Martínez-Lapiscina EH, Clavero P, Toledo E, et al. Mediterranean diet improves cognition: the PREDIMED-NAVARRA randomised trial. J Neurol Neurosurg Psychiatry. 2013 May 13. Epub ahead of print.
The PREDIMED study was a randomized, parallel-group, cardiovascular primary prevention trial conducted in Spain that ran from May 2005 to December 2010. It compared 2 groups following a Mediterranean diet (supplemented with either extra virgin olive oil or mixed nuts) versus a low-fat diet. This new study enrolled participants from the initial trial who underwent further neuropsychological testing to seek an association between cognitive decline and the dietary intervention to which they had been assigned in the earlier study.
The 522 participants selected for this study were all part of the PREDIMED-NAVARRA cohort of 1,055 participants. This larger cohort took part in a large prospective clinical trial on the impact of dietary changes on cardiovascular disease risk. Neuropsychological testing was conducted on the same days that blood tests were performed for the PREDIMED trial. Of the 969 participants who were alive at the end of that trial, 522 underwent a final series of neuropsychological tests after a mean follow-up of 6.5 years. Mean age of the participants was 74.6 years and 44.6% were men. All participants were at high risk of cardiovascular disease (CVD).
Study Medication and Dosage
In the initial study, participants were divided into 3 groups. Two were encouraged to follow a Mediterranean diet. One of these groups was supplied with supplemental extra virgin olive oil, one liter per week, while the second group was supplied with mixed nuts. Those receiving olive oil were encouraged to consume ¼ cup per day. Those receiving nuts were told to eat 30 grams per day. The third group was encouraged to follow a low-fat diet.
Two neuropsychological tests were administered after a mean follow-up of 6.5 years: the Mini-Mental State Examination (MMSE) and the Clock Drawing Test (CDT). Medical records of all participants were checked for incidence of mild cognitive impairment (MCI), dementia, or depression. A comprehensive cognitive evaluation for MCI or dementia was performed.
Mean MMSE and CDT scores were significantly higher for participants in the extra virgin olive oil group compared to the control group told to eat a low fat diet. There were not significant differences between the nut group and the control group. However, in multivariate regression analyses, both the olive oil group and the nut group scored higher than the control group.
There were 60 cases of MCI in the entire group, 18 in the olive oil arm, 19 in the nut arm and 23 in the low-fat arm of the study. There were 35 cases of dementia in the total group: 12 in the olive oil group, 6 in the nut group, and 17 in the low-fat arm of the study.
This study will generate attention as it suggests that the Mediterranean diet protects against cognitive decline. That would be exciting, but a few key weaknesses make such claims inaccurate based on this study. The data do tell us that consuming extra virgin olive oil and nuts has significant impact, but they say little about the Mediterranean diet.
This study relies on dietary data from the same cohort that Estruch et al used for their cardiovascular disease study, and thus we are in the same predicament that initial data left us in.1
Namely, few of the participants in these trials significantly changed their overall diets. Martínez-Lapiscina et al, the authors of this current paper on cognition, write, “The average values for the 14-item short questionnaire after a 5-year intervention were 10.5 (SD:3.3) in MedDiet+EVOO, 9.1 (SD:4.9) in MedDiet+Nuts and 5.8 (SD:4.7) in the control group (P<0.001). After a 6-year intervention, these figures were 10.8(SD:2.7) in the MedDiet+EVOO; 10.1 (SD:4.0) in MedDiet+Nuts and 6.3 (SD:4.7) in the control group (P<0.001).”
On first read that looks good. Once we take the standard deviations into account, these scores were not significantly different; they all overlap. The only difference is that one group ate nuts, one group ate extra virgin olive oil, and one group did neither. These scores suggest adherence to a Mediterranean diet did not differ significantly between groups. Even if these scores were significantly different, it does not tell us the diets were different, only that after nearly 20 sessions with dieticians, those assigned to a Mediterranean diet knew how to answer the questionnaires.
This problem is clearer in Estruch et al’s earlier look at this same cohort. Their paper, “Primary prevention of cardiovascular disease with a Mediterranean diet,” was published in February 2013 in the New England Journal of Medicine. Many writers announced these results as evidence that the Mediterranean diet could be used to treat cardiovascular disease. New York Times writer Gina Kolata described the study as proving that “About 30 percent of heart attacks, strokes and deaths from heart disease can be prevented in people at high risk if they switch to a Mediterranean diet rich in olive oil, nuts, beans, fish, fruits and vegetables, and even drink wine with meals.”2
I wish it were that simple.
