Glycemic Dysregulations Are Associated With Worsening Cognitive Function in Older Participants at High Risk of Cardiovascular Disease: Two-Year Follow-up in the PREDIMED-Plus Study Salas-Salvadó, Jordi Bueno Cavanillas, Aurora Predimed-Plus Investigators Cognitive function Diabetes duration Glycated (glycosylated) hemoglobin Insulin resistance Type 2 diabetes Prediabetes The authors wish to thank the PREDIMED-Plus participants and staff for their engagement, as well as to the primary care centers involved in the study. We also thank the Cerca Programme of the Generalitat de Catalunya, and the CIBEROBN, CIBERESP and CIBERDEM initiatives of Instituto de Salud Carlos III in Spain, and the collaborators in the PRIME consortium for helpful input. The first version of the present article has been published in the public repository Research Square as a preprint publication of our work (44). We particularly thank Stephanie Nishi for her assistance with manuscript language revision. Introduction: Type 2 diabetes has been linked to greater cognitive decline, but other glycemic parameters such as prediabetes, diabetes control and treatment, and HOMA-IR and HbA1c diabetes-related biomarkers have shown inconsistent results. Furthermore, there is limited research assessing these relationships in short-term studies. Thus, we aimed to examine 2-year associations between baseline diabetes/glycemic status and changes in cognitive function in older participants at high risk of cardiovascular disease. Methods: We conducted a 2-year prospective cohort study (n=6,874) within the framework of the PREDIMED-Plus study. The participants (with overweight/obesity and metabolic syndrome; mean age 64.9 years; 48.5% women) completed a battery of 8 cognitive tests, and a global cognitive function Z-score (GCF) was estimated. At baseline, participants were categorized by diabetes status (no-diabetes, prediabetes, and <5 or ≥5-year diabetes duration), and also by diabetes control. Furthermore, insulin resistance (HOMA-IR) and glycated hemoglobin (HbA1c) levels were measured, and antidiabetic medications were recorded. Linear and logistic regression models, adjusted by potential confounders, were fitted to assess associations between glycemic status and changes in cognitive function. Results: Prediabetes status was unrelated to cognitive decline. However, compared to participants without diabetes, those with ≥5-year diabetes duration had greater reductions in GCF (β=-0.11 (95%CI -0.16;-0.06)], as well as in processing speed and executive function measurements. Inverse associations were observed between baseline HOMA-IR and changes in GCF [β=-0.0094 (95%CI -0.0164;-0.0023)], but also between HbA1c levels and changes in GCF [β=-0.0085 (95%CI -0.0115, -0.0055)], the Mini-Mental State Examination, and other executive function tests. Poor diabetes control was inversely associated with phonologic fluency. The use of insulin treatment was inversely related to cognitive function as measured by the GCF [β=-0.31 (95%CI -0.44, -0.18)], and other cognitive tests. Conclusions: Insulin resistance, diabetes status, longer diabetes duration, poor glycemic control, and insulin treatment were associated with worsening cognitive function changes in the short term in a population at high cardiovascular risk. Clinical Trial Registration: http://www.isrctn.com/ISRCTN89898870, identifier ISRCTN: 89898870. 2021-11-29T12:32:32Z 2021-11-29T12:32:32Z 2021-10-29 journal article Gómez-Martínez C, Babio N, Júlvez J, Becerra-Tomás N, Martínez-González MÁ, Corella D, Castañer O, Romaguera D, Vioque J, Alonso-Gómez ÁM, Wärnberg J, Martínez JA, Serra-Majem L, Estruch R, Tinahones FJ, Lapetra J, Pintó X, Tur JA, López-Miranda J, Bueno-Cavanillas A, Gaforio JJ, Matía-Martín P, Daimiel L, Martín-Sánchez V, Vidal J, Vázquez C, Ros E, Dalsgaard S, Sayón-Orea C, Sorlí JV, de la Torre R, Abete I, Tojal-Sierra L, Barón-López FJ, Fernández-Brufal N, Konieczna J, García-Ríos A, Sacanella E, Bernal-López MR, Santos-Lozano JM, Razquin C, Alvarez-Sala A, Goday A, Zulet MA, Vaquero-Luna J, Diez-Espino J, Cuenca-Royo A, Fernández-Aranda F, Bulló M and Salas-Salvadó J (2021) Glycemic Dysregulations Are Associated With Worsening Cognitive Function in Older Participants at High Risk of Cardiovascular Disease: Two-Year Follow-up in the PREDIMED-Plus Study. Front. Endocrinol. 12:754347. [doi: 10.3389/fendo.2021.754347] http://hdl.handle.net/10481/71819 10.3389/fendo.2021.754347 eng http://creativecommons.org/licenses/by/3.0/es/ open access Atribución 3.0 España Frontiers Media