Mediterranean Diet Improves Cognition
Mediterranean Diet Improves Cognition
To the best of our knowledge, this is the first study evaluating the effect of a long-term randomised intervention aimed to change the overall dietary pattern on global cognitive function. Our trial suggests that nutritional intervention with MedDiet supplemented with either EVOO or nuts is associated with improved global cognition. The benefit of MedDiet was independent of potential confounders such as age, family history of cognitive impairment or dementia, ApoE genotype, education, physical activity, vascular risk factors and energy intake.
Our longitudinal results concur with the recent findings from a cross-sectional analysis at baseline in another PREDIMED subgroup (Barcelona) whereby increased consumption of EVOO and walnuts were independently related to better cognition. They are also consistent with the weak but not significant association observed for olive oil, monounsaturated fatty acids and the MedDiet in the European Prospective Investigation into Cancer and Nutrition-Greek (EPIC-Greek) study, with a similar but stronger association observed in a large Italian cohort and with a slightly improved cognitive performance in the Three-City French cohort.
Our findings are consistent with previous, but not all, observational studies conducted outside the Mediterranean basin. In a community-based American cohort study, a higher adherence to the MedDiet was associated with slower rates of cognitive decline after a 7.6-year follow-up. Another American cohort study found that a higher adherence to the MedDiet was associated with a lower risk of developing MCI and AD (Alzheimer's disease) as well as lower risk of MCI conversion to AD. Scarmeas et al found a protective effect of MedDiet pattern on incidence of dementia in two studies with larger sample sizes of 2258 and 1880 and higher incidences of dementia, 262 and 282 cases, respectively. Subsequently, Gu et al found similar results in a study with 1219 participants and 118 cases of incident dementia. In the total sample of participants from the PREDIMED-NAVARRA centre, we observed a lower incidence of dementia (35/1055), so even admitting that case-ascertainment for dementia incidence maybe more accurate, it is probable that our study was underpowered to address a protective effect of MedDiet on dementia development, given the small number of total cases observed. On the other hand, the results observed in our trial in terms of MMSE score changes are also of relatively small magnitude but our study was adequately powered to detect them and our findings support a beneficial effect. The fact that our study was a randomised controlled trial with a long follow-up period may account for a relatively greater magnitude of effect than in some shorter previous observational studies which reported a smaller benefit or null results. Thus, an Australian cohort with a 4-year and 8-year follow-up and another American cohort with 5.4-year follow-up found no association between higher adherence to the MedDiet and cognitive decline or MCI. Recently, results from French participants who agreed to participate in a postsupplementation observational follow-up of the SU.VI.MAX [Supplementation en Vitamines et Mineraux Antioxydants] trial and results from participants from the Nurses Health Study who performed a telephone-based cognitive evaluation have been published. None of them supports a global protective effect of the MedDiet on cognitive decline. These heterogeneous findings can be explained by several reasons, including the probably long induction period for the effect of nutritional changes on cognition, the use of a definition for the MedDiet in observational epidemiology which is highly dependent on sample-specific cut-off points for food consumption, and the intake of other foods or supplements not included in the score used to appraise adherence to the MedDiet. These other nutritional factors can be responsible for residual confounding. More importantly, nutritional assessment tools used in observational epidemiology are prone to measurement errors that usually may lead to null associations. Another reason that may explain these heterogeneous findings may be related to characteristics of study populations. Some demographic factors and comorbidities should be also taken into account in order to evaluate the effect of the MedDiet on cognition. Most studies have evaluated participants with a mean age ≥75 years. Since the MedDiet may exert its protective effect relatively early on the neurodegeneration process, this may minimise the effective size of the Mediterranean diet. Vascular, inflammatory and oxidative mechanisms are involved in the pathogenesis of dementia. In populations with high vascular risk, a more important vascular contribution to dementia can be expected. It would be interesting to address if the effect of the MedDiet is different in these populations. Unfortunately, only one of the cohorts mentioned above, evaluated the effect of diet on a population with a high vascular comorbidity and provided negative results.
Finally, the only randomised controlled trial to date assessing the very short-term effect of MedDiet on cognition found that participants allocated to a diet change (to a MedDiet pattern) improved only visuospatial working memory while participants allocated to the control group (no change) improved numerical working memory and word recognition. It is possible that some limitations of that previous trial such as small sample size (27 subjects), young age (19–30 years) of the studied population and the extremely short duration of the intervention (10 days) could be partly responsible for these inconsistent results.
