This study suggests that higher adherence to the MeDi is associated with (i) a borderline reduction in risk for developing MCI and (ii) a reduction in risk for conversion from MCI to AD. The gradual reduction in risks for higher tertiles of MeDi adherence also suggests a possible dose-response effect. The associations between MeDi and risk for development of MCI and of MCI conversion to AD did not attenuate even when simultaneously adjusting for many commonly considered potential confounders, such as age, gender, ethnicity, education, APOE genotype, caloric intake and BMI. Adherence to MeDi did not seem to differentially affect risk for development of MCI with or without memory impairment. The association between higher adherence to the MeDi and lower risk for conversion to AD was much more prominent for MCI subjects without memory impairment.
Higher adherence to the MeDi has been related to lower risk for AD 4, 5
. MCI has been described as a predictor or a transitional stage between normal cognition and AD 35, 36
. Thus, we expected that higher adherence to the MeDi would be related to MCI. The association between MeDi and MCI incidence was similar for MCI with and without memory impairment, while the protective MeDi effect for AD conversion was stronger for MCI subjects without memory impairment. Vascular comorbidity, including diabetes, hypertension, dyslipidemia and white matter abnormalities have been related to MCI 37–47
and it has been proposed that non-amnestic MCI in particular may be related to cerebrovascular disease 35, 36, 48
. There is an increasing recognition of vascular comorbidity regarding AD risk 49, 50
and there is strong evidence relating the MeDi to lower risk of vascular risk factors such as dyslipidemia 51, 52
, hypertension 51–54
and coronary heart disease 3, 52, 55, 56
. Therefore the stronger effect of the MeDi for non-memory MCI conversion rates to AD may relate to underlying vascular mechanisms. Nevertheless, non-vascular biological mediating mechanisms (i.e. metabolic, oxidative and inflammatory) may also potentially mediate the epidemiological MeDi MCI associations4
Both MCI and the MeDi have been associated with metabolic abnormalities. MCI has been linked to dysregulation of glucose and insulin homeostasis 57–61
and diabetes 37–41
. At the same time, according to the vast majority of the literature (but see 62, 63
), higher adherence to the MeDi seems to improve carbohydrate metabolism and in interventional studies it has been associated with significant reductions in plasma glucose 52, 54
, serum insulin and insulin resistance 54, 64
Oxidative stress could be another biological mechanisms relating MCI and the MeDi. Higher oxidative stress has been clearly invoked in MCI 65–70
. Complex phenols and many other substances with important antioxidant properties such as olive oil 71, 72
, wine, fruits and vegetables, vitamins C, E and carotenoids 73–78
are found in high concentrations in the typical components of the MeDi 79
. Typical Mediterranean meals 80
or meals rich in typical Mediterranean food elements 81, 82
have been shown to increase enzymes with antioxidant properties such as paroxonase and plasma carotenoids 80
. Intervention studies with Mediterranean-type foods, have indicated significant reductions of markers of oxidative stress, such as isoprostanes 79, 83
Finally, the protective effect of the MeDi for MCI may be mediated via inflammatory pathways. Links between MCI and higher inflammatory states have been demonstrated 84–88
. Two small studies reported no effect of MeDi on inflammatory markers such as CRP 62, 63
or IL-6 62
. Higher adherence to the MeDi has been associated with lower CRP in multiple large both observational 51, 89, 90
and interventional 54, 80
studies. As another example, tyrosol and caffeic acid, both found in extra virgin olive oil and in wine, (which are essential components of the MeDi), have been shown to significantly reduce IL-6 production from peripheral blood mononuclear cells of healthy volunteers 91
. Higher adherence to the MeDi has been associated with lower IL-6 levels in both observational 51 90
and interventional 54
studies. Higher adherence to the MeDi is in general associated with significant reduction in a series of other inflammatory markers including white blood cell counts etc 51
The potentially beneficial effect of the MeDi may be the result of some of its individual food components. For example, potentially beneficial effects for MCI or MCI conversion to AD have been reported for alcohol 7, 11
, fish 10
, PUFA 10, 11
(also for age-related cognitive decline 8
), and lower SFA 10
. Interestingly, in other studies alcohol 7, 12
, PUFA 6
or other nutrients such as vitamin E 92, 93
have failed to be associated with protection for MCI or MCI conversion to AD. Differences in the definition of the outcome (MCI [objective cognitive cutoffs in different cognitive domains + memory complaint + absence of functional impairment + absence of dementia] vs. age-related cognitive decline [only a particular cognitive cutoff on a summary cognitive score such as the MMSE]) may partially account for the discrepancies. Nevertheless, it is also possible that a composite dietary pattern such as the MeDi may better capture nutritional dimensions that may be missed by single nutrients (i.e. potential additive and interactive effects among nutritional components).
