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.

Safety and preliminary efficacy on cognitive performance and adaptive functionality of epigallocatechin gallate (EGCG) in children with Down syndrome. A randomized phase Ib clinical trial (PERSEUS study).

PURPOSE: Although some caregivers are using epigallocatechin gallate (EGCG) off label in hopes of improving cognition in young adults with Down syndrome (DS), nothing is known about its safety, tolerability, and efficacy in the DS pediatric population. We aimed to evaluate safety and tolerability of a dietary supplement containing EGCG and if EGCG improves cognitive and functional performance. METHODS: A total of 73 children with DS (aged 6-12 years) were randomized. Participants received 0.5% EGCG (10 mg/kg daily dose) or placebo for 6 months with 3 months follow up after treatment discontinuation. RESULTS: In total, 72 children were treated and 66 completed the study. A total of 38 participants were included in the EGCG group and 35 in the placebo group. Of 72 treated participants, 62 (86%) had 229 treatment-emergent adverse events (AEs). Of 37 participants in the EGCG group, 13 (35%) had 18 drug-related treatment-emergent AEs and 12 of 35 (34%) from the placebo group had 22 events. In the EGCG group, neither severe AEs nor increase in the incidence of AEs related to safety biomarkers were observed. Cognition and functionality were not improved compared with placebo. Secondary efficacy outcomes in girls point to a need for future work. CONCLUSION: The use of EGCG is safe and well-tolerated in children with DS, but efficacy results do not support its use in this population.

Psychological and metabolic risk factors in older adults with a previous history of eating disorder: A cross-sectional study from the Predimed-Plus study.

GOALS: To explore affective and cognitive status, later in life, in individuals with and without previous history of eating disorder (ED), and also its association with higher risk for metabolic syndrome (MetS) symptomatology. METHODS: A cross-sectional analysis of 6756 adults, aged 55-75 years with overweight/obesity and MetS participating in the Predimed-Plus study was conducted. Participants completed self-reported questionnaires to examine lifetime history of ED, according to DSM-5 criteria, and other psychopathological and neurocognitive factors. Anthropometric and metabolic measurements were also collected. RESULTS: Of the whole sample, 24 individuals (0.35%) reported a previous history of ED. In this subsample, there were more women and singles compared to their counterparts, but they also presented higher levels of depressive symptoms and higher cognitive impairment, but also higher body mass index (BMI) and severe obesity, than those without lifetime ED. CONCLUSIONS: This is one of the first studies to analyse the cognitive and metabolic impact of a previous history of ED. The results showed that previous ED was associated with greater affective and cognitive impairment, but also with higher BMI, later in life. No other MetS risk factors were found, after controlling for relevant variables.

A Randomised Controlled Comparison of Second-Level Treatment Approaches for Treatment-Resistant Adults with Bulimia Nervosa and Binge Eating Disorder: Assessing the Benefits of Virtual Reality Cue Exposure Therapy.

A question that arises from the literature on therapy is whether second-level treatment is effective for patients with recurrent binge eating who fail first-level treatment. It has been shown that subjects who do not stop binge eating after an initial structured cognitive-behavioural treatment (CBT) programme benefit from additional CBT (A-CBT) sessions; however, it has been suggested that these resistant patients would benefit even more from cue exposure therapy (CET) targeting features associated with poor response (e.g. urge to binge in response to a cue and anxiety experienced in the presence of binge-related cues). We assessed the effectiveness of virtual reality-CET as a second-level treatment strategy for 64 patients with bulimia nervosa and binge eating disorder who had been treated with limited results after using a structured CBT programme, in comparison with A-CBT. The significant differences observed between the two groups at post-treatment in dimensional (behavioural and attitudinal features, anxiety, food craving) and categorical (abstinence rates) outcomes highlighted the superiority of virtual reality-CET over A-CBT. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

Identifying specific cues and contexts related to bingeing behavior for the development of effective virtual environments.