There are mechanisms that can explain the protective effect of MedDiet on cognitive status, including antioxidative and anti-inflammatory effects and reduced vascular comorbidities. Oxidative stress has been associated with neurodegeneration. The main components of the MedDiet intervention in the PREDIMED trial, EVOO and nuts, have antioxidant properties and, together with other polyphenol-rich foods in the MedDiet, are suggested to relate to improved cognitive function. In fact, a previous assessment from the PREDIMED-NAVARRA trial found that the intervention in this subgroup of the trial was able to increase after 3 years the total plasma antioxidant capacity. Further evidence suggests that inflammation could play a role in the pathogenesis of dementia. The MedDiet and especially the typical traditional Mediterranean components such as EVOO and nuts have been associated with lower serum concentrations of different inflammatory markers. The protective effect of the MedDiet on vascular comorbidities also supports the biological plausibility of our results. Compliance with the MedDiet is inversely associated with vascular risk factors. At the same time, there is increasing evidence that major vascular risk factors are associated with a higher risk of cognitive decline and dementia. Therefore, the protective effect of the MedDiet on cognition might be related in part to improvements in underlying vascular risk factors. Due to the randomised design of the study, vascular risk factors at baseline were well-balanced among the three groups, a reason why the results did not materially change after adjusting for vascular risk factors.
There are limitations to our study. First, the most important limitation is that cognitive function of participants was not assessed at baseline. Cognitive status assessment was not initially included in the protocol since the study was primarily designed to assess the effect of MedDiet on incident CVD. The randomised design of the trial and the similarity of the three groups in all other baseline characteristics, however, are reasons to hold the assumption that cognitive performance at baseline was well balanced as well. Beyond the randomised design, another reason to accept the appropriate comparability of the groups is that our comparisons were fully-adjusted for a wide array of potential confounders. Even if small between-group differences in cognition might have existed at baseline, it would be very unlikely that they may remain after conditioning on all these covariates. Second, we did not control for depressive symptoms at baseline nor during the cognitive assessment. Similarly, considering the even distribution of other confounders at baseline among groups, it should not undermine the validity of the results. A mood disorder may affect the assessment of cognitive performance and some authors have noted a favourable effect of the Mediterranean diet on mood so it is possible that this effect could also be observed in our patients. However, in the substudy with 268 participants from the same cohort in whom we assessed the effect of the MedDiet on cognitive domains, and the incidence of MCI and dementia, the results did not significantly change after controlling for depressive symptoms at the time of cognitive assessment. The adjudication committee obtained information on the incidence of depression at the end of the study coinciding with the cognitive evaluation. Having a new medical diagnosis of depression or a new antidepressant drug prescription was used for case ascertainment of depression in the PREDIMED study. It is possible that milder cases of depression might have gone undetected. However, most severe ones and all cases with a severity significant enough as to require treatment were identified. Our results were similar when we adjusted for incident depression. For the MedDiet+EVOO group, the adjusted differences versus the control group were +0.63 95% CI +0.20 to +1.06, p=0.004 for MMSE and +0.51 95% CI +0.20 to +0.81, p=0.001 for CDT. For the MedDiet+Nuts group versus the control group, the adjusted differences were +0.56 95% CI +0.10 to +1.01, p=0.017 for MMSE, and +0.33 95% CI (+0.008 to +0.66), p=0.045 for CDT. This suggests that the effect of the Mediterranean diet on cognitive function is independent of its potential effect on mood.
We acknowledge that our sample size was relatively small with respect to the observed effect size; therefore our estimates have wide CIs. Another limitation of the study is its single blinded nature, but there is no possibility of conducting true double-blind long-term trials in nutrition. Finally, by study design, we included participants at high risk of CVD, thus the generalisation of our findings to the average general population is uncertain.
Our study also has strengths. First, the study was a long-term randomised controlled trial where MedDiets were supplemented with hallmark food components such as EVOO and mixed nuts, both with strong antioxidant and anti-inflammatory properties. Second, we controlled for several potential confounders and randomisation allows us to rule out residual confounding as an alternative explanation of our results. Third, previous observational studies have considered the changes in dietary habits in the prodromal phase of dementia as a reverse causation bias. A synchronous timing of dietary and cognitive assessments or a short follow-up period render a study more vulnerable to reverse causation bias. Our long follow-up period helps to avoid this potential bias. Fourth, as we performed our analyses on an intention-to-treat principle, the presence of participants who failed to comply with the proposed dietary intervention due to an undiagnosed cognitive decline would bias the effect of the MedDiet on cognitive function toward the null. Even considering this possibility, we found an association of the MedDiet with better cognitive scores.
In conclusion, an intervention with MedDiet supplemented with either EVOO or mixed nuts was associated with a better global cognitive performance after 6.5 years of follow-up compared with a control group who received advice on a lower-fat diet. Our findings support increasing evidence on the protective effects of the MedDiet on cognitive function. Future interventional research including both baseline and follow-up assessments of global and multiple domains of cognition is needed to obtain firmer evidence regarding potential benefits of MedDiet on cognition.
