Ageing Research Reviews 20 (2015) 74–78
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Review
Cognitive health and Mediterranean Diet: Just diet or lifestyle pattern? Mary Yannakoulia a , Meropi Kontogianni a , Nikolaos Scarmeas b,c,∗,1 a
Department of Nutrition and Dietetics, Harokopio University, Athens, Greece Taub Institute for Research in Alzheimer’s Disease and the Aging Brain, Gertrude H. Sergievsky Center, Department of Neurology, Columbia University, New York, NY, USA c Department of Social Medicine, Psychiatry and Neurology, National and Kapodistrian University of Athens, Greece b
a r t i c l e
i n f o
Article history: Received 1 April 2014 Received in revised form 13 July 2014 Accepted 8 October 2014 Available online 18 October 2014 Keywords: Alzheimer’s disease Mediterranean diet Cognitive decline Nutrition Lifestyle Behaviors
a b s t r a c t Mediterranean diet is a term used to describe the traditional eating habits of people in Crete, South Italy and other Mediterranean countries. It is a predominantly plant-based diet, with olive oil being the main type of added fat. There are many observational studies exploring the potential association between adherence to the Mediterranean diet and cognitive decline. The present review focuses on longitudinal studies with repeated cognitive assessments. It also evaluates evidence on behaviors related to the Mediterranean way of living, that have been shown to be associated with cognition, namely social interaction, participation in leisure activities, including physical activities, and sleep quality. The synergistic association-effect of these lifestyle behaviors, including diet, is unknown. Lifestyle patterns may constitute a new research and public health perspective. © 2014 Elsevier B.V. All rights reserved.
Contents 1.
2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. What lies behind the Mediterranean diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Effects on health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evidence for the effect of the Mediterranean diet on cognition and dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Moving from the Mediterranean diet to a Mediterranean lifestyle: should we look beyond foods when evaluating associations with cognition? References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction 1.1. What lies behind the Mediterranean diet The concept of the Mediterranean diet was originally conceived by Ancel Keys, in the Seven Countries Study (Keys, 1970; Nestle, 1995). However, the core foods of the diet of people living around the Mediterranean basin can be recognized in the BC era: bread, olive oil, and wine were the basis of the Greek and Roman diets and,
∗ Corresponding author E-mail address: [email protected] (N. Scarmeas). 1 Address: National and Kapodistrian University of Athens, Department of Social Medicine, Psychiatry, and Neurology, 72 Vasilisis Sofias Avenue, Athens 11528, Greece. http://dx.doi.org/10.1016/j.arr.2014.10.003 1568-1637/© 2014 Elsevier B.V. All rights reserved.
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thereafter, important within Christian religions. Bread was symbolic of agriculture and human civilization and olive trees were the identity of Mediterranean lands (Ferrari and Rapezzi, 2011). Following Key’s observations that all-cause and coronary heart disease death rates were lower in cohorts with olive oil as the main dietary fat compared to northern European ones (Keys et al., 1986), the notion that the high consumption of olive oil, bread, fruits, vegetables, and cereals may be responsible for profound health benefits was spread in the scientific community (Sofi et al., 2013). Nowadays, the term Mediterranean diet is widely used to describe the traditional dietary habits of people in Crete, South Italy and other Mediterranean countries, and is schematically depicted as a food pyramid (Simopoulos, 2001; Willett et al., 1995). This dietary pattern is characterized by abundance of plant foods: fruits, mainly as the typical after-dinner dessert, vegetables, either as main or side dish, a lot of bread, other forms of cereals, legumes, nuts,
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and seeds. Olive oil is the principal source of fat. Mediterranean diet also includes moderate amounts of dairy products (principally cheese and yogurt), low to moderate amounts of fish and poultry, red meat in low amounts and wine, consumed modestly, normally with meals (Kafatos et al., 2000; Willett et al., 1995). 1.2. Effects on health In numerous epidemiological studies, greater adherence to the Mediterranean diet has been associated, with longevity and with lower prevalence of several chronic diseases. In specific, greater adherence to the Mediterranean diet has been associated with a significant reduction in total mortality, mortality from cardiovascular disease and cancer mortality, both in Mediterranean and non-Mediterranean populations (Lopez-Garcia et al., 2014; Sofi et al., 2010; Trichopoulou et al., 2003). Furthermore, adherence to the Mediterranean diet has been related to lower cancer risk (Couto et al., 2011; Sofi et al., 2010), to primary and secondary prevention of coronary artery disease (including strokes) (Barzi et al., 2003; de Lorgeril et al., 1999; Estruch et al., 2013; Sofi et al., 2010). Prospective studies and randomized trials have provided consistent evidence regarding the favorable association of the adherence to the Mediterranean diet on type 2 diabetes mellitus risk and management (Abiemo et al., 2013; Esposito et al., 2009; Itsiopoulos et al., 2011; Martinez-Gonzalez et al., 2008; Romaguera et al., 2011; Toobert et al., 2003). Recent meta-analysis has linked greater adherence to the Mediterranean diet with reduced risk of the metabolic syndrome and its resolution (Kastorini et al., 2011). Higher adherence to a Mediterranean-style diet was inversely associated with the development of frailty in community-dwelling older adults (Talegawkar et al., 2012) and with the incidence of hip fracture in a prospective European study (Benetou et al., 2013). The more prevailing mechanisms underlying the aforementioned