One needs to read that study in detail to grasp the problem with this current study on cognition. This earlier paper came from a large multicenter trial conducted in Spain. About 7,500 people who were at high risk of having a heart attack or stroke were divided into 3 groups. As in the current paper on cognition, one group was instructed to follow a ‘low-fat diet.’ The other 2 groups were instructed to follow a Mediterranean style diet and also supplement their diet with either extra virgin olive oil or nuts. That they did so was confirmed via blood tests: hydroxytyrosol to measure olive oil consumption and alpha-linolenic acid to measure nut consumption. Participants met 4 times a year with a dietician who encouraged them to follow their respective diets.
Estruch et al tracked the occurrence of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes) as the primary end point.
It appears that the extensive dietary counseling did nothing to change what participants ate, even though these should have been motivated people.
After only 4.8 years, a primary endpoint had occurred in 288 of the participants. Those study participants supplementing with extra virgin olive oil had a 30% lower risk of having a cardiovascular event, and those supplementing with nuts had a 28% lower risk than the “low-fat” control group.3
When you do examine the data, it appears that the extensive dietary counseling did nothing to change what participants ate, even though these should have been motivated people. Study participants were all at high risk for heart attacks or strokes, and most were already on medications for cholesterol, blood pressure, and diabetes. The study participants, despite 4 counseling sessions a year with dieticians, hardly changed what they ate at all.
Over the almost 5 years of the initial trial, the only significant dietary changes made by those in the 2 Mediterranean diet groups were slight increases in fish and bean consumption; fish consumption increased by one-third a serving per week and beans by just less than half a serving per week. No other changes were statistically significant—except for extra virgin olive oil or nut consumption in the respective study arms. This was Spain after all. People already eat a Mediterranean diet. The low-fat control group’s adherence score to a Mediterranean diet averaged about 9 out of a possible 14 points throughout the course of the trial. This is better than we can probably achieve with most patients in the United States.
We cannot pretend that eating an additional third of a serving of fish or less than a half a serving more of beans per week will make the difference in CVD occurrence that Estruch reported. Recall the results of Belin’s 2011 study in which 5 servings of fish per week were required to see a similar 30% decrease in CVD risk.4 It was likely the change in olive oil or nut consumption alone that changed CVD risk.
Earlier, smaller, and shorter studies do tell us that similar protocols are associated with significant improvements in various biomarkers of CVD, such as reducing levels of c-reactive protein,5 interleukin-6 (IL6), endothelial and monocytary adhesion molecules, chemokines,6 and plasma brain-derived neurotrophic factor (BDNF).7 There is a lot to be said in favor of eating extra virgin olive oil and nuts.
In the current study, there were differences in nut consumption between the experimental and control groups. By the end of the trial nearly 91% of people in the nut group were eating 3 or more servings of nuts a week while less than 17% of the low-fat group ate that many. Thus we should take the data on the nut group at face value.
Though we are talking relatively ancient history here, I must mention Fraser’s 1992 study, which tracked about 31,000 Seventh Day Adventists and reported that those who “consumed nuts frequently (more than 4 times per week) experienced substantially fewer definite fatal CHD events (relative risk, 0.52) and definite nonfatal myocardial infarctions (relative risk, 0.49) when compared with those who consumed nuts less than once per week.” Though these reductions were greater than those that Estruch reports, remember that Fraser’s population was healthy and not at as high risk for CVD as were those in these current studies.8
Some writers have wanted to say that Estruch et al proves that low-fat diets have no benefit in treating CVD. They are wrong. Neither of these studies compares a Mediterranean diet against a low-fat diet.9 In fact we can’t say anything about a low=fat diet based on these data. The amount of fat consumed by the control group, the so-called ‘low-fat diet’ group, did not change significantly over the course of the study. The percentage of Total Energy in the Diet from Fat dropped by less than 2%.10,11 This is not enough to be statistically significant, and certainly not clinically significant.
Suffice to say that when the added nuts or oil were accounted for, the diets hardly differed. The low-fat control group consumed nearly as much olive oil as the experimental group; the difference was only in type of oil. The low-fat group was purchasing standard olive oil, while the experimental group used extra virgin olive oil.
Thus what both of these studies really tell us is that adding extra virgin olive oil or nuts into the diet protects against cardiovascular disease and cognitive decline. Those who would try to use this study to argue in favor of the Mediterranean diet have misread the details.