Discussion
To the best of our knowledge, this is the first study evaluating the effect of a long-term randomised intervention aimed to change the overall dietary pattern on global cognitive function. Our trial suggests that nutritional intervention with MedDiet supplemented with either EVOO or nuts is associated with improved global cognition. The benefit of MedDiet was independent of potential confounders such as age, family history of cognitive impairment or dementia, ApoE genotype, education, physical activity, vascular risk factors and energy intake.
Our longitudinal results concur with the recent findings from a cross-sectional analysis at baseline in another PREDIMED subgroup (Barcelona) whereby increased consumption of EVOO and walnuts were independently related to better cognition. They are also consistent with the weak but not significant association observed for olive oil, monounsaturated fatty acids and the MedDiet in the European Prospective Investigation into Cancer and Nutrition-Greek (EPIC-Greek) study, with a similar but stronger association observed in a large Italian cohort and with a slightly improved cognitive performance in the Three-City French cohort.
Our findings are consistent with previous, but not all, observational studies conducted outside the Mediterranean basin. In a community-based American cohort study, a higher adherence to the MedDiet was associated with slower rates of cognitive decline after a 7.6-year follow-up. Another American cohort study found that a higher adherence to the MedDiet was associated with a lower risk of developing MCI and AD (Alzheimer's disease) as well as lower risk of MCI conversion to AD. Scarmeas et al found a protective effect of MedDiet pattern on incidence of dementia in two studies with larger sample sizes of 2258 and 1880 and higher incidences of dementia, 262 and 282 cases, respectively. Subsequently, Gu et al found similar results in a study with 1219 participants and 118 cases of incident dementia. In the total sample of participants from the PREDIMED-NAVARRA centre, we observed a lower incidence of dementia (35/1055), so even admitting that case-ascertainment for dementia incidence maybe more accurate, it is probable that our study was underpowered to address a protective effect of MedDiet on dementia development, given the small number of total cases observed. On the other hand, the results observed in our trial in terms of MMSE score changes are also of relatively small magnitude but our study was adequately powered to detect them and our findings support a beneficial effect. The fact that our study was a randomised controlled trial with a long follow-up period may account for a relatively greater magnitude of effect than in some shorter previous observational studies which reported a smaller benefit or null results. Thus, an Australian cohort with a 4-year and 8-year follow-up and another American cohort with 5.4-year follow-up found no association between higher adherence to the MedDiet and cognitive decline or MCI. Recently, results from French participants who agreed to participate in a postsupplementation observational follow-up of the SU.VI.MAX [Supplementation en Vitamines et Mineraux Antioxydants] trial and results from participants from the Nurses Health Study who performed a telephone-based cognitive evaluation have been published. None of them supports a global protective effect of the MedDiet on cognitive decline. These heterogeneous findings can be explained by several reasons, including the probably long induction period for the effect of nutritional changes on cognition, the use of a definition for the MedDiet in observational epidemiology which is highly dependent on sample-specific cut-off points for food consumption, and the intake of other foods or supplements not included in the score used to appraise adherence to the MedDiet. These other nutritional factors can be responsible for residual confounding. More importantly, nutritional assessment tools used in observational epidemiology are prone to measurement errors that usually may lead to null associations. Another reason that may explain these heterogeneous findings may be related to characteristics of study populations. Some demographic factors and comorbidities should be also taken into account in order to evaluate the effect of the MedDiet on cognition. Most studies have evaluated participants with a mean age ≥75 years. Since the MedDiet may exert its protective effect relatively early on the neurodegeneration process, this may minimise the effective size of the Mediterranean diet. Vascular, inflammatory and oxidative mechanisms are involved in the pathogenesis of dementia. In populations with high vascular risk, a more important vascular contribution to dementia can be expected. It would be interesting to address if the effect of the MedDiet is different in these populations. Unfortunately, only one of the cohorts mentioned above, evaluated the effect of diet on a population with a high vascular comorbidity and provided negative results.
Finally, the only randomised controlled trial to date assessing the very short-term effect of MedDiet on cognition found that participants allocated to a diet change (to a MedDiet pattern) improved only visuospatial working memory while participants allocated to the control group (no change) improved numerical working memory and word recognition. It is possible that some limitations of that previous trial such as small sample size (27 subjects), young age (19–30 years) of the studied population and the extremely short duration of the intervention (10 days) could be partly responsible for these inconsistent results.
