This study suggests that higher adherence to the MeDi is associated with a reduction in risk for AD and slower cognitive decline. The gradual reduction in AD risk for higher tertiles of MeDi adherence also suggests a possible dose–response effect. The associations between MeDi and incident AD remained unchanged and significant even when simultaneously adjusting for the most commonly considered potential confounders for AD, such as age, sex, ethnicity, education, APOE genotype, caloric intake, and body mass index. Higher adherence to MeDi reduced risk for probable AD either with or without coexisting stroke.
The association between high adherence to the MeDi and lower risk for AD may be mediated by the composite effect of some of its beneficial components, such as higher intake of fish,12,13
fruits, and vegetables rich in antioxidants such as vitamin C,4–6
and higher intake of unsaturated fatty acids.10–12
Some of the inconsistencies regarding some of the above dietary elements and risk for AD in the existing literature may be a result of failure to consider possible additive and interactive (antagonistic or synergistic) effects among nutritional components, which may be captured in a composite dietary pattern such as the MeDi. For example, the effect of fish consumption in reducing blood pressure57
and blood lipids58
appears to be much more pronounced in subjects following a low-fat diet. When individual components used to derive the MeDi pattern were examined in our study, mild-to-moderate alcohol consumption and higher vegetable intake were associated with decreased risk for AD in unadjusted models. Nevertheless, none of the individual components was a significant AD predictor when other confounders were considered. These results strengthen even further our initial hypothesis that composite dietary patterns can capture dimensions of nutrition that may be missed by individual components, and that an overall dietary pattern is likely to have a greater effect on health than a single nutrient.
The MeDi may play a role in multiple potential mechanisms including oxidative stress and inflammation, which are both important in the pathogenesis of AD.59
Complex phenols and many other substances with important antioxidant properties such as vitamin C, vitamin E, and carotenoid60–62
are found in high concentrations in the typical components of the MeDi. In the Attica epidemiological study, participants on the highest tertile of the MeDi score had 20% lower CRP levels and 17% lower interleukin-6 serum levels.63
Higher adherence to the MeDi also has been associated with significant reduction in various other inflammatory and coagulation markers including white blood cell counts and fibrinogen levels.63
Given the growing evidence for contribution of vascular risk factors in AD risk,64,65
vascular mechanisms are important to consider.59
There is strong evidence relating the MeDi to lower risk for vascular risk factors such as hypertension, dyslipidemia, and diabetes.29,34,35,66
Subjects in the highest tertile of MeDi adherence have also been reported to have 15% lower homocysteine levels.63
Thus, vascular variables are likely to be in the causal pathway between MeDi and AD and should be considered as possible mediators. Because mediators, as contrasted with confounders, should not be controlled for in the statistical analysis,67
and in accordance with previous MeDi-related analytical approaches,68
we did not include specific vascular variables in our models.
Although most studies of the MeDi have been conducted in Mediterranean populations, recent studies have indicated MeDi-related health benefits in other populations such as northern European,68,69
and Australian populations,70
suggesting that the advantages of the MeDi are transferable to other populations. Our study provided the opportunity to examine the effect of MeDi in a multiethnic community in the United States, and our results support the notion that the beneficial effects of the MeDi are generalizable to different populations.
This study has limitations. The use of an a priori distribution-derived MeDi score assumes underlying monotonic effects, does not address possible thresholds or the shape of the underlying curve, and weighs equally the underlying individual food categories, which, in turn, are composed of different numbers of food constituents. Frequencies of food intake are based on relatively few diet constituents, which may underestimate the overall quantity of food in each food category, and a common limitation of studies of diet and disease is misclassification of exposure due to limited accuracy. However, assuming that the measurement error was random, our results may actually underestimate the association between high MeDi adherence and lower AD risk.
Despite the use of standard criteria, the diagnostic expertise of our center, and the thorough workup, there is always the possibility of disease misclassification bias.71
We partially addressed this issue by conducting secondary analyses considering only probable AD without stroke as the outcome, and our results were virtually unchanged. Subjects who were lost to follow-up were younger, less educated, and had more medical comorbidities, but MeDi was not related to age, education, or medical comorbidity burden. Also, the MeDi scores did not differ between subjects who remained in the study and those lost to follow-up. Therefore, it does not appear likely that our results could be explained by biases related to loss to follow-up.
It is possible that diet is related to socioeconomic status or to other habits or characteristics related to better health and a lower risk for AD. In our data, MeDi was not related to education or the overall burden of medical comorbidities, but was related to ethnicity and smoking. We addressed this by adjusting for years of education, ethnic group, medical comorbidity index, and smoking, but we cannot completely rule out residual confounding as an explanation for our findings. Another confounder usually considered in nutritional epidemiology is caloric intake,42,72
and higher MeDi adherence was related to lower caloric intake in our data. We used caloric intake adjusted residuals for MeDi calculation and also included caloric intake as a covariate (as Willet and Stampfer42
recommended). We found that higher MeDi adherence was related to a lower risk for AD over and above caloric intake.
Despite an average follow-up of 4 years, several studies have shown that subtle cognitive changes antedate the clinical diagnosis of AD by many years.55,73
Therefore, it is still possible that lower adherence to the MeDi could represent a consequence and not a cause of AD. We addressed this possibility in several ways. We found remarkable stability in MeDi scores over intervals greater than 7 years for subjects with multiple dietary assessments regardless of dementia status. In addition, the associations between MeDi score and incident AD did not change when subjects with mild cognitive deficits at baseline and subjects with less than 2 years of follow-up were excluded. Thus, bias due to preclinical disease does not appear to be a likely explanation for our findings.
Confidence in our findings is also strengthened by the following factors. Dietary data were collected with a previously validated instrument that was used widely in epidemiological studies.41
We used an a priori developed dietary pattern.27,31,74
Measures for multiple potential AD risk factors have been recorded carefully and adjusted for in the analyses. The diagnosis of AD took place in a university hospital with expertise in dementia and was based on comprehensive assessment and standard research criteria. The patients were followed prospectively at relatively short intervals. The study is community-based and the population is multiethnic, increasing the external validity of the findings.