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

Abstract

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.

Keywords: 2-AG; Cognition; Endocannabinoids; Mediterranean diet; Metabolic syndrome; Sex differences.

Fig. 1

Sex and gender differences in baseline cognitive performance (A, C, E) and in cognitive change after 3 years of MedDiet intervention (B, D, F), represented in terms of global cognition (A-B), memory (C-D) and executive functioning (E-F) composites. Each plot consists of two panels: the left panel displays mean values (95%CI), while the right panel depicts modeled differences between men and women. A negative value of the modeled differences (β, 95%CI) indicates an effect favoring men. Gender differences are evaluated using unadjusted (crude) models, while sex differences are tested in models adjusted for gender-related factors (years of education, diabetes, use of tranquilizers or sedatives, use of lipid-lowering agents, baseline MedDiet adherence and baseline physical activity), age and APOE genotype. Bold values denote statistical significance at the p < 0.05 level. Further details are available in Supplementary Tables 1–2

Fig. 2

Estimated smoothness of baseline eCBs or NAEs on cognitive performance by sex derived from GAMs. The Y-axis depicts the partial effect of baseline 2-AG on baseline global cognition in men (A), baseline OEA on baseline memory in men (B), baseline ratio OEA/AEA on baseline memory in men (C), and baseline ratio OEA/AEA on baseline memory in women (D). The shaded area is the standard-error confidence intervals. Red lines indicate the inflection point for non-linear relationships. Regression coefficients (β) and 95%CI were obtained from linear models for improving the interpretability of linear relationships. The p-value indicates the significance of the smooth term in the GAM

Fig. 3

Estimated smoothness of change in eCBs or NAEs on cognitive change by sex derived from GAMs. The Y-axis depicts the partial effect of 1-year change in 2-AG on 1-year change in global cognition in men (A), 1-year change in 2-AG on 1-year change in memory in men (B), 1-year change in the ratio OEA/AEA on 1-year change in memory in men (C), 1-year change in the ratio OEA/PEA on 1-year change in memory in men (D), 3-year change in DHEA on 3-year change in global cognition in women (E), and 3-year change in the ratio DHEA/AEA on 3-year change in global cognition in women (F). The shaded area is the standard-error confidence intervals, and δ indicates change after 1 or 3 years. Red lines indicate the inflection point for non-linear relationships. Regression coefficients (β) and 95%CI were obtained from ANCOVA models for improving the interpretability of linear relationships. The p-value indicates the significance of the smooth term in the GAM

Fig. 4

Estimated smoothness of change in eCBs or NAEs on cognitive change by APOE-ɛ4 genotype derived from GAMs. The Y-axis depicts the partial effect of 1-year change in 2-AG on 1-year change in global cognition in APOE-ɛ4 (A), 1-year change in 2-AG on 1-year change in executive functions in APOE-ɛ4 carriers (B), and 3-year change in the ratio OEA/AEA on 3-year change in executive functions in APOE-ɛ4 noncarriers. The shaded area is the standard-error confidence intervals, and δ indicates change after 1 or 3 years. Regression coefficients (β) and 95%CI were obtained from ANCOVA models for improving the interpretability of linear relationships. The p-value indicates the significance of the smooth term in the GAM.

Fig. 5

Proposed mechanism of cognitive change by the MedDiet via the endocannabinoid system