health benefits are the anti-inflammatory and anti-oxidative properties of this diet. In specific, adherence to the Mediterranean diet has been consistently associated with decreased biomarkers of subclinical inflammation (Barbaresko et al., 2013; Estruch, 2010) and increased levels of adiponectin, an insulin sensitizing hormone secreted by adipose tissue, affecting glucose and lipid metabolism and exerting distinct antiatherogenic, antidiabetogenic, and antiinflammatory actions (Fragopoulou et al., 2010). Moreover, the Mediterranean diet has been proposed to protect individuals from oxidative stress, as it has been consistently associated with lower blood levels of oxidative molecules and higher blood antioxidant capacity (Bullo et al., 2011; Zamora-Ros et al., 2013). Much research has been conducted in regards to the potentially beneficial nutrients abundant in the Mediterranean diets, namely monounsaturated fatty acids, a balanced ratio of (n6):(n-3) essential fatty acids, high amounts of fiber, antioxidants, such as vitamins E and C, resveratrol, polyphenols, selenium, glutathione (Simopoulos, 2001). However, the properties of the whole pattern seem to be well beyond the individual effects of nutrients. By investigating and evaluating the Mediterranean diet as a dietary pattern, we take into account nutrients and foods, their interactions, intercorrelations and cumulative effects. Eating is a complex behavior consisting of several individual behaviors, among others, the choice of specific foods or food groups, the organization of food into meals, and the conditions around or preceding eating. Aim of this review is to evaluate existing evidence on the effect of the Mediterranean diet as a pattern on cognitive function and risk of dementia and to explore potential interactions between this dietary pattern and other behaviors, implying the potential synergistic effect of a lifestyle pattern.
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2. Evidence for the effect of the Mediterranean diet on cognition and dementia There are biological mechanisms that may potentially link Mediterranean diet with cognitive decline and disease. Vascular risk factors, such as dyslipidemia, hypertension, and coronary artery disease, together with white matter lesions, have been related to dementia, Alzheimer disease (AD) and mild cognitive impairment (MCI) (Peters, 2009). Nonvascular biological mechanisms, namely metabolic, oxidative, and inflammatory, have been also proposed to be implicated in the pathophysiology of cognitive decline. Among the foods and nutrients abundant in the Mediterranean Diet, olive oil (through monounsaturated fatty acids and tyrosol, caffeic acid and other phenolic compounds), fish (and n-3 polyunsaturated fatty acids), wine (through alcohol, and phenolic compounds like resveratrol) and fruits and vegetables abundant in flavonoids and vitamins like C and E, have been associated with lower inflammatory and oxidative load and have been inversely associated with cardiometbolic risk factors, cognitive decline and dementia (Frisardi et al., 2010). Many observational studies explored the hypothesis on the potential relation between adherence to the Mediterranean diet and AD and/or cognitive decline. Cross-sectional approaches have been useful for initial explorations, but due to methodological limitations, interpretations and conclusions deriving from such are tentative. Hence, in the present review, we briefly examine evidence only from longitudinal observational studies with repeated cognitive assessments, as there is essentially no randomized clinical trial with cognitive primary outcomes, so far (Martinez-Lapiscina et al., 2013; Scarmeas, 2013). In 2006, the potential association between adherence to Mediterranean Diet and cognition was evaluated in a prospective investigation, of 2258 community-based non-demented individuals, aged >65 years in New York. Participants were prospectively evaluated every 1.5 years for an average of 4 years follow-up. One unit increment in the Mediterranean diet score was associated with 9–10% lower risk for development of AD, even after adjustment for potential confounders (Scarmeas et al., 2006). These results were, then, replicated in other US samples (Tangney et al., 2011; Tsivgoulis et al., 2013). A large number of participants (n = 3790) in the Chicago Health and Aging Project were evaluated repeatedly during a mean of 7.6 years: a dietary index based on the traditional Mediterranean diet was associated with slower rates of cognitive decline (Tangney et al., 2011). Interestingly, in contrast to the Mediterranean diet, no association between cognition and the Healthy Eating Index 2005 (recommended by the US department of Agriculture) was noted. In the REGARDS study, a very large (n = 17,478), geographically dispersed cohort, with oversampling of black subjects, after a mean follow-up period of 4 years, high adherence to the Mediterranean diet was associated with lower likelihood of incident cognitive impairment (Tsivgoulis et al., 2013). Interestingly, in a European cohort of 1410 adults from Bordeaux, 65 years or older, Feart et al. (2009) found that adherence to this dietary pattern was associated with slower decline on the Mini Mental State Examination (MMSE) over 5 years of follow-up; no association with the risk for incident dementia was noted but power for detection of such association was quite limited. Other studies, on the other hand, failed to detect an association between a score related to adherence to the Mediterranean diet and prospectively assessed measures of cognitive decline. The two US-based, longitudinal studies in women, the Women’s Health Study and the Nurses’ Health Study, did not detect any association of adherence to the Mediterranean diet with cognitive change (Samieri et al., 2013a,b). In the Mayo Clinic Study of Aging, the reduced risk of mild cognitive impairment or dementia, in subjects in the upper tertile of adherence to the Mediterranean diet at