BACKGROUND: Binge eating behavior constitutes a central feature of both bulimia nervosa (BN) and binge eating disorder (BED). Cue exposure therapy (CET) has been proposed as an effective intervention. OBJECTIVE: To determine which situations and specific cues trigger higher levels of binge craving and to use the results in the development of virtual reality scenarios in which CET could be applied with BN and BED patients. METHOD: Participants were 101 outpatients, 50 with BED and 51 with BN, according to DSM-5 criteria, and 63 healthy undergraduate students who completed a self-administered questionnaire to assess binge craving. RESULTS: The likelihood of binge craving in the clinical group was greater when alone at home, during the afternoon/early evening and in the late evening/at night, at weekends, and at dinner time or between meals. Higher levels of craving were produced in the kitchen, bedroom, dining room, and bakery situations. With regard to the specific cues reported, the presence of and access to high calorie food and snacks was the most commonly reported cue. Although some gender differences regarding triggering factors were obtained, no statistical differences were observed between ED subtypes. BN and BED patients showed significantly higher levels of binge craving than controls in all the contexts except when feeling positive affect; in this situation, levels of craving were low in both groups. CONCLUSIONS: This information regarding trigger contexts and specific cues can be used to create valid and reliable virtual environments for CET. Indeed, the data from this study may serve to develop a wide range of situations with different levels of binge craving, in which the therapeutic aim is to extinguish conditioned responses and facilitate the generalization of craving extinction.

Disruption of brain white matter microstructure in women with anorexia nervosa.

BACKGROUND: The etiology of anorexia nervosa is still unknown. Multiple and distributed brain regions have been implicated in its pathophysiology, implying a dysfunction of connected neural circuits. Despite these findings, the role of white matter in anorexia nervosa has been rarely assessed. In this study, we used diffusion tensor imaging (DTI) to characterize alterations of white matter microstructure in a clinically homogeneous sample of patients with anorexia nervosa. METHODS: Women with anorexia nervosa (restricting subtype) and healthy controls underwent brain DTI. We used tract-based spatial statistics to compare fractional anisotropy (FA) and mean diffusivity (MD) maps between the groups. Furthermore, axial (AD) and radial diffusivity (RD) measures were extracted from regions showing group differences in either FA or MD. RESULTS: We enrolled 19 women with anorexia nervosa and 19 healthy controls in our study. Patients with anorexia nervosa showed significant FA decreases in the parietal part of the left superior longitudinal fasciculus (SLF; p(FWE) < 0.05), with increased MD and RD but no differences in AD. Patients with anorexia nervosa also showed significantly increased MD in the fornix (p(FWE) < 0.05), accompanied by decreased FA and increased RD and AD. LIMITATIONS: Limitations include our modest sample size and cross-sectional design. CONCLUSION: Our findings support the presence of white matter pathology in patients with anorexia nervosa. Alterations in the SLF and fornix might be relevant to key symptoms of anorexia nervosa, such as body image distortion or impairments in body-energy-balance and reward processes. The differences found in both areas replicate those found in previous DTI studies and support a role for white matter pathology of specific neural circuits in individuals with anorexia nervosa.

Physiological and brain activity after a combined cognitive behavioral treatment plus video game therapy for emotional regulation in bulimia nervosa: a case report.

BACKGROUND: PlayMancer is a video game designed to increase emotional regulation and reduce general impulsive behaviors, by training to decrease arousal and improve decision-making and planning. We have previously demonstrated the usefulness of PlayMancer in reducing impulsivity and improving emotional regulation in bulimia nervosa (BN) patients. However, whether these improvements are actually translated into brain changes remains unclear. OBJECTIVE: The aim of this case study was to report on a 28-year-old Spanish woman with BN, and to examine changes in physiological variables and brain activity after a combined treatment of video game therapy (VGT) and cognitive behavioral therapy (CBT). METHODS: Ten VGT sessions were carried out on a weekly basis. Anxiety, physiological, and impulsivity measurements were recorded. The patient was scanned in a 1.5-T magnetic resonance scanner, prior to and after the 10-week VGT/CBT combined treatment, using two paradigms: (1) an emotional face-matching task, and (2) a multi-source interference task (MSIT). RESULTS: Upon completing the treatment, a decrease in average heart rate was observed. The functional magnetic resonance imaging (fMRI) results indicated a post-treatment reduction in reaction time along with high accuracy. The patient engaged areas typically active in healthy controls, although the cluster extension of the active areas decreased after the combined treatment. CONCLUSIONS: These results suggest a global improvement in emotional regulation and impulsivity control after the VGT therapy in BN, demonstrated by both physiological and neural changes. These promising results suggest that a combined treatment of CBT and VGT might lead to functional cerebral changes that ultimately translate into better cognitive and emotional performances.

