Females with type 2 diabetes are at higher risk for accelerated cognitive decline than males: CAROLINA-COGNITION study

Background and aim: Cognitive dysfunction is increasingly recognized as an important comorbidity of type 2 diabetes (T2D). We aimed to establish if the risk of accelerated cognitive decline (ACD) is higher in females with T2D than males. Methods and results: 3163 participants (38% female) with T2D from the cognition substudy of CAROLINA (R) (NCT01243424) were included (mean age 64.4 +/- 9.2 years; T2D duration 7.6 +/- 6.1 years). The cognitive outcome was occurrence of ACD at end of follow-up, defined as a regression based index score <16th percentile on either the Mini-Mental State Examination (MMSE) or a composite measure of attention and executive functioning (Trail Making and Verbal Fluency Test). Potential confounders, were taken into account at an individual patient level. Lo-gistic regression analysis was used to investigate ACD risk by sex. We assessed potential media-tors for sex differences in ACD using Causal Mediation Analysis (CMA). After a median follow-up duration of 6.1 +/- 0.7 years, 361 (30.0%) females compared to 494 (25.2%) males exhibited ACD (OR 1.27 [95%CI 1.08-1.49], p = .003). Depressive symptoms, which were more common in fe -males (24.3% vs 12.5%), mediated between sex and ACD (mediation effect 20.3%, p = 0.03). There were no other significant mediators. Conclusion: Females with T2D had a higher risk of ACD compared to males. This was partly ex-plained by depressive symptoms. After evaluation of vascular and diabetes-related risk factors, complications and treatment, a major share of the higher risk of ACD in females remained unex-plained. Our results highlight the need for further research on causes of sex-specific ACD in T2D. (c) 2021 The Author(s). Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Automated summary

This study found that females with type 2 diabetes are at a higher risk of accelerated cognitive decline (ACD) compared to males. Depressive symptoms partially mediated the relationship between sex and ACD. However, even after considering vascular and diabetes-related factors, complications, and treatment, a significant portion of the higher risk in females remained unexplained. Further research is needed to understand the causes of sex-specific ACD in type 2 diabetes.