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baseline, did not reach statistical significance (Roberts et al., 2010). This study was of relatively limited power, as there were only 116 incident cases (93 with MCI and 23 with dementia) over a relatively short follow-up (median = 2.2 years). Negative were also the results by Cherbuin and Anstey, who evaluated 1528 individuals, aged 60–64 years and observed that greater adherence to the Mediterranean Diet was not protective against cognitive impairment, but power was quite limited with only 10 incident MCI cases (Cherbuin and Anstey, 2012). Similarly, in a large sample of communitydwelling women aged ≥65 years with pre-existing vascular disease or at high vascular risk, no associations were observed between Mediterranean-style eating pattern adherence and 5-year cognitive decline (Vercambre et al., 2012). Finally, the SUVIMAX study did not reveal association between midlife adherence to a Mediterranean Diet and cognitive performance assessed 13 y later, when major confounders including lifestyle behaviors, sociodemographic factors, and health events were accounted for Kesse-Guyot et al. (2013). Nevertheless, only a single cognitive assessment was available in this study. Two attempts of combining some of the some of the evidence stated before have been undertaken. The meta-analysis by Psaltopoulou et al. (2013) reviewed not only longitudinal but also all cross-sectional and case control studies, whereas the one by Singh et al. (2014) focused only on the longitudinal studies; both concluded that the Mediterranean diet is protective against mild and advanced cognitive impairment, including AD. Several explanations have been given for the conflicting aspects of this literature. Although diet may share important associations with cognitive health, these associations are complex and could vary across geographic, cultural, or sociodemographic contexts. Mediating factors, gene-environment interactions, or environmental interactions may be present and influence outcomes in different population groups (Coppede et al., 2006). As an example, in one of the studies adherence to Mediterranean diet was associated with lower likelihood of incident impaired cognitive status in nondiabetic individuals but not in diabetic participants, implying that diabetes mellitus may be one of the mediating factors (Tsivgoulis et al., 2013). Methodological issues related to the evaluation of the adherence to a Mediterranean dietary pattern could also partly explain the inconsistent study results, as previously discussed by Feart et al. (2013). The Mediterranean diet score developed by Trichopoulou et al. (2003) is population specific; the same score could reflect different patterns of food consumption in different studies and this issue may be important in relation to cognitive/dementia outcomes. Furthermore, in the indexes used so far, all components (i.e. foods, food groups) contribute equally to the total score, i.e. no different weights are being assigned to each of the score components. We may add to this discussion on the discrepancies between studies that lifestyle, as a whole entity, can potentially be more important than diet per se or it may have a greater, more easily detectable effect in cognitive measures. A lifestyle approach may also cover some of the environmental interplay and interactions. It has been previously evaluated in relation to obesity (Kontogianni et al., 2010; Yannakoulia et al., 2010) and, in the following section we will explore it in relation to cognitive decline.
3. Moving from the Mediterranean diet to a Mediterranean lifestyle: should we look beyond foods when evaluating associations with cognition? In the earlier work by Keys (1970) as well as in the early Mediterranean diet pyramid (Willett et al., 1995), lifestyle behaviors have been underlined as important component of the Mediterranean way of living: apart from physical activity, lifestyle factors that were
extracted as being of particular interest are social support, sharing food, having lengthy meals and post-lunch siestas. They have never, though, been taken into account in studies of the Mediterranean dietary model. There are some fragmentary reports noting that food consumption habits, including meal patterns, structure and commensal rituals, are important issues to consider when trying to maintain or implement the Mediterranean diet (Tessier and Gerber, 2005). Nevertheless, there is no systematic study in relation to health outcomes. The new Mediterranean diet concept developed by the Mediterranean Diet Foundation was launched in 2011. It was again depicted in the form of a pyramid, but, interestingly, it refers more to a lifestyle pattern (Bach-Faig et al., 2011). It includes both quantitative and qualitative elements regarding eating, lifestyle and cultural factors as follows. Moderation in food consumption and frugality are promoted. The preference for seasonal, fresh and minimally processed foods may, in most cases, maximize the content of protective nutrients and molecules in the diet. Consuming traditional, local, eco-friendly and biodiverse products contributes to the sustainable character of the diet. The conviviality aspect of eating is important, as it contributes to strengthening socialization, communication and social support, whereas devoting enough time and space to culinary activities is also stressed. Finally, regular practice of moderate physical activity (at least 30 min throughout the day) and adequate sleep and resting during daytime (naps) serve as basic complements to the dietary pattern. This revised clustering of patterns related to food intake, physical activity and social life has not been evaluated in relation to dementia. However, there is evidence indicating that these individual factors are important to cognitive function and decline; they may inter-correlate or act synergistically. Social interaction, as the participation of a person in group-related activities, such as mealtime conversations, group leisure activities or other forms of social engagement, has been studied in relation to the prevalence, incidence of a dementia or in the context of non-pharmacological treatments, mainly along with physical activity. Socialization has been related to better cognitive performance (Gallucci et al., 2009). There are some longitudinal studies on the association of socialization (in terms of social networks and social engagement) and incident dementia and AD (Bennett et al., 2006; Fratiglioni et al., 2000; Wang et al., 2002). Mealtimes, seen as opportunities for social interactions have been found to maintain and reaffirm individual and group identities in families living with dementia (Genoe et al., 2010; I and Keller, 2014; Keller et al., 2006). It has also been hypothesized that increased social interaction may benefit Alzheimer’s patients by minimizing one’s sense of loneliness, isolation, stress, and, also vascular factors that contribute to cognitive decline. It can also improve patients’ sense of self-worth (Ruthirakuhan et al., 2012). Participation in leisure activities, including physical activities, has been consistently associated with a reduced risk of dementia (Akbaraly et al., 2009; Buchman et al., 2012; Scarmeas et al., 2001, 2009; Verghese et al., 2003). The meta-analysis of Sofi and colleagues showed that subjects who performed physical activity at baseline had a significantly reduced risk of cognitive decline during follow-up (Sofi et al., 2011). When studies were grouped according to the different levels of physical activity, subjects who reported to be more physically active had a 38% reduced risk of cognitive decline compared to those who reported being sedentary. The significant protection against cognitive decline during follow-up was still observed when low-to-moderate levels of physical activity were taken into consideration. Positive were also the results of an earlier meta-analysis of training interventions that examined whether an aerobic fitness intervention can have a robust and beneficial influence on cognition in sedentary older adults: fitness training increased performance 0.5 SD on average, regardless
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of the type of cognitive task, the training methods or participants characteristics (Colcombe and Kramer, 2003). There is also some more recent evidence from randomized controlled trials (Barnes et al., 2013; Lautenschlager et al., 2008). In 126 inactive older adults with cognitive complaints, 12 weeks of physical plus mental activity was associated with significant improvements in global cognitive function but without any evidence of difference between intervention and active control groups (Barnes et al., 2013). A 24-week home-based program of physical activity (approximately participants performed at least 150 min of moderate-intensity physical activity per week, mainly walking) improved cognitive function in older adults with subjective and objective mild cognitive impairment; the benefits were evident after 6 months and persisted for at least another 12 months following the discontinuation of the intervention (Lautenschlager et al., 2008). Sleep parameters are currently under study in relation to cognition. In a prospective cohort of cognitively intact older men and women low sleep quality has been significantly linked with incident cognitive impairment in men, but not in women (Potvin et al., 2012). Non-depressed older men reporting symptoms of insomnia at both baseline and 3 years later, had increased odds of cognitive decline (Cricco et al., 2001). Sleep-disordered breathing (characterized by recurrent arousals from sleep and intermittent hypoxemia) was associated with increased risk for MCI or dementia in a prospective study of 298 older women (Yaffe et al., 2011). Interestingly, napping behavior was negatively associated with incident cognitive impairment in cognitively unimpaired individuals, with those who napped being less likely to become cognitively impaired at 2 and 10 years follow up, whereas short night time sleep duration (≤6.5 h) and daytime sleepiness were associated with increased incident cognitive impairment (Keage et al., 2012). Summarizing, some lifestyle behaviors, beyond diet, have an evidence-based association with cognitive health. Their synergistic association-effect, though, is not well studied. As dietary patterns have been shown to be a promising strategy to investigate the link between food and cognitive decline (Alles et al., 2012), lifestyle patterns may take us a step further. Interactions are the rule rather than the exception in science and combining different aspects of lifestyle is one of the ways to partially address this issue. Of course this approach may result in reductionistic limitations, such as being unable to pinpoint the exact behavior (and possibly the related biological pathway) that could be protective for medical conditions and diseases, but it is interesting from a public health point of view. Regarding the optimal approach of estimating lifestyle patterns, it is obviously a complex topic. One could evaluate different lifestyle aspects and adjust for the presence of others by simultaneously considering them in the same model. However, as different dimensions of behavior are often highly intercorrelated, potential issues of colinearity may arise. Another approach would be to consider different aspects of lifestyle (or even their sub-constituents) independently in sequential models, but type I error inflation and adjustment for multiple comparisons may be necessary. Lifestyle patterns may be derived with use of a priori approaches (similar to Mediterranean diet approach – i.e. by including behaviors that are known to be protective for other health outcomes) or a posteriori approaches (with use of a series of multivariate analyses such as cluster analysis and principal component analysis, using data-driven structure of underlying dimensions) or a priori/a posteriori combinations (i.e. reduced rank regression analysis). Overall, methodological issues regarding derivation of patterns constitute an extensive area of research that goes beyond the scope of this paper. In conclusion, along the lines of the concept of “food synergy” (Jacobs and Tapsell, 2013), we propose a “lifestyle behavior synergy”. The so far individually published work on Mediterranean
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Contents lists available at ScienceDirect
