Relationship between sex, APOE genotype, endocannabinoids and cognitive change in older adults with metabolic syndrome during a 3-year Mediterranean diet intervention.

BACKGROUND: The Mediterranean diet (MedDiet) has demonstrated efficacy in preventing age-related cognitive decline and modulating plasma concentrations of endocannabinoids (eCBs) and N-acylethanolamines (NAEs, or eCB-like compounds), which are lipid mediators involved in multiple neurological disorders and metabolic processes. Hypothesizing that eCBs and NAEs will be biomarkers of a MedDiet intervention and will be related to the cognitive response, we investigated this relationship according to sex and apolipoprotein E (APOE) genotype, which may affect eCBs and cognitive performance. METHODS: This was a prospective cohort study of 102 participants (53.9% women, 18.8% APOE-ɛ4 carriers, aged 65.6 ± 4.5 years) from the PREDIMED-Plus-Cognition substudy, who were recruited at the Hospital del Mar Research Institute (Barcelona). All of them presented metabolic syndrome plus overweight/obesity (inclusion criteria of the PREDIMED-Plus) and normal cognitive performance at baseline (inclusion criteria of this substudy). A comprehensive battery of neuropsychological tests was administered at baseline and after 1 and 3 years. Plasma concentrations of eCBs and NAEs, including 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and N-docosahexaenoylethanolamine (DHEA), were also monitored. Baseline cognition, cognitive changes, and the association between eCBs/NAEs and cognition were evaluated according to gender (crude models), sex (adjusted models), and APOE genotype. RESULTS: At baseline, men had better executive function and global cognition than women (the effect size of gender differences was - 0.49, p = 0.015; and - 0.42, p = 0.036); however, these differences became nonsignificant in models of sex differences. After 3 years of MedDiet intervention, participants exhibited modest improvements in memory and global cognition. However, greater memory changes were observed in men than in women (Cohen's d of 0.40 vs. 0.25; p = 0.017). In men and APOE-ε4 carriers, 2-AG concentrations were inversely associated with baseline cognition and cognitive changes, while in women, cognitive changes were positively linked to changes in DHEA and the DHEA/AEA ratio. In men, changes in the OEA/AEA and OEA/PEA ratios were positively associated with cognitive changes. CONCLUSIONS: The MedDiet improved participants' cognitive performance but the effect size was small and negatively influenced by female sex. Changes in 2-AG, DHEA, the OEA/AEA, the OEA/PEA and the DHEA/AEA ratios were associated with cognitive changes in a sex- and APOE-dependent fashion. These results support the modulation of the endocannabinoid system as a potential therapeutic approach to prevent cognitive decline in at-risk populations. TRIAL REGISTRATION: ISRCTN89898870.

Glycated hemoglobin, type 2 diabetes, and poor diabetes control are positively associated with impulsivity changes in aged individuals with overweight or obesity and metabolic syndrome.

Impulsivity has been proposed to have an impact on glycemic dysregulation. However, it remains uncertain whether an unfavorable glycemic status could also contribute to an increase in impulsivity levels. This study aims to analyze associations of baseline and time-varying glycemic status with 3-year time-varying impulsivity in older adults at high risk of cardiovascular disease. A 3-year prospective cohort design was conducted within the PREDIMED-Plus-Cognition substudy. The total population includes 487 participants (mean age = 65.2 years; female = 50.5%) with overweight or obesity and metabolic syndrome. Insulin resistance (HOMA-IR), glycated hemoglobin (HbA1c), presence of type 2 diabetes mellitus, and type 2 diabetes control were evaluated. Impulsivity was measured using the Impulsive Behavior Scale questionnaire and various cognitive measurements. Impulsivity z-scores were generated to obtain Global, Trait, and Behavioral Impulsivity domains. Linear mixed models were used to study the longitudinal associations across baseline, 1-year, and 3-year follow-up visits. HOMA-IR was not significantly related to impulsivity. Participants with higher HbA1c levels, type 2 diabetes, and poor control of diabetes showed positive associations with the Global Impulsivity domain over time, and those with higher HbA1c levels were further related to increases in the Trait and Behavioral Impulsivity domains over the follow-up visits. These results suggest a potential positive feedback loop between impulsivity and glycemic-related dysregulation.