Clinical validation of a virtual environment for normalizing eating patterns in eating disorders.

The purpose of the present study was to examine the clinical validation of a Virtual Reality Environment (VRE) designed to normalize eating patterns in Eating Disorders (ED). The efficacy of VR in eliciting emotions, sense of presence and reality of the VRE were explored in 22 ED patients and 37 healthy eating individuals. The VRE (non-immersive) consisted of a kitchen room where participants had to eat a virtual pizza. In order to assess the sense of presence and reality produced by the VRE, participants answered seven questions with a Likert scale (0-10) during the experience, and then filled out the Reality Judgment and Presence Questionnaire (RJPQ) and ITC-Sense of Presence Inventory (ITC-SOPI). The results showed that the VRE induced a sense of presence and was felt as real for both groups, without differences in the experience of "ease" with the VRE, sense of physical space, or the ecological validity assigned to the virtual kitchen and eating virtually. However, the ED patients reported paying more attention and experiencing greater emotional involvement and dysphoria after virtual eating. The results suggest that the VRE was clinically meaningful to the ED patients and might be a relevant therapy tool for normalizing their eating patterns.

Video game therapy for emotional regulation and impulsivity control in a series of treated cases with bulimia nervosa.

Although standard psychological treatments have been successful in treating several core features in eating disorders (ED), other characteristics such as emotional regulation or impulsivity appear to be more resistant to change. There is a growing body of evidence to support the efficacy of cognitive remediation for cognitive and emotional difficulties in ED. Playmancer/ Islands is a video game (VG) designed to specifically treat mental disorders, characterized by problems in impulse control. The objective of the game is to increase self-control over emotions, decision making and behaviours. The aim of this study is to describe the results from a consecutive series of nine bulimia nervosa patients who were treated with the VG in addition to cognitive behaviour therapy (CBT). The outcomes included clinical and psychopathological questionnaires, and physiological measures were obtained during the VG. Emotional regulation improved, heart rate variability increased, and respiratory rate and impulsivity measures reduced after the treatment. These findings suggest that VG training may enhance treatment for ED.

Intensive assessment of executive functions derived from performance in cognitive training games.

Traditional neuropsychological tests accurately describe the current cognitive state but fall short to characterize cognitive change over multiple short time periods. We present an innovative approach to remote monitoring of executive functions on a monthly basis, which leverages the performance indicators from self-administered computerized cognitive training games (NUP-EXE). We evaluated the measurement properties of NUP-EXE in N = 56 individuals (59% women, 60-80 years) at increased risk of Alzheimer's disease (APOE-ϵ4 carriers with subjective cognitive decline) who completed a 12-month multimodal intervention for preventing cognitive decline. NUP-EXE presented good psychometric properties and greater sensitivity to change than traditional tests. Improvements in NUP-EXE correlated with improvements in functionality and were affected by participants' age and gender. This novel data collection methodology is expected to allow a more accurate characterization of an individual's response to a cognitive decline preventive intervention and to inform development of outcome measures for a new generation of intervention trials.

Poor decision making in male patients with anorexia nervosa.

