Cognitive decline, dietary factors and gut–brain interactions

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Mechanisms of Ageing and Development journal homepage: www.elsevier.com/locate/mechagedev

Cognitive decline, dietary factors and gut–brain interactions Barbara Caracciolo a,b,*, Weili Xu a, Stephen Collins c, Laura Fratiglioni a,d a

Aging Research Center, Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet and Stockholm University, Stockholm, Sweden Stress Research Institute, Stockholm University, Stockholm, Sweden c Farncombe Family Digestive Health Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada d Stockholm Gerontology Research Center, Stockholm, Sweden b

A R T I C L E I N F O

A B S T R A C T

Article history: Available online xxx

Cognitive decline in elderly people often derives from the interaction between aging-related changes and age-related diseases and covers a large spectrum of clinical manifestations, from intact cognition through mild cognitive impairment and dementia. Epidemiological evidence supports the hypothesis that modifiable lifestyle-related factors are associated with cognitive decline, opening new avenues for prevention. Diet in particular has become the object of intense research in relation to cognitive aging and neurodegenerative disease. We reviewed the most recent findings in this rapidly expanding field. Some nutrients, such as vitamins and fatty acids, have been studied longer than others, but strong scientific evidence of an association is lacking even for these compounds. Specific dietary patterns, like the Mediterranean diet, may be more beneficial than a high consumption of single nutrients or specific food items. A strong link between vascular risk factors and dementia has been shown, and the association of diet with several vascular and metabolic diseases is well known. Other plausible mechanisms underlying the relationship between diet and cognitive decline, such as inflammation and oxidative stress, have been established. In addition to the traditional etiological pathways, new hypotheses, such as the role of the intestinal microbiome in cognitive function, have been suggested and warrant further investigation. ß 2013 Published by Elsevier Ireland Ltd.

Keywords: Cognitive decline MCI Dementia Diet Gut–brain axis Nutrients Protective factors

1. Introduction Aging affects the brain in several ways, from the cellular to the functional level. Changes associated with age manifest themselves as decline in several abilities, including sensory, motor, and higher cognitive functions (Salthouse, 2009; Schaffer et al., 2012). Specific diseases strongly related to age cause lesions in the brain that exacerbate the physiological changes that occur during normal aging. Cognitive decline is a classic example of this interaction between aging-related changes and age-related diseases in older people. Cognitive decline covers a large spectrum of clinical manifestations, a continuum that ranges from intact cognition through mild cognitive impairment (MCI), and finally, dementia. Dementia is characterized by progressive deterioration in multiple cognitive domains that is severe enough to interfere with daily functioning (APA, 2013). Alzheimer’s disease is the most common cause of dementia in elderly people, accounting for 60– 70% of all dementia cases when traditional diagnostic criteria for

* Corresponding author at: Aging Research Center, Ga¨vlegatan 16, 113 30, Stockholm, Sweden. Tel.: +46 70 3148518. E-mail address: [email protected] (B. Caracciolo).

dementia subtypes are used (Blennow et al., 2006; Fratiglioni et al., 1999). AD is strictly related to a neuropathological diagnosis determined by the presence of neurofibrillary tangles and senile plaques in the brain (Blennow et al., 2006). Vascular dementia (VaD) is the second most common cause of dementia in elderly people. VaD is defined as loss of cognitive function resulting from ischemic, hypoperfusive, or hemorrhagic brain lesions due to cerebrovascular disease or cardiovascular pathology (Roman, 2003). The combination of AD and VaD pathological changes in the brain of older people is extremely common, making mixed dementia probably the most common type of dementia (Langa et al., 2004). The age-specific prevalence of dementia nearly doubles every five years, from approximately 1.5% in persons aged 60–69 years to 40% in nonagenarians. The global prevalence of dementia in people over 60 years is 3.9%. The regional prevalence varies from 1.6% in Africa to 3.9% in Eastern Europe, 4.0% in China, 4.6% in Latin America, 5.4% in Western Europe, and 6.4% in North America. There is a similar pattern in the distribution of dementia subtypes across the world (Qiu et al., 2007). In Europe, the age-adjusted prevalence of dementia of any kind among people 65 years and older is 6.4%; of AD, 4.4%; and of VaD, 1.6% (Lobo et al., 2000; McVeigh and Passmore, 2006). It has been estimated that 36 million people have

