In our study of community-dwelling older Mexican adults with type 2 DM, a poor glycemic control (HbA1c ≥ 8%) was associated with worse cognitive performance when compared to intensive control group. The uncontrolled type 2 DM group had a positive association with overall low cognitive performance, while the standard controlled population (HbA1c 7-7.9%) did not show an association.
A high HbA1c level (>10%) is associated with an increased risk of all type dementia (HR 1.20, 95% CI 1.07-1.35) 21. However, studies that analyze glycemic control, specifically, HbA1c levels ≥8% and their association with cognitive performance, are scarce. After a sub-analysis, a US prospective study of 5,099 participants showed an association between HbA1c levels (≥8% and 7-7.9%) and mild cognitive impairment (MCI) measured by proxy (Hazzard Risk (HR) 1.89, CI 95% 1.14-3.14, p<0.05 and HR 1.65, CI 95% 1.13-2.42, p<0.01, respectively) in an older adult population 22. Our results support these association, as an HbA1c ≥8% was associated with worse cognitive performance.
Multiple studies have identified that an intensive vs a standard glycemic treatment had no beneficial or detrimental effects on cognition 12,23,24. A meta-analysis involving five studies, that included 24,297 participants, found that neither intensive (HbA1c 6.0-7.0%) nor standard (HbA1c 7.1-8.0%) glycemic control, when compared to each other, had significant cognitive decline rates (SMD=0.02; 95% CI= - 0.03 to 0.08) 25. One of the studies mentioned above included, where guideline recommendations are based mostly is the ACCORD-MIND study. 2,977 participants (aged 55-80 years) with higher HbA1c levels (>7.5%) were randomly assigned to an intensive treatment goal (HbA1c < 6.0%) or a standard strategy (HbA1c: 7.0-7.9). In this North American trial, as previously, authors found no difference when comparing cognitive outcomes between groups after 40-week treatment, establishing a greater amplitude of therapy goal for patients 12. In our study, we were not able to find an association between standard glycemic control (HbA1c 7-7.9%) and low cognitive performance, supporting the previously reported analysis.
Several studies have evaluated the impact of type 2 DM on cognition; however, methodological differences are noted 25. Data from the English Longitudinal Study of Ageing (ELSA) showed in 5,189 participants, a longitudinal association between HbA1c levels and a rate of change in cognitive scores, where 1 mmol/mol increment in HbA1c was significantly associated with increased rate of decline in global cognitive z scores (-0.0009 SD/ year, 95% CI -0.0014, -0.003, p 0.002) 26. Our study provides an association of glycemic control levels and global cognitive performance supporting the data mentioned above; unlike other studies, additional specific HbA1c goals are analyzed and type 2 DM is not taken as a single entity.
After several studies of diabetes and cognitive impairment, authors have gone as far as proposing the possibility of type 3 of DM. Chronic hyperglycemia contributes to conditions such as inflammation, accumulation of advanced glycation end products, and oxidative stress, which in turn lead to cognitive impairment 27. Studies have shown that persons with DM experience a progressive cognitive decline, particularly characterized by a lower psychomotor speed and alterations in cognitive domains such as attention and executive function 28. Disruption in glucose metabolism leads to lower cognitive dysfunctions through different mechanisms; a) GLUT transporter altered sensitivity, b) insulin resistance, and c) vascular dysfunction. Chronic hyperglycemia is a phenomenon that inhibits brain autoregulation since GLUT transporters diminish their function in order to protect neurons from an increased glucose influx. When glucose is restored to a normal level, GLUT transporters fail to recover, causing an absence of intraneuronal glucose in a process called neuroglycopenia 29. Insulin resistance could lead to apoptosis by disruption of a secondary pathway; insulin receptor phosphorylation which disrupts long term potentiation, thus increasing inflammation and generating oxidative stress 30. Vascular homeostasis is also affected by type 2 DM. The presence of atherosclerotic plaques, endothelial dysfunction, increased shear stress, inflammation, impaired vasodilation, and increased vasoconstriction, are some of the mechanisms that lead to vascular injury. The theories presented above, often converge into a type 3 DM diagnosis 31,32.
The combination of factors seen in the type 2 DM population (hypertense, obese, IHD) mirrors the population’s clinical characteristics that physicians are set to treat in the present and near future. As type 2 DM control is one of the strongest modifiable comorbidities that affect brain function, hypertension and obesity are equally relevant risk factors to target. Since currently there are no therapies to cure dementia, the treatment of modifiable risk factors should be emphasized 2,3.
Some other factors may impact the glycemic control in older adults. In our study, type 2 DM participants with low cognitive performance were older and had a lower educational level. Studies have shown that age is the most important and non-reversible risk factor for the development of cognitive dysfunctions 33. In elderly adults pharmacologic management with multiple drugs leads to a low treatment adherence, given a higher number of side effects. Besides, non-pharmacologic treatments such as a diet and lifestyle interventions are generally less effective, since the modification of eating and physical activity habits is usually a difficult task 34,35. Education has previously been described as a protective factor for cognitive impairment, as higher education allows the development of “cognitive reserve” and a lower educational level is associated with a 5.6 greater risk of dementia 36. Also, a lower educational level could influence glycemic control. Adherence to treatment and lifestyle recommendations, disease complications, and awareness are some of the variables in which a lower educational level, over time, has a negative impact 37.
Our study has several limitations. The cross-sectional nature of this study is a major limitation for making cause-effect statements. Also, since the MHAS data was gathered through a survey, many subjects were excluded because there was a lack of biomarker availability. In addition, only a small sample of the cohort was analyzed as we sought to study fulfill the diagnosis of diabetes in community dwelling residents; this could lead to low statistical power and limiting the external validity of the results. Regarding type 2 DM, diagnosis was limited to one HbA1c measurement. A history of duration in years and information on previous control strategies was not obtained. Nevertheless, our study has several strengths. The MHAS is a large representative sample of community older adults; considering that control of cognitive impairment risk factors is a primary prevention strategy that should be prioritized.