Plenty of data from other studies suggest the association between diet and cognitive decline is true. Tangney et al reported in 2011 that a higher score on Mediterranean diet adherence was associated with slower cognitive decline in a cohort known as the Chicago Health and Aging Project (CHAP). CHAP participants (2,280 blacks and 1,510 whites) as the name suggests, were drawn from Chicago, Illinois.12
A May 2013 meta-analysis combined data from 22 studies and looked for associations between Mediterranean diet adherence, Parkinson’s, depression, and cognitive impairment. “High adherence to Mediterranean diet was consistently associated with reduced risk for stroke (RR=0.71, 95% CI: 0.57–0.89), depression (RR=0.68, 95% CI: 0.54–0.86), and cognitive impairment (RR=0.60, 95% CI: 0.43–0.83). Moderate adherence was similarly associated with reduced risk for depression and cognitive impairment, whereas the protective trend concerning stroke was only marginal.”13
Though these clinical trials do not prove it, following the Mediterranean diet may certainly be helpful both at lowering risk of CVD and preventing cognitive decline. The question is whether we can convince people to change their diets.
These data have another clinical implication worth noting. Those study participants assigned to the Mediterranean diet arms of the study met with highly trained dieticians 4 times a year for 5 years. This counseling had little impact. On the other hand, supplying the participants with regular supplies of nuts or oil did change their consumption patterns. The participants were highly compliant at consuming these delivered foods. Perhaps we need to shift our emphasis from telling people how to eat to getting them to subscribe to services that regularly deliver the key selected foods we want them to consume.
- Estruch R, Ros E, Salas-Salvadó J, Covas MI, et al. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet. N Engl J Med. 2013 Feb 25.
- Gina Kolata Mediterranean Diet Shown to Ward Off Heart Attack and Stroke New York Times February 25, 2013
- Estruch R, Ros E, Salas-Salvadó J, Covas MI, D Pharm, Corella D, Arós F, Gómez-Gracia E, Ruiz-Gutiérrez V, Fiol M, Lapetra J, Lamuela-Raventos RM, Serra-Majem L, Pintó X, Basora J, Muñoz MA, Sorlí JV, Martínez JA, Martínez-González MA; the PREDIMED Study Investigators. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet. N Engl J Med. 2013 Feb 25.
- Belin RJ, Greenland P, Martin L, Oberman A, Tinker L, Robinson J, Larson J, et al. Fish intake and the risk of incident heart failure: the Women's Health Initiative. Circ Heart Fail. 2011 Jul;4(4):404-13.
- Estruch R, Martínez-González MA, Corella D, Salas-Salvadó J, Ruiz-Gutiérrez V, Covas MI, Fiol M, et al. Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med. 2006 Jul 4;145(1):1-11.
- Urpi-Sarda M, Casas R, Chiva-Blanch G, Romero-Mamani ES, Valderas-Martínez P, Arranz S, Andres-Lacueva C, et al. Virgin olive oil and nuts as key foods of the Mediterranean diet effects on inflammatory biomakers related to atherosclerosis. Pharmacol Res. 2012 Jun;65(6):577-83.
- Sánchez-Villegas A, Galbete C, Martinez-González MA, Martinez JA, Razquin C, Salas-Salvadó J, Estruch R, et al. The effect of the Mediterranean diet on plasma brain-derived neurotrophic factor (BDNF) levels: the PREDIMED-NAVARRA randomized trial. Nutr Neurosci. 2011 Sep;14(5):195-201. doi: 10.1179/1476830511Y.0000000011.
- Fraser GE, Sabaté J, Beeson WL, Strahan TM. A possible protective effect of nut consumption on risk of coronary heart disease. The Adventist Health Study. Arch Intern Med. 1992 Jul;152(7):1416-24.
- Estruch et al: Table S5. Participants with a Positive Answer (%) to each of the 14 Items of the Mediterranean Diet Score by Treatment Arm during Follow-up.
- Estruch et al: Table S7. Intake of Energy, Nutrients and Supplemental Foods at Baseline and the end of the Trial by Study Group.
- Estruch et al: Table S8. Mean Baseline Values and Changes in Energy, Nutrient and Supplemental Food Intake by Study Arm.
- Tangney CC, Kwasny MJ, Li H, et al. Adherence to a Mediterranean-type dietary
pattern and cognitive decline in a community population. Am J Clin Nutr
- Psaltopoulou T, Sergentanis TN, Panagiotakos DB, Sergentanis IN, Kosti R, Scarmeas N. Mediterranean diet and stroke, cognitive impairment, depression: A meta-analysis. Ann Neurol. 2013 May 30.