There are mechanisms that can explain the protective effect of MedDiet on cognitive status, including antioxidative and anti-inflammatory effects and reduced vascular comorbidities. Oxidative stress has been associated with neurodegeneration. The main components of the MedDiet intervention in the PREDIMED trial, EVOO and nuts, have antioxidant properties and, together with other polyphenol-rich foods in the MedDiet, are suggested to relate to improved cognitive function. In fact, a previous assessment from the PREDIMED-NAVARRA trial found that the intervention in this subgroup of the trial was able to increase after 3 years the total plasma antioxidant capacity. Further evidence suggests that inflammation could play a role in the pathogenesis of dementia. The MedDiet and especially the typical traditional Mediterranean components such as EVOO and nuts have been associated with lower serum concentrations of different inflammatory markers. The protective effect of the MedDiet on vascular comorbidities also supports the biological plausibility of our results. Compliance with the MedDiet is inversely associated with vascular risk factors. At the same time, there is increasing evidence that major vascular risk factors are associated with a higher risk of cognitive decline and dementia. Therefore, the protective effect of the MedDiet on cognition might be related in part to improvements in underlying vascular risk factors. Due to the randomised design of the study, vascular risk factors at baseline were well-balanced among the three groups, a reason why the results did not materially change after adjusting for vascular risk factors.
There are limitations to our study. First, the most important limitation is that cognitive function of participants was not assessed at baseline. Cognitive status assessment was not initially included in the protocol since the study was primarily designed to assess the effect of MedDiet on incident CVD. The randomised design of the trial and the similarity of the three groups in all other baseline characteristics, however, are reasons to hold the assumption that cognitive performance at baseline was well balanced as well. Beyond the randomised design, another reason to accept the appropriate comparability of the groups is that our comparisons were fully-adjusted for a wide array of potential confounders. Even if small between-group differences in cognition might have existed at baseline, it would be very unlikely that they may remain after conditioning on all these covariates. Second, we did not control for depressive symptoms at baseline nor during the cognitive assessment. Similarly, considering the even distribution of other confounders at baseline among groups, it should not undermine the validity of the results. A mood disorder may affect the assessment of cognitive performance and some authors have noted a favourable effect of the Mediterranean diet on mood so it is possible that this effect could also be observed in our patients. However, in the substudy with 268 participants from the same cohort in whom we assessed the effect of the MedDiet on cognitive domains, and the incidence of MCI and dementia, the results did not significantly change after controlling for depressive symptoms at the time of cognitive assessment. The adjudication committee obtained information on the incidence of depression at the end of the study coinciding with the cognitive evaluation. Having a new medical diagnosis of depression or a new antidepressant drug prescription was used for case ascertainment of depression in the PREDIMED study. It is possible that milder cases of depression might have gone undetected. However, most severe ones and all cases with a severity significant enough as to require treatment were identified. Our results were similar when we adjusted for incident depression. For the MedDiet+EVOO group, the adjusted differences versus the control group were +0.63 95% CI +0.20 to +1.06, p=0.004 for MMSE and +0.51 95% CI +0.20 to +0.81, p=0.001 for CDT. For the MedDiet+Nuts group versus the control group, the adjusted differences were +0.56 95% CI +0.10 to +1.01, p=0.017 for MMSE, and +0.33 95% CI (+0.008 to +0.66), p=0.045 for CDT. This suggests that the effect of the Mediterranean diet on cognitive function is independent of its potential effect on mood.
We acknowledge that our sample size was relatively small with respect to the observed effect size; therefore our estimates have wide CIs. Another limitation of the study is its single blinded nature, but there is no possibility of conducting true double-blind long-term trials in nutrition. Finally, by study design, we included participants at high risk of CVD, thus the generalisation of our findings to the average general population is uncertain.
Our study also has strengths. First, the study was a long-term randomised controlled trial where MedDiets were supplemented with hallmark food components such as EVOO and mixed nuts, both with strong antioxidant and anti-inflammatory properties. Second, we controlled for several potential confounders and randomisation allows us to rule out residual confounding as an alternative explanation of our results. Third, previous observational studies have considered the changes in dietary habits in the prodromal phase of dementia as a reverse causation bias. A synchronous timing of dietary and cognitive assessments or a short follow-up period render a study more vulnerable to reverse causation bias. Our long follow-up period helps to avoid this potential bias. Fourth, as we performed our analyses on an intention-to-treat principle, the presence of participants who failed to comply with the proposed dietary intervention due to an undiagnosed cognitive decline would bias the effect of the MedDiet on cognitive function toward the null. Even considering this possibility, we found an association of the MedDiet with better cognitive scores.
In conclusion, an intervention with MedDiet supplemented with either EVOO or mixed nuts was associated with a better global cognitive performance after 6.5 years of follow-up compared with a control group who received advice on a lower-fat diet. Our findings support increasing evidence on the protective effects of the MedDiet on cognitive function. Future interventional research including both baseline and follow-up assessments of global and multiple domains of cognition is needed to obtain firmer evidence regarding potential benefits of MedDiet on cognition.
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