Although Hispanics reported higher adherence to the MeDi they also have higher risk for MCI 14
and AD 94
. A particular ethnic group may have a mixture of multiple protective and risk factors, the overall interaction of which determine the probability of developing a complex disease, such as AD. For example, the Hispanics may be placed at risk by their low education and by their SORL1 gene status 95
, while they may be protected by their dietary habits and by the lack of detrimental effect of the APOE genotype 94
. At the same time there may be multiple other genes or behavioral traits unique to the Hispanics that may contribute to AD, resulting in an overall higher risk in this ethnic group.
Study limitations regarding duration of follow-up, demographics of subjects with either missing data for MCI diagnostic assignment or missing follow-up have been discussed in detail in a previous publication 14
. Subjects excluded from the present analyses because of missing dietary information had slightly lower cognitive performance, were less educated and had higher BMI. Worse cognition and lower educational level indicate that these subjects were more likely at higher risk for MCI and AD, but higher BMI indicates the opposite. Most important, these subjects did not differ in most other characteristics. Potential confounding from associations between adherence to the MeDi and total caloric intake or ethnicity was addressed by adjusting for these factors. Limitations, relating to the construction of the MeDi score (i.e. use of an a priori dietary pattern score, equal weighing of underlying food categories, underestimation of total food and caloric intake etc) have been discussed in detail in previous publications 4, 5
. All models were adjusted for total caloric intake (largely determined by (i) metabolic efficiency, (ii) BMI and (iii) physical activity). Given that metabolic efficiency is unmeasurable and that BMI was included as a covariate, when we adjust for total caloric intake we essentially adjust for physical activity29
. Nevertheless, we cannot completely exclude the possibility that physical activity may partially account for some of the MeDi’s effect. Although adherence to the MeDi was not related to education or to overall level of medical comorbidities in our data, it is possible that a better diet is related to higher socioeconomic status or to other habits or characteristics related to better health. Therefore, despite adjusting for multiple variables the study is observational and we cannot completely exclude residual confounding or ‘healthy person bias’ (that can be only addressed via the randomization of an interventional study). In conservative (for the study size and follow-up) models using age as the timing variable of survival models the associations were significantly attenuated. Although age was not related to MeDi we cannot completely exclude the possibility that the noted associations are confounded by age. Finally, because the current study had started before the concept of MCI was developed, diagnosis of MCI was retrospectively applied in already collected data (rather than being applied synchronously with the diagnostic consensus conference).
Because of the synchronous timing of dietary and cognitive assessments and the relatively short follow-up we cannot completely exclude reverse causation (i.e. dietary habits being affected by cognitive status rather than the opposite). Nevertheless, in two previous publications, using a subset of 390 subjects with repeated (2 – 4) dietary assessments over a course of ~8 (and up to 13) years, we demonstrated that adherence to the MeDi is remarkably stable over time 4, 5
. Therefore, we consider it more likely that the MeDi adherence reported reflects our population’s longstanding dietary habits. Finally, since this is the 1st
study demonstrating an association between the MeDi and MCI, replication in other populations is necessary.
Confidence in our findings is strengthened by the following factors. The study is community-based and the population is multiethnic, increasing the external validity of the findings. Dietary data were collected with an instrument that has been previously validated and has been used widely in epidemiological studies. The diagnosis of MCI and AD took place in a University hospital with expertise in such disorders and was based on comprehensive assessment and standard research criteria. The patients were followed prospectively at relatively short intervals. Measures for multiple potential confounders were carefully recorded and adjusted for in the analyses.
Overall, the effects of dietary habits in MCI have not been adequately explored. These results provide support that MeDi-type habits may affect risk for both developing MCI for MCI conversion to AD. Possible biological mechanisms underlying this association remain to be explored. Exploration of such mechanisms and potential future interventional studies will provide a more complete and convincing picture of the conceivably important role of a healthy diet in risk of cognitive impairment and AD.