Ageing Research Reviews journal homepage: www.elsevier.com/locate/arr
Review
Cognitive health and Mediterranean Diet: Just diet or lifestyle pattern? Mary Yannakoulia a , Meropi Kontogianni a , Nikolaos Scarmeas b,c,∗,1 a
Department of Nutrition and Dietetics, Harokopio University, Athens, Greece Taub Institute for Research in Alzheimer’s Disease and the Aging Brain, Gertrude H. Sergievsky Center, Department of Neurology, Columbia University, New York, NY, USA c Department of Social Medicine, Psychiatry and Neurology, National and Kapodistrian University of Athens, Greece b
a r t i c l e
i n f o
Article history: Received 1 April 2014 Received in revised form 13 July 2014 Accepted 8 October 2014 Available online 18 October 2014 Keywords: Alzheimer’s disease Mediterranean diet Cognitive decline Nutrition Lifestyle Behaviors
a b s t r a c t Mediterranean diet is a term used to describe the traditional eating habits of people in Crete, South Italy and other Mediterranean countries. It is a predominantly plant-based diet, with olive oil being the main type of added fat. There are many observational studies exploring the potential association between adherence to the Mediterranean diet and cognitive decline. The present review focuses on longitudinal studies with repeated cognitive assessments. It also evaluates evidence on behaviors related to the Mediterranean way of living, that have been shown to be associated with cognition, namely social interaction, participation in leisure activities, including physical activities, and sleep quality. The synergistic association-effect of these lifestyle behaviors, including diet, is unknown. Lifestyle patterns may constitute a new research and public health perspective. © 2014 Elsevier B.V. All rights reserved.
Contents 1.
2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. What lies behind the Mediterranean diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Effects on health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evidence for the effect of the Mediterranean diet on cognition and dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Moving from the Mediterranean diet to a Mediterranean lifestyle: should we look beyond foods when evaluating associations with cognition? References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction 1.1. What lies behind the Mediterranean diet The concept of the Mediterranean diet was originally conceived by Ancel Keys, in the Seven Countries Study (Keys, 1970; Nestle, 1995). However, the core foods of the diet of people living around the Mediterranean basin can be recognized in the BC era: bread, olive oil, and wine were the basis of the Greek and Roman diets and,
∗ Corresponding author E-mail address: [email protected] (N. Scarmeas). 1 Address: National and Kapodistrian University of Athens, Department of Social Medicine, Psychiatry, and Neurology, 72 Vasilisis Sofias Avenue, Athens 11528, Greece. http://dx.doi.org/10.1016/j.arr.2014.10.003 1568-1637/© 2014 Elsevier B.V. All rights reserved.
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thereafter, important within Christian religions. Bread was symbolic of agriculture and human civilization and olive trees were the identity of Mediterranean lands (Ferrari and Rapezzi, 2011). Following Key’s observations that all-cause and coronary heart disease death rates were lower in cohorts with olive oil as the main dietary fat compared to northern European ones (Keys et al., 1986), the notion that the high consumption of olive oil, bread, fruits, vegetables, and cereals may be responsible for profound health benefits was spread in the scientific community (Sofi et al., 2013). Nowadays, the term Mediterranean diet is widely used to describe the traditional dietary habits of people in Crete, South Italy and other Mediterranean countries, and is schematically depicted as a food pyramid (Simopoulos, 2001; Willett et al., 1995). This dietary pattern is characterized by abundance of plant foods: fruits, mainly as the typical after-dinner dessert, vegetables, either as main or side dish, a lot of bread, other forms of cereals, legumes, nuts,
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and seeds. Olive oil is the principal source of fat. Mediterranean diet also includes moderate amounts of dairy products (principally cheese and yogurt), low to moderate amounts of fish and poultry, red meat in low amounts and wine, consumed modestly, normally with meals (Kafatos et al., 2000; Willett et al., 1995). 1.2. Effects on health In numerous epidemiological studies, greater adherence to the Mediterranean diet has been associated, with longevity and with lower prevalence of several chronic diseases. In specific, greater adherence to the Mediterranean diet has been associated with a significant reduction in total mortality, mortality from cardiovascular disease and cancer mortality, both in Mediterranean and non-Mediterranean populations (Lopez-Garcia et al., 2014; Sofi et al., 2010; Trichopoulou et al., 2003). Furthermore, adherence to the Mediterranean diet has been related to lower cancer risk (Couto et al., 2011; Sofi et al., 2010), to primary and secondary prevention of coronary artery disease (including strokes) (Barzi et al., 2003; de Lorgeril et al., 1999; Estruch et al., 2013; Sofi et al., 2010). Prospective studies and randomized trials have provided consistent evidence regarding the favorable association of the adherence to the Mediterranean diet on type 2 diabetes mellitus risk and management (Abiemo et al., 2013; Esposito et al., 2009; Itsiopoulos et al., 2011; Martinez-Gonzalez et al., 2008; Romaguera et al., 2011; Toobert et al., 2003). Recent meta-analysis has linked greater adherence to the Mediterranean diet with reduced risk of the metabolic syndrome and its resolution (Kastorini et al., 2011). Higher adherence to a Mediterranean-style diet was inversely associated with the development of frailty in community-dwelling older adults (Talegawkar et al., 2012) and with the incidence of hip fracture in a prospective European study (Benetou et al., 2013). The more prevailing mechanisms underlying the