To the best of our knowledge, this is the first prospective study investigating associations between glycemic status (diabetes status/control/treatment, and HOMA-IR and HbA1c biomarkers) and cognitive function as measured by a battery of neuropsychological tests in a same large cohort of older adults at high risk of cardiovascular disease. In this community-based population, compared to participants without diabetes, those with diabetes showed a higher decline in several cognitive performance measurements. Additionally, longer duration of diabetes was associated with greater decreases in scores of tests measuring processing speed and executive functions. Furthermore, poor diabetes control, the use of insulin treatment, and increases in HOMA-IR and HbA1c were inversely associated with cognitive functioning over a 2-year period.
Our results concur with those of meta-analyses of prospective studies, suggesting a higher risk of cognitive decline in type 2 diabetes [6–8]. The mechanisms explaining these associations remains largely unknown. Several risk factors for cognitive dysfunction in diabetes have been reported, but each of them appears to have weak isolated effects [28, 29]. In order to control for these potential confounding factors, we have adjusted our statistical models for several recognized confounders, such as hypertension or depression .
Our results are similar to those reported in other studies, suggesting a greater risk of cognitive decline in participants with type 2 diabetes, especially affecting executive functions [5, 8, 30]. Regarding the visuospatial function, discrepancies in longitudinal studies have been reported in case of individuals with type 2 diabetes [31, 32]. Nevertheless, a small effect size in this function was reported in a meta-analysis conducted in 2014 . In our study, a non-significant inverse association between diabetes and the CDT test was also observed. However, longer follow-up of our population may be needed to observe a greater decline in this cognitive dimension. Concerning the memory function, we only assessed immediate verbal memory by the DST-f test. This cognitive function remained borderline inversely associated with the presence of diabetes. Additionally, our results did not show in participants with diabetes a decrease in working memory related to executive functioning measured by the DST-b. These results are in line with those reported in a recent meta-analysis, in which immediate (measured by the DST-f) and working memory (measured by the DST-b) were not affected in type 2 diabetes, while the rest of memory and executive function abilities were reduced .
Our results also show that, compared to participants without diabetes, those with diabetes had a borderline increased risk of developing a cognitive impairment as measured by the GCF score, even with only 2 years of follow-up. Meta-analyses including prospective studies showed cognitive impairment in participants presenting type 2 diabetes [6, 33]. However, it was not usual to report short-time periods in the association between type 2 diabetes and cognitive function, and it may be the reason for the discrepancies showed between the aforementioned meta-analyses and our study.
As far as we know, no longitudinal studies have been conducted assessing associations between diabetes status and cognitive dysfunction, while also considering both the prediabetes status and the duration of diabetes. Longitudinal cohorts showed contradictory results regarding the effect that prediabetes has on cognition [5, 12, 31, 34], which can be explained by the different range of ages and sample sizes, the tests and cognitive domains assessed, and the length of follow-up.
The observed interaction of the GCF score with age in prediabetes has not been previously reported in the literature and cannot be explained by a specific mechanism. We cannot rule out that this interaction was a random finding and it is a result that requires further studies. Concerning diabetes duration, our results are in line with other longitudinal studies in which higher rates of cognitive decline were described in individuals with longer duration of diabetes [5, 12].
Several mechanisms have been suggested to explain the association between diabetes status and control with changes in cognitive functioning. Among them, insulin resistance, hyperglycemic excursions and glycemic control have received much attention. Insulin resistance linked to low-grade inflammation is a factor contributing to the onset of diabetes, that appears to play a key role in the cognitive impairment associated with obesity and diabetes, given the role that insulin has in the brain promoting neuronal survival and synaptic plasticity and inhibiting apoptosis and neuroinflammation . In case of peripheral insulin resistance and type 2 diabetes, a decrease in insulin permeation through the blood-brain barrier was observed, leading to a smaller amount of insulin reaching the brain, thus impairing neuronal activation, and inducing changes in synaptic plasticity, neuronal apoptosis and neuroinflammation, all responsible of cognitive deterioration .
Longitudinal studies linking insulin resistance, as measured by HOMA-IR, and cognitive dysfunction showed discrepancies. In an older U.S. population with 8 years of follow-up, baseline HOMA-IR was not associated to changes in global cognitive function . However, in surviving patients with coronary heart disease, baseline HOMA-IR was associated with subsequent poorer cognitive performance overall and on cognitive domains on the tests of memory, executive function and attention over a 15-year period . Our results were in line with those of the latter study, as we also observed an inverse association between baseline HOMA-IR and changes in cognitive performance using the GCF score.
Another mechanism explaining the deleterious effect of diabetes on cognitive functioning is the hyperglycemic status and glycemic excursions. Increased HbA1c levels or high levels of repeated glucose measurements through time have been linked to cognitive decline and an increased risk of dementia in people without diabetes . In our study, no associations between HbA1c levels and changes in cognitive function were observed in participants without diabetes (data not shown). Nevertheless, when HbA1c was measured as a continuous variable, we found a negative association between HbA1c and all cognitive tests measurements except in case of the CDT and the DSTs, being in line with recent studies [34, 36]
When diabetes is established, increased HbA1c levels have been linked to diabetes-associated cognitive decline and dementia, but the strength of these relationships is weak . In our study, compared to participants with optimal diabetes control, those with poor control showed a higher 2-year decrease in cognitive performance measured by the VFT-p test, but this association was not observed in case of the GCF score and other cognitive assessments. Unlike other typical diabetic end-organ complications, no clear evidence exists that the increased risk of cognitive impairment can be attributed solely to hyperglycaemic excursions and glycaemic control . For example, the ACCORD MIND trial , which compared intensive with standard treatment with the aim to lower HbA1c in people with long-standing type 2 diabetes, found no association between the interventions and cognition.
Several other mechanisms have been implicated in diabetes-related cognitive decline and dementia. For example, type 2 diabetes has substantial adverse effects on blood vessels and the heart , leading to an increased risk of stroke and small cerebral vessel disease. Indeed, neuropathological studies also report an increased burden of cerebrovascular lesions, especially of lacunar type, in people with diabetes .
Observational studies have reported that some oral glucose-lowering medications may have potential beneficial or deleterious effects on cognition [6, 13]. In our study, contrary to other results showing an improved cognitive function , no associations between metformin and cognition were observed, as well as is not found for IDDP-4 or sulfonylureas use. However, in line with findings of recent meta-analyses, insulin-treated participants showed higher cognitive decline than those not treated with insulin [6, 13]. This could be explained because usually these individuals had a worse glycaemic control and higher risk of hypoglycaemia, a condition that has been clearly linked to cognitive decline and dementia risk [42, 43].
It is worth to mention that a strength of the present study is the novelty of being one of the largest population-based studies longitudinally exploring at the same time relationships between cognition and diabetes status, markers of glucose metabolism, and diabetes control and treatment in an older population at high cardiovascular risk, including a large sample size in each diabetes status categories. Nevertheless, the present findings should be considered in the context of some limitations. Firstly, although we adjusted the models for many potential confounding factors, there may be residual confounding factors not assessed, such as genetic susceptibility (APOE genotype). Unfortunately, genetic data was not available in all PREDIMED-Plus study population. Secondly, some of the explored associations might not be significant given that they have been explored in the context of a short period of time (2 years). Finally, our study has been conducted in older Mediterranean individuals with overweight/obesity and metabolic syndrome, and therefore we cannot extrapolate our results to other populations.