0047-6374/$ – see front matter ß 2013 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.mad.2013.11.011

Please cite this article in press as: Caracciolo, B., et al., Cognitive decline, dietary factors and gut–brain interactions. Mech. Ageing Dev. (2013), http://dx.doi.org/10.1016/j.mad.2013.11.011

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dementia worldwide (Wimo and Prince, 2010) and that there are 4.6 million new cases of dementia every year (Ferri et al., 2005). A study from UK reported that later-born populations have a lower risk of prevalent dementia than those born earlier in the past century (Matthews et al., 2013). Dementia incidence does not show great geographical variation in the world. The global annual incidence of dementia is around 7.5 per 1000 person-years. The incidence rate of dementia increases exponentially with age, from approximately one per 1000 person-years in people aged 60–64 years to more than 70 per 1000 person-years in 90+ years (Qiu et al., 2007). A recent study showed that prevalence of dementia was stable from the late 1980s to the early 2000s in central Stockholm, Sweden, whereas survival of patients with dementia increased. These results suggest that incidence of dementia may have decreased during this period (Qiu et al., 2013). Dementia represents an advanced stage of cognitive deterioration and can be regarded as the tip of an iceberg, as milder cognitive syndromes are even more common than dementia among older adults (Caracciolo et al., 2012; Wimo and Prince, 2010). The term mild cognitive impairment (MCI) indicates an intermediate stage of cognitive deterioration in which functional independence is preserved but there is impairment in one or more cognitive areas, as confirmed by neuropsychological investigation (Petersen, 2004). Prevalence estimates of MCI are highly variable, spanning a range between 3% and 42% (Ward et al., 2012), but most studies converge toward a prevalence of around 16.5% among people 60 years or older (Petersen et al., 2009). Incidence rates of MCI also exhibit variation, ranging between 21.5 and 71.3 per 1000 person-years (Caracciolo et al., 2008; Luck et al., 2010; Ward et al., 2012). 2. Diet: a key modifiable risk factor for dementia and predementia syndromes Epidemiological evidence supports the hypothesis that modifiable lifestyle-related factors are associated with cognitive decline, which opens new avenues for prevention (Solfrizzi et al., 2008). Diet in particular has become the object of intense research in relation to cognitive aging and neurodegenerative diseases. In this critical review, we summarize and update the state of the art of this rapidly expanding research field by focusing both on key individual studies and on previous reviews. 2.1. Brain, nutrients, and neuroprotection Nutrients are bioactive molecules that are essential for human health and functioning (Morris, 2012). Most cannot be synthesized internally by human body (not at all, or not in sufficient amount) and need to be obtained from food. The brain is a complex organ with high metabolism and high turnover of nutrients, and this makes it a high-maintenance device in terms of optimal nutrient intake. Indeed, a myriad of nutrient-specific transport systems and physiological mechanisms constantly work to replace the nutrients used by the brain (Morris, 2012). The possible biological effects of dietary nutrients on underlying mechanisms of neuronal and cell aging is discussed below. 2.1.1. Oxidative stress and vitamins Since the brain is an organ with high metabolism rate, oxidative stress is a common phenomenon in its neural tissue (Bishop et al., 2010). Two main types of antioxidant compounds are involved in oxidative stress regulation in the body: antioxidant enzymes, that catalyze neutralizing reactions against free radicals and reactive oxygen species, and antioxidant nutrients, which help as co-factors in catalytic activities (Morris, 2012; Sardesai, 1995). Antioxidant enzymes are