aforementioned health benefits are the anti-inflammatory and anti-oxidative properties of this diet. In specific, adherence to the Mediterranean diet has been consistently associated with decreased biomarkers of subclinical inflammation (Barbaresko et al., 2013; Estruch, 2010) and increased levels of adiponectin, an insulin sensitizing hormone secreted by adipose tissue, affecting glucose and lipid metabolism and exerting distinct antiatherogenic, antidiabetogenic, and antiinflammatory actions (Fragopoulou et al., 2010). Moreover, the Mediterranean diet has been proposed to protect individuals from oxidative stress, as it has been consistently associated with lower blood levels of oxidative molecules and higher blood antioxidant capacity (Bullo et al., 2011; Zamora-Ros et al., 2013). Much research has been conducted in regards to the potentially beneficial nutrients abundant in the Mediterranean diets, namely monounsaturated fatty acids, a balanced ratio of (n6):(n-3) essential fatty acids, high amounts of fiber, antioxidants, such as vitamins E and C, resveratrol, polyphenols, selenium, glutathione (Simopoulos, 2001). However, the properties of the whole pattern seem to be well beyond the individual effects of nutrients. By investigating and evaluating the Mediterranean diet as a dietary pattern, we take into account nutrients and foods, their interactions, intercorrelations and cumulative effects. Eating is a complex behavior consisting of several individual behaviors, among others, the choice of specific foods or food groups, the organization of food into meals, and the conditions around or preceding eating. Aim of this review is to evaluate existing evidence on the effect of the Mediterranean diet as a pattern on cognitive function and risk of dementia and to explore potential interactions between this dietary pattern and other behaviors, implying the potential synergistic effect of a lifestyle pattern.
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2. Evidence for the effect of the Mediterranean diet on cognition and dementia There are biological mechanisms that may potentially link Mediterranean diet with cognitive decline and disease. Vascular risk factors, such as dyslipidemia, hypertension, and coronary artery disease, together with white matter lesions, have been related to dementia, Alzheimer disease (AD) and mild cognitive impairment (MCI) (Peters, 2009). Nonvascular biological mechanisms, namely metabolic, oxidative, and inflammatory, have been also proposed to be implicated in the pathophysiology of cognitive decline. Among the foods and nutrients abundant in the Mediterranean Diet, olive oil (through monounsaturated fatty acids and tyrosol, caffeic acid and other phenolic compounds), fish (and n-3 polyunsaturated fatty acids), wine (through alcohol, and phenolic compounds like resveratrol) and fruits and vegetables abundant in flavonoids and vitamins like C and E, have been associated with lower inflammatory and oxidative load and have been inversely associated with cardiometbolic risk factors, cognitive decline and dementia (Frisardi et al., 2010). Many observational studies explored the hypothesis on the potential relation between adherence to the Mediterranean diet and AD and/or cognitive decline. Cross-sectional approaches have been useful for initial explorations, but due to methodological limitations, interpretations and conclusions deriving from such are tentative. Hence, in the present review, we briefly examine evidence only from longitudinal observational studies with repeated cognitive assessments, as there is essentially no randomized clinical trial with cognitive primary outcomes, so far (Martinez-Lapiscina et al., 2013; Scarmeas, 2013). In 2006, the potential association between adherence to Mediterranean Diet and cognition was evaluated in a prospective investigation, of 2258 community-based non-demented individuals, aged >65 years in New York. Participants were prospectively evaluated every 1.5 years for an average of 4 years follow-up. One unit increment in the Mediterranean diet score was associated with 9–10% lower risk for development of AD, even after adjustment for potential confounders (Scarmeas et al., 2006). These results were, then, replicated in other US samples (Tangney et al., 2011; Tsivgoulis et al., 2013). A large number of participants (n = 3790) in the Chicago Health and Aging Project were evaluated repeatedly during a mean of 7.6 years: a dietary index based on the traditional Mediterranean diet was associated with slower rates of cognitive decline (Tangney et al., 2011). Interestingly, in contrast to the Mediterranean diet, no association between cognition and the Healthy Eating Index 2005 (recommended by the US department of Agriculture) was noted. In the REGARDS study, a very large (n = 17,478), geographically dispersed cohort, with oversampling of black subjects, after a mean follow-up period of 4 years, high adherence to the Mediterranean diet was associated with lower likelihood of incident cognitive impairment (Tsivgoulis et al., 2013). Interestingly, in a European cohort of 1410 adults from Bordeaux, 65 years or older, Feart et al. (2009) found that adherence to this dietary pattern was associated with slower decline on the Mini Mental State Examination (MMSE) over 5 years of follow-up; no association with the risk for incident dementia was noted but power for detection of such association was quite limited. Other studies, on the other hand, failed to detect an association between a score related to adherence to the Mediterranean diet and prospectively assessed measures of cognitive decline. The two US-based, longitudinal studies in women, the Women’s Health Study and the Nurses’ Health Study, did not detect any association of adherence to the Mediterranean diet with cognitive change (Samieri et al., 2013a,b). In the Mayo Clinic Study of Aging, the reduced risk of mild cognitive impairment or dementia, in subjects in the upper tertile of adherence to the Mediterranean diet at
