Similarly to our previous findings,12
in this different AD population we observe that higher adherence to the MeDi is associated with reduced disease odds. Similarly to our previous report,12
we note a gradual reduction in AD risk for higher tertiles of MeDi adherence, suggesting a possible dose-response effect. Additionally, in accordance with our previous results,12
the associations between MeDi and AD remain 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 BMI. Higher adherence to MeDi reduced risk for probable AD either with or without coexisting stroke.
Given the growing evidence for contribution of vascular risk factors in AD risk, vascular mechanisms are important to consider.32–34
At the same time, there is strong evidence relating the MeDi to lower risk of vascular risk factors such as dyslipidemia,5,6
abnormal glucose metabolism,3,6
and coronary heart disease.6,8–10
Thus, vascular variables are likely to be in the causal pathway between MeDi and AD and should be considered as possible mediators. However, when we considered vascular risk factors in our models, the association between MeDi and AD did not change. This was the case despite our attempt to capture vascular comorbidity in the most complete possible way by simultaneously considering both a long list and alternative definitions of vascular variables. Additionally, the associations between MeDi and odds for AD were present even in the subset of subjects with AD without any history of stroke. There are at least 2 possible explanations for our findings.
First, lack of significant associations may be related to measurement error of the vascular variables biasing our results toward the null hypothesis. Many of the vascular risk factors in our final analyses were ascertained by self-report, which is likely to underestimate the real prevalence of disease, as is, for example, the case with diabetes.35
Although the prevalence of self-reported diabetes in our sample is comparable with that in previous reports for the same age groups and ethnic composition,35
the prevalence of diabetes in the general population is higher than what is diagnosed,35
and self-reported diabetes underestimates the true prevalence. Self-report of vascular risk factors has been shown to be reliable and accurate in our data,27
and we additionally attempted to include even more detailed measurements of some vascular variables (ie, blood pressure measurements and lipid measurements). However, we lacked data on the precise duration and severity of all vascular risk factors. This calls for a more accurate assessment of vascular pathways. For example, it is possible that a mediating vascular effect could be detected if measurement of vascular co-morbidity was performed with use of instruments or bio-markers more accurate and more biologically proximal to either vascular disease or to vascular-mediated neural damage (ie, left ventricular hypertrophy, direct measures of blood vessel atherosclerosis, homocysteine, glycosylated hemoglobin, brain imaging data such as strokes or white matter hyperintensities, etc).
Second, the MeDi effect may be mediated by nonvascular mechanisms, such as oxidation or inflammation. Growing evidence implicates oxidative damage in the pathogenesis of AD36,37
with neurons at risk for AD degeneration having increased lipid peroxidation, nitration, free carbonyls, and nucleic acid oxidation. Complex phenols and many other substances with important antioxidant properties such as olive oil,38,39
wine, fruits and vegetables, vitamins C and E, and carotenoids40–45
are found in high concentrations in the typical components of the MeDi.46
Typical Mediterranean meals47
or meals rich in typical Mediterranean food elements such as olive oil48
or pomegranate juice49
have been shown to increase enzymes with antioxidant properties such as paraoxonase and plasma carotenoids.47
Food intervention studies with either different tomato products (a very commonly used food in Mediterranean areas46
) or a typical Mediterranean dish such as gazpacho (a cold vegetable soup that contains about 75% vegetables [tomato, cucumber, pepper], 2%–10% olive oil, and other minor components [onion, garlic, wine vinegar, and sea salt])50
have indicated significant reductions of markers of oxidative stress such as isoprostanes. Therefore, the MeDi could be capturing the composite effect of dietary antioxidants and this could, at least partially, explain the association with a lower risk of AD.
Inflammation is another potential mechanism for AD pathogenesis.34,51–54
Inflammation has been found to be associated with a higher risk for AD and cognitive decline.55
For example, C-reactive protein (CRP) (an inflammatory marker that has been detected in neuritic plaques and neurofibrillary tangles in the brains of patients with AD56,57
and is up-regulated in AD brains58–60
) has been proposed as a possible biomarker for AD.62
Higher adherence to the MeDi has been associated with lower CRP levels in both observational5,63,64
studies. In the ATTICA epidemiological study, participants on the highest tertile of the MeDi score had 20% lower CRP levels,5
and in the Nurses’ Health Study, there was a 24% reduction in CRP levels for subjects belonging to the upper quintile of a MeDi adherence index.64
As another example, IL-6, a cytokine that mediates inflammatory reactions, has been consistently detected in diffuse early amyloid plaques without neuritic pathologic abnormalities of cortical regions of patients with AD62
and has been associated with greater cognitive decline65
and an increased risk of dementia during follow-up.66
Additionally, polymorphisms of the IL-6 gene related to reduced IL-6 activity have been associated with delayed age at onset and reduced risk for AD.67
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.68
In the ATTICA study, subjects in the highest tertile of MeDi adherence have been reported to have 17% lower IL-6 serum levels,5
and in the Nurses’ Health Study, there was a 16% reduction in IL-6 levels for subjects belonging to the upper quintile of a MeDi adherence index.64
In a clinical trial, as compared with subjects assigned to the control diet, the subjects assigned to the MeDi had significantly reduced levels of IL-6.3
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.5
Thus, it is possible that the MeDi may (at least partially) lower the risk for AD by affecting inflammatory processes.
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 consist of different numbers of foods. Frequencies of food intake are based on relatively few diet constituents, which may underestimate the overall quantity of food in each food category; a common limitation of studies of diet and disease is misclassification of exposure because of 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.69
As compared with subjects included in the present analyses, subjects with missing dietary information were more likely to have AD and to be Hispanic and nonsmokers. Given that subjects with AD have lower MeDi adherence while Hispanic individuals and nonsmokers have higher, it seems that subjects with missing dietary information should not preferentially adhere more or less to the MeDi. Additionally, subjects with missing dietary information were older and less educated and had lower BMIs, all parameters unrelated to MeDi adherence. Therefore, although we cannot completely exclude it, it does not seem likely that our results could be explained by biases related to missing dietary information.
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 the overall burden of medical and vascular comorbidities or to education but was related to ethnicity. We addressed this potential bias by adjusting for years of education, ethnic group, medical comorbidity index, smoking, and vascular variables, but we cannot completely rule out residual confounding as an explanation for our findings.
Another explanation for our findings is that lower adherence to the MeDi could represent a consequence and not a cause of AD. Although we cannot completely exclude it, we addressed this possibility in several ways. First, we included in our analyses only patients with AD at the early stages of the disease (a CDR not higher than 1). Second, we found remarkable stability in MeDi scores over intervals greater than 7 years for subjects with multiple dietary assessments who were not demented at baseline but developed AD during follow-up. Additionally, we have previously reported similar stability for MeDi adherence even for nondemented subjects.12
Finally, we have previously noted an association between MeDi adherence and risk for incident AD in a longitudinal prospective design.12
Confidence in our findings is strengthened by the following factors. Dietary data were collected with a previously validated instrument that has been used widely in epidemiological studies.20
We used an a priori developed dietary pattern.1,8
Measures for multiple potential AD risk factors have been carefully recorded 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 study is community-based and the population is multiethnic, increasing the external validity of the findings.