OBJECTIVE: Decision making is impaired in female patients with anorexia nervosa (AN), but it is unclear if the same impairment is present in male patients with AN. METHOD: Decision making was assessed in 48 AN individuals (19 male and 29 female patients) and 61 healthy controls (20 male and 41 female patients) using the Iowa Gambling Task (IGT). RESULTS: Both male and female patients with AN performed significantly worse than healthy controls on the IGT. No gender differences in IGT performance were found across groups. Male patients had higher impulsivity scores, but impulsivity had not predicted poor decision-making performance. DISCUSSION: Impaired decision making is present in male and female patients with AN. These data suggest that male patients with AN are very similar to female patients in decision making, and as a result, treatment approaches that seek to improve this ability should be similar in both genders.

The facial and subjective emotional reaction in response to a video game designed to train emotional regulation (Playmancer).

Several aspects of social and emotional functioning are abnormal in people with eating disorders. The aim of the present study was to measure facial emotional expression in patients with eating disorders and healthy controls whilst playing a therapeutic video game (Playmancer) designed to train individuals in emotional regulation. Participants were 23 ED patients (11 AN, 12 BN) and 11 HCs. ED patients self reported more anger at baseline but expressed less facial expression of anger during the Playmancer game. The discrepancy between self-report and non-verbal expression may lead to problems in social communication.

Impulsive Personality Traits Predicted Weight Loss in Individuals with Type 2 Diabetes after 3 Years of Lifestyle Interventions.

Impulsivity has been associated with type 2 diabetes (T2D) and may negatively impact its management. This study aimed to investigate impulsive personality traits in an older adult population with T2D and their predicting role in long-term weight control and glycemic management, through glycated hemoglobin (HbA1c), following 3 years of intervention with a Mediterranean diet. The Impulsive Behavior Scale (UPPS-P) was administered as a measure of impulsive traits at baseline. Results showed higher total baseline scores of UPPS-P, and higher positive urgency in individuals with T2D, compared with those without T2D. The regression analysis in patients with T2D showed that sensation seeking and lack of perseverance predicted weight loss at follow-up. By contrast, impulsive traits did not predict follow-up levels of HbA1c. In conclusion, the present findings suggest that higher impulsive traits in individuals with T2D seem to affect long-term weight control, but not glycemic control.

Suicide attempts in anorexia nervosa subtypes.

OBJECTIVE: The risk for suicide attempts is elevated in anorexia nervosa (AN), yet we know little about the relation between suicide and personality in this group. We explored the prevalence of lifetime suicide attempts in women with AN and compared those who had and had not attempted suicide on eating disorder symptoms, general psychopathology, and personality both relative to a healthy control group and then across AN subtypes. METHOD: One hundred four outpatients with restricting AN, 68 outpatients with purging AN, and 146 comparison individuals participated in the study. RESULTS: The prevalence of suicide attempts differed significantly across the 3 groups (P = .003), with 0% in the controls, 8.65% in the restricting AN group, and 25.0% in the purging AN group. Depression measures were elevated in those with suicide attempts. Within the restricting AN group, those who attempted suicide scored significantly higher on Phobic Anxiety, measured by means of the Symptom Checklist-Revised, than those who did not (P = .001). CONCLUSION: The presence of purging and depressive symptoms in individuals with AN should increase vigilance for suicidality; and among restrictors, greater anxiety may index greater suicide risk.

Mobile Device-assisted Dietary Ecological Momentary Assessments for the Evaluation of the Adherence to the Mediterranean Diet in a Continuous Manner.

Mobile device-assisted dietary ecological momentary assessments (EMAs) have emerged as a new tool allowing the evaluation of dietary intake in real time, in a real-world setting and in a continuous manner. They have the potential to minimize recall bias, participant, and investigator burden, and decrease economic and time investment while maximizing ecological validity. We developed a set of EMAs aimed at evaluating continuous adherence to the MedDiet. Four multiple-choice EMAs are sent daily in a randomized manner from a total of eight questions. The EMAs enquire about the consumption of 11 key food groups of the Mediterranean diet in the last 24-48 h in a semi-quantitative way. EMAs capture the daily frequency of consumption of fruits, vegetables, and extra virgin olive oil on different days of the week. Additionally, EMAs capture the weekly frequency of consumption of whole grain products, sugary drinks, nuts, legumes, sweets, fish and seafood, and red and processed meats. A designed scoring system behind the EMAs extracts the percentage of adherence to the MedDiet recommendations and calculates a quality index of the diet every week. Individualized reports are sent periodically to the volunteers highlighting the strengths and weaknesses of their diet. EMAs are also expected to have a behavioral effect, reinforcing the choice of Mediterranean foods.