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baseline, did not reach statistical significance (Roberts et al., 2010). This study was of relatively limited power, as there were only 116 incident cases (93 with MCI and 23 with dementia) over a relatively short follow-up (median = 2.2 years). Negative were also the results by Cherbuin and Anstey, who evaluated 1528 individuals, aged 60–64 years and observed that greater adherence to the Mediterranean Diet was not protective against cognitive impairment, but power was quite limited with only 10 incident MCI cases (Cherbuin and Anstey, 2012). Similarly, in a large sample of communitydwelling women aged ≥65 years with pre-existing vascular disease or at high vascular risk, no associations were observed between Mediterranean-style eating pattern adherence and 5-year cognitive decline (Vercambre et al., 2012). Finally, the SUVIMAX study did not reveal association between midlife adherence to a Mediterranean Diet and cognitive performance assessed 13 y later, when major confounders including lifestyle behaviors, sociodemographic factors, and health events were accounted for Kesse-Guyot et al. (2013). Nevertheless, only a single cognitive assessment was available in this study. Two attempts of combining some of the some of the evidence stated before have been undertaken. The meta-analysis by Psaltopoulou et al. (2013) reviewed not only longitudinal but also all cross-sectional and case control studies, whereas the one by Singh et al. (2014) focused only on the longitudinal studies; both concluded that the Mediterranean diet is protective against mild and advanced cognitive impairment, including AD. Several explanations have been given for the conflicting aspects of this literature. Although diet may share important associations with cognitive health, these associations are complex and could vary across geographic, cultural, or sociodemographic contexts. Mediating factors, gene-environment interactions, or environmental interactions may be present and influence outcomes in different population groups (Coppede et al., 2006). As an example, in one of the studies adherence to Mediterranean diet was associated with lower likelihood of incident impaired cognitive status in nondiabetic individuals but not in diabetic participants, implying that diabetes mellitus may be one of the mediating factors (Tsivgoulis et al., 2013). Methodological issues related to the evaluation of the adherence to a Mediterranean dietary pattern could also partly explain the inconsistent study results, as previously discussed by Feart et al. (2013). The Mediterranean diet score developed by Trichopoulou et al. (2003) is population specific; the same score could reflect different patterns of food consumption in different studies and this issue may be important in relation to cognitive/dementia outcomes. Furthermore, in the indexes used so far, all components (i.e. foods, food groups) contribute equally to the total score, i.e. no different weights are being assigned to each of the score components. We may add to this discussion on the discrepancies between studies that lifestyle, as a whole entity, can potentially be more important than diet per se or it may have a greater, more easily detectable effect in cognitive measures. A lifestyle approach may also cover some of the environmental interplay and interactions. It has been previously evaluated in relation to obesity (Kontogianni et al., 2010; Yannakoulia et al., 2010) and, in the following section we will explore it in relation to cognitive decline.
3. Moving from the Mediterranean diet to a Mediterranean lifestyle: should we look beyond foods when evaluating associations with cognition? In the earlier work by Keys (1970) as well as in the early Mediterranean diet pyramid (Willett et al., 1995), lifestyle behaviors have been underlined as important component of the Mediterranean way of living: apart from physical activity, lifestyle factors that were
extracted as being of particular interest are social support, sharing food, having lengthy meals and post-lunch siestas. They have never, though, been taken into account in studies of the Mediterranean dietary model. There are some fragmentary reports noting that food consumption habits, including meal patterns, structure and commensal rituals, are important issues to consider when trying to maintain or implement the Mediterranean diet (Tessier and Gerber, 2005). Nevertheless, there is no systematic study in relation to health outcomes. The new Mediterranean diet concept developed by the Mediterranean Diet Foundation was launched in 2011. It was again depicted in the form of a pyramid, but, interestingly, it refers more to a lifestyle pattern (Bach-Faig et al., 2011). It includes both quantitative and qualitative elements regarding eating, lifestyle and cultural factors as follows. Moderation in food consumption and frugality are promoted. The preference for seasonal, fresh and minimally processed foods may, in most cases, maximize the content of protective nutrients and molecules in the diet. Consuming traditional, local, eco-friendly and biodiverse products contributes to the sustainable character of the diet. The conviviality aspect of eating is important, as it contributes to strengthening socialization, communication and social support, whereas devoting enough time and space to culinary activities is also stressed. Finally, regular practice of moderate physical activity (at least 30 min throughout the day) and adequate sleep and resting during daytime (naps) serve as basic complements to the dietary pattern. This revised clustering of patterns related to food intake, physical activity and social life has not been evaluated in relation to dementia. However, there is evidence indicating that these individual factors are important to cognitive function and decline; they may inter-correlate or act synergistically. Social interaction, as the participation of a person in group-related activities, such as mealtime conversations, group leisure activities or other forms of social engagement, has been studied in relation to the prevalence, incidence of a dementia or in the context of non-pharmacological treatments, mainly along with physical activity. Socialization has been related to better cognitive