to greater cognitive decline [23, 24]. However, findings from randomised clinical trials are conflicting. No effect on cognitive decline was observed following an intervention to reduce HbA 1c levels in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Memory in Diabetes Study (ACCORD-MIND) [25], while slower cognitive decline was observed following an intervention at an HbA 1c level of 53.0 mmol/mol (7.0%) or less in the Informatics in Diabetes Education and Telemedicine Study (IDEATel) [26]. Additionally, no benefits for cognitive function were reported by the Anglo–Danish–Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care–Netherlands (ADDITION-Netherlands) in their comparison of the effectiveness of intensive multifactorial treatment (including keeping HbA 1c levels lower than 53.0 mmol/mol [7.0%]) with routine care [27]. However, all the studies mentioned above emphasise the importance of early intervention to prevent or delay diabetes onset. Modest cognitive function decrements are already present during the early stage of diabetes [28], and the effects of tight glycaemic control on those with established diabetes are complicated and yet to be determined. In addition, HbA 1c levels were recently recommended to be used in clinical practice in the UK, to assess diabetes and serve as a biomarker for blood glucose management according to the guidelines of the National Institute for Health and Care Excellence [29]. This is consistent with our opinion that HbA 1c levels are important for the prevention and management of diabetes. Given that HbA 1c levels were not used in clinical practice during the conduct of the present study, we also investigated whether fasting glucose levels and HbA 1c levels produced different diabetes diagnoses. As shown in ESM Table 9, HbA 1c levels identified more diabetic participants than did fasting glucose levels; the mismatch rate was approximately 1.4% in total. Therefore, the effect of mismatch between different diagnosis standards on our results is likely to be minimal.

Notably, the observed linear correlation of HbA 1c levels with global cognitive decline was primarily driven by impairments in the domains of memory and executive function, which were assessed by immediate and delayed word recall tests and a verbal fluency task, respectively. This may suggest that cognitive decline related to high circulating glucose levels could be specific to dysfunction of certain brain regions or subcortical pathways involved in memory and executive function. Another possible explanation is that the orientation test, with only four questions and a score ranging from 0 to 4, was relatively insensitive to the small increments of cognitive decline induced by high glucose levels. Nevertheless, it is still worth mentioning that, although the observed associations were statistically significant, the effect sizes were quite small.

While the precise mechanisms underlying the association of diabetes with cognitive decline remain unclear, several potential mechanisms have been proposed. Diabetes has been implicated to be related to subsequent cognitive impairment through both direct mechanisms (e.g. by inducing amyloid accumulation) and indirect mechanisms (e.g. by increasing microvascular disease of the central nervous system—believed to play a very important role in vascular dementia) [8]. In addition, individuals with diabetes are at increased risk of comorbidities such as depression, obesity, hypertension and hyperlipidaemia, all of which could affect cognitive performance [30]. However, only small attenuations of associations were noted after adjustment for such factors, indicating that diabetes is an independent and strong risk factor for cognitive decline. A critical aspect of successful ageing is maintaining cognitive function and ensuring a high quality of life. It has been shown that even a modest decrease in cognitive function could result in substantially greater cognitive decline over several years [31]. As there is currently no cure for dementia, early intervention on modifiable risk factors, such as diabetes, may offer an important way to prevent cognitive decline. Indeed, it has been established that intervention for treating and addressing modifiable risk factors for dementia could prevent up to a quarter of dementia cases [30].

A major strength of the present study is that it is one of the largest general population-based studies exploring the relationship between HbA 1c levels and cognition over a long-term 10 year follow-up period. Another strength is that we obtained repeated measures of cognitive function over the follow-up period, providing a robust assessment of cognitive deterioration and enabling us to capture the cumulative burden and chronicity of estimates of long-term trajectories of cognitive decline. Nevertheless, the present findings should be considered in the context of some potential limitations. First, the extent to which we can infer a causal relationship between HbA 1c levels and cognitive decline is limited because of the observational study design. It has been argued that even longitudinal designs cannot completely assuage this criticism. However, our findings show that high HbA 1c levels were not independently related to poorer cognitive function at baseline, but to a greater longitudinal cognitive decline, thus implying that poor cognition is a corollary of high HbA 1c levels, but not vice versa. Second, our study lacked a clinical dementia diagnosis during follow-up; therefore, we cannot analyse the temporal relationship between HbA 1c levels, diabetes and incident dementia. Third, although we adjusted for many potential confounding factors, there may be residual confounding factors such as genetic susceptibility, including the APOE genotype. Genetic data are not available for the ELSA and so we cannot adjust for the APOE genotype; however, previous studies indicated that there is no interaction with APOE status and diabetes on cognitive decline [7, 8, 32]. Fourth, only 55.0% of participants who completed the wave 2 survey were eligible for this study, which might have led to selection bias. Non-response analyses show that the study sample was healthier than the original ELSA population, which may affect the internal validity of estimates and limit generalisation to the English population. Using only the responders might have diluted the association between baseline diabetes and future cognitive decline, because dropouts and non-responders had a higher percentage of self-reported diabetes and might have had an even faster cognitive decline compared with responders. Thus, a stronger association could be expected if there had been full participation. Finally, cognitive function was assessed using isolated tasks; a more elaborate neuropsychological assessment may result in different associations.