Prevention of cognitive decline in subjective cognitive decline APOE ε4 carriers after EGCG and a multimodal intervention (PENSA): Study design.

INTRODUCTION: Subjects exhibiting subjective cognitive decline (SCD) are at an increased risk for mild cognitive impairment and dementia. Given the delay between risk exposure and disease onset, SCD individuals are increasingly considered a good target population for cost-effective lifestyle-based Alzheimer's disease prevention trials. METHODS: The PENSA study is a randomized, double-blind, controlled clinical trial that aims to evaluate the efficacy of a personalized multimodal intervention in lifestyle (diet counseling, physical activity, cognitive training, and social engagement) combined with the use of epigallocatechin gallate (EGCG) over 12 months, in slowing down cognitive decline and improving brain connectivity. The study population includes 200 individuals meeting SCD criteria and carrying the apolipoprotein E ε4 allele, who will be randomized into four treatment arms (multimodal intervention + EGCG/placebo, or lifestyle recommendations + EGCG/placebo). The primary efficacy outcome is change in the composite score for cognitive performance measured with the Alzheimer's Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC-like) adding to the original version the Interference score from the Stroop Color and Word Test and the Five Digit Test. Secondary efficacy outcomes are (1) change in functional magnetic resonance imaging (fMRI) and structural neuronal connectivity (structural MRI) and (2) the safety assessment of the EGCG compound. This study is framed within the WW-FINGERS consortium. DISCUSSION: The use of new technologies (i.e., mobile ecological momentary assessments [EMAs], activity tracker) in the PENSA study allows the collection of continuous data on lifestyle behaviors (diet and physical activity) and mood, enabling a personalized design as well as an intensive follow-up of participants. These data will be used to give feedback to participants about their own performance along the intervention, promoting their involvement and adherence. The results of the study may aid researchers on the design of future clinical trials involving preventive lifestyle multicomponent interventions.

Effects of COVID-19 Home Confinement on Mental Health in Individuals with Increased Risk of Alzheimer's Disease.

We explored the impact of the Spanish COVID-19 strict home confinement on mental health and cognition in non-infected subjects (N = 16, 60-80 years) diagnosed with subjective cognitive decline and APOEɛ3/ɛ4 carriers. Mental health was monitored for 2 months on a daily, weekly, or monthly basis, and compared to pre-confinement values. Emotional distress, anxiety, and depression scores increased to pathological threshold values during and after confinement. Those with lower mood during confinement experienced a decline in their mood after confinement. Cognition did not change. These preliminary results suggest that mental health consequences of corona measures in preclinical stages of Alzheimer's disease should be further evaluated.

Metabolic, Affective and Neurocognitive Characterization of Metabolic Syndrome Patients with and without Food Addiction. Implications for Weight Progression.

According to the food addiction (FA) model, the consumption of certain types of food could be potentially addictive and can lead to changes in intake regulation. We aimed to describe metabolic parameters, dietary characteristics, and affective and neurocognitive vulnerabilities of individuals with and without FA, and to explore its influences on weight loss progression. The sample included 448 adults (55-75 years) with overweight/obesity and metabolic syndrome from the PREDIMED-Plus cognition sub-study. Cognitive and psychopathological assessments, as well as dietary, biochemical, and metabolic measurements, were assessed at baseline. Weight progression was evaluated after a 3-year follow up. The presence of FA was associated with higher depressive symptomatology, neurocognitive decline, low quality of life, high body mass index (BMI), and high waist circumference, but not with metabolic comorbidities. No differences were observed in the dietary characteristics except for the saturated and monounsaturated fatty acids consumption. After three years, the presence of FA at baseline resulted in a significantly higher weight regain. FA is associated with worse psychological and neurocognitive state and higher weight regain in adults with metabolic syndrome. This condition could be an indicator of bad prognosis in the search for a successful weight loss process.