performance (Gallucci et al., 2009). There are some longitudinal studies on the association of socialization (in terms of social networks and social engagement) and incident dementia and AD (Bennett et al., 2006; Fratiglioni et al., 2000; Wang et al., 2002). Mealtimes, seen as opportunities for social interactions have been found to maintain and reaffirm individual and group identities in families living with dementia (Genoe et al., 2010; I and Keller, 2014; Keller et al., 2006). It has also been hypothesized that increased social interaction may benefit Alzheimer’s patients by minimizing one’s sense of loneliness, isolation, stress, and, also vascular factors that contribute to cognitive decline. It can also improve patients’ sense of self-worth (Ruthirakuhan et al., 2012). Participation in leisure activities, including physical activities, has been consistently associated with a reduced risk of dementia (Akbaraly et al., 2009; Buchman et al., 2012; Scarmeas et al., 2001, 2009; Verghese et al., 2003). The meta-analysis of Sofi and colleagues showed that subjects who performed physical activity at baseline had a significantly reduced risk of cognitive decline during follow-up (Sofi et al., 2011). When studies were grouped according to the different levels of physical activity, subjects who reported to be more physically active had a 38% reduced risk of cognitive decline compared to those who reported being sedentary. The significant protection against cognitive decline during follow-up was still observed when low-to-moderate levels of physical activity were taken into consideration. Positive were also the results of an earlier meta-analysis of training interventions that examined whether an aerobic fitness intervention can have a robust and beneficial influence on cognition in sedentary older adults: fitness training increased performance 0.5 SD on average, regardless
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of the type of cognitive task, the training methods or participants characteristics (Colcombe and Kramer, 2003). There is also some more recent evidence from randomized controlled trials (Barnes et al., 2013; Lautenschlager et al., 2008). In 126 inactive older adults with cognitive complaints, 12 weeks of physical plus mental activity was associated with significant improvements in global cognitive function but without any evidence of difference between intervention and active control groups (Barnes et al., 2013). A 24-week home-based program of physical activity (approximately participants performed at least 150 min of moderate-intensity physical activity per week, mainly walking) improved cognitive function in older adults with subjective and objective mild cognitive impairment; the benefits were evident after 6 months and persisted for at least another 12 months following the discontinuation of the intervention (Lautenschlager et al., 2008). Sleep parameters are currently under study in relation to cognition. In a prospective cohort of cognitively intact older men and women low sleep quality has been significantly linked with incident cognitive impairment in men, but not in women (Potvin et al., 2012). Non-depressed older men reporting symptoms of insomnia at both baseline and 3 years later, had increased odds of cognitive decline (Cricco et al., 2001). Sleep-disordered breathing (characterized by recurrent arousals from sleep and intermittent hypoxemia) was associated with increased risk for MCI or dementia in a prospective study of 298 older women (Yaffe et al., 2011). Interestingly, napping behavior was negatively associated with incident cognitive impairment in cognitively unimpaired individuals, with those who napped being less likely to become cognitively impaired at 2 and 10 years follow up, whereas short night time sleep duration (≤6.5 h) and daytime sleepiness were associated with increased incident cognitive impairment (Keage et al., 2012). Summarizing, some lifestyle behaviors, beyond diet, have an evidence-based association with cognitive health. Their synergistic association-effect, though, is not well studied. As dietary patterns have been shown to be a promising strategy to investigate the link between food and cognitive decline (Alles et al., 2012), lifestyle patterns may take us a step further. Interactions are the rule rather than the exception in science and combining different aspects of lifestyle is one of the ways to partially address this issue. Of course this approach may result in reductionistic limitations, such as being unable to pinpoint the exact behavior (and possibly the related biological pathway) that could be protective for medical conditions and diseases, but it is interesting from a public health point of view. Regarding the optimal approach of estimating lifestyle patterns, it is obviously a complex topic. One could evaluate different lifestyle aspects and adjust for the presence of others by simultaneously considering them in the same model. However, as different dimensions of behavior are often highly intercorrelated, potential issues of colinearity may arise. Another approach would be to consider different aspects of lifestyle (or even their sub-constituents) independently in sequential models, but type I error inflation and adjustment for multiple comparisons may be necessary. Lifestyle patterns may be derived with use of a priori approaches (similar to Mediterranean diet approach – i.e. by including behaviors that are known to be protective for other health outcomes) or a posteriori approaches (with use of a series of multivariate analyses such as cluster analysis and principal component analysis, using data-driven structure of underlying dimensions) or a priori/a posteriori combinations (i.e. reduced rank regression analysis). Overall, methodological issues regarding derivation of patterns constitute an extensive area of research that goes beyond the scope of this paper. In conclusion, along the lines of the concept of “food synergy” (Jacobs and Tapsell, 2013), we propose a “lifestyle behavior synergy”. The so far individually published work on Mediterranean
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