Effects of a psychosocial intervention at one-year follow-up in a PREDIMED-plus sample with obesity and metabolic syndrome.

This study examines if overweight/obesity are related to higher impulsivity, food addiction and depressive symptoms, and if these variables could be modified after 1 year of a multimodal intervention (diet, physical activity, psychosocial support). 342 adults (55-75 years) with overweight/obesity and metabolic syndrome (MetS) from the PREDIMED-Plus Cognition study were randomized to the intervention or to the control group (lifestyle recommendations). Cognitive and psychopathological assessments were performed at baseline and after 1-year follow-up. At baseline, higher impulsivity was linked to higher food addiction and depressive symptoms, but not to body mass index (BMI). Food addiction not only predicted higher BMI and depressive symptoms, but also achieved a mediational role between impulsivity and BMI/depressive symptoms. After 1 year, patients in both groups reported significant decreases in BMI, food addiction and impulsivity. BMI reduction and impulsivity improvements were higher in the intervention group. Higher BMI decrease was achieved in individuals with lower impulsivity. Higher scores in food addiction were also related to greater post-treatment impulsivity. To conclude, overweight/obesity are related to higher impulsivity, food addiction and depressive symptoms in mid/old age individuals with MetS. Our results also highlight the modifiable nature of the studied variables and the interest of promoting multimodal interventions within this population.

Metformin Use and Cognitive Function in Older Adults With Type 2 Diabetes Following a Mediterranean Diet Intervention.

Background and Purpose: Both adherence to the Mediterranean diet (MedDiet) and the use of metformin could benefit the cognitive performance of individuals with type 2 diabetes, but evidence is still controversial. We examined the association between metformin use and cognition in older adults with type 2 diabetes following a MedDiet intervention. Methods: Prospective cohort study framed in the PREDIMED-Plus-Cognition sub-study. The PREDIMED-Plus clinical trial aims to compare the cardiovascular effect of two MedDiet interventions, with and without energy restriction, in individuals with overweight/obesity and metabolic syndrome. The present sub-study included 487 cognitively normal subjects (50.5% women, mean ± SD age of 65.2 ± 4.7 years), 30.4% of them (N = 148) with type 2 diabetes. A comprehensive battery of neurocognitive tests was administered at baseline and after 1 and 3 years. Individuals with type 2 diabetes that exhibited a good glycemic control trajectory, either using or not using metformin, were compared to one another and to individuals without diabetes using mixed-effects models with inverse probability of treatment weights. Results: Most subjects with type 2 diabetes (83.1%) presented a good and stable glycemic control trajectory. Before engaging in the MedDiet intervention, subjects using metformin scored higher in executive functions (Cohen's d = 0.51), memory (Cohen's d = 0.38) and global cognition (Cohen's d = 0.48) than those not using metformin. However, these differences were not sustained during the 3 years of follow-up, as individuals not using metformin experienced greater improvements in memory (ß = 0.38 vs. ß = 0.10, P = 0.036), executive functions (ß = 0.36 vs. ß = 0.02, P = 0.005) and global cognition (ß = 0.29 vs. ß = -0.02, P = 0.001) that combined with a higher MedDiet adherence (12.6 vs. 11.5 points, P = 0.031). Finally, subjects without diabetes presented greater improvements in memory than subjects with diabetes irrespective of their exposure to metformin (ß = 0.55 vs. ß = 0.10, P < 0.001). However, subjects with diabetes not using metformin, compared to subjects without diabetes, presented greater improvements in executive functions (ß = 0.33 vs. ß = 0.08, P = 0.032) and displayed a higher MedDiet adherence (12.6 points vs. 11.6 points, P = 0.046). Conclusions: Although both metformin and MedDiet interventions are good candidates for future cognitive decline preventive studies, a higher adherence to the MedDiet could even outweigh the potential neuroprotective effects of metformin in subjects with diabetes.