endogenous; however, they need exogenous nutrients for proper functioning (Sardesai, 1995). These exogenous antioxidants include—but are not limited to—vitamin E (tocopherols), vitamin C, carotenoids such as b-carotene (vitamin A), and traceminerals such as manganese, copper, selenium and zinc. 2.1.1.1. ACE vitamins. Epidemiological studies evaluating the association between dietary intake of antioxidants and cognitive decline have reported inconsistent results. The majority of longitudinal studies that focused on vitamin E found an association between higher levels of vitamin E dietary intake and a decrease in the risk of AD (Devore et al., 2010; Engelhart et al., 2002b) and cognitive decline (Morris et al., 2002, 2005b; Wengreen et al., 2007). However, discordant findings have also been reported, and some studies found no effect of vitamin E on dementia/AD and cognitive decline (Corrada et al., 2005; Laurin et al., 2004; Luchsinger et al., 2003). Evidence of a protective effect of vitamins C and A on the development of dementia and cognitive decline has been sparse (Engelhart et al., 2002b; Wengreen et al., 2007), as the majority of the prospective longitudinal studies found no association between vitamin C (Corrada et al., 2005; Devore et al., 2010; Laurin et al., 2004; Luchsinger et al., 2003; Morris et al., 2002) or b-carotene (Corrada et al., 2005; Devore et al., 2010; Engelhart et al., 2002b; Laurin et al., 2004; Luchsinger et al., 2003; Morris et al., 2002) and cognitive change over time. Most randomized controlled trials (RCTs) of antioxidant vitamin supplementation have shown either no association between supplementation and dementia/cognitive decline (Gillette-Guyonnet et al., 2013), or even an harmful effect of high supplement intake (Gillette-Guyonnet et al., 2013). A possible explanation for the failure of RCTs of vitamin E supplementation could be the fact that in such studies high doses of a specific type of vitamin E, i.e. alpha-tocopherol, were administered; while what is generally consumed as food is a mix of different forms of vitamin E (alpha-, beta-, delta- and gamma-tocopherols). In particular, plasma levels of total tocopherols rather than the concentration of specific single tocopherols have been found to predict AD development (Mangialasche et al., 2010). Therefore, studies modeling vitamin E as a single tocopherol may not be as valid as studies considering total tocopherols. What has been shown for vitamin E can also easily translate to vitamins in general, as it has been shown that a combined intake of different dietary antioxidants has higher neuroprotective effects than single antioxidants intake. Indeed some of the few RCT studies that did find an association between cognition and antioxidants supplementation used a complex (up to 34 different elements) antioxidant blend (Kawsar et al., 2010; Stevenson and Hurst, 2007). 2.1.2. Inflammation, polyphenols and unsaturated fats Inflammation plays an important role in the pathogenesis of atherosclerosis, and neuroinflammation is believed to be part of the neurodegenerative cascade that leads to Alzheimer’s pathologies and clinical dementia (Gorelick, 2010). Elevated serum Creactive protein (CRP) in midlife is associated with an increased risk of both AD and VaD, which supports the hypothesis that inflammatory markers are involved in dementia and act through both peripheral and cerebral vascular mechanisms (Gorelick, 2010). Several nutrients have been found to exert an anti-inflammatory action on the brain; among these, polyphenols and unsaturated fatty acids have been widely investigated. 2.1.2.1. Polyphenols. Phenolic compounds are secondary metabolites of plants and include flavonoids, lignans, stilbenes, coumarins, and tannins (Ghosh and Scheepens, 2009). Flavonoids are the most-studied group of polyphenols in relation to brain health.

Please cite this article in press as: Caracciolo, B., et al., Cognitive decline, dietary factors and gut–brain interactions. Mech. Ageing Dev. (2013), http://dx.doi.org/10.1016/j.mad.2013.11.011

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Depending on their biochemical structure, flavonoids are classified into anthocyanins, flavones, isoflavones, flavonols, flavanones, or flavanols. Polyphenols are present in fruits, vegetables, and plant-derived foods and beverages and are particularly abundant in colorful fruits (such as blueberries, grapes, and tomatoes), tea, spices, herbs, and olive oil. Polyphenols seem to act on the brain in several ways. Like antioxidant vitamins, dietary polyphenols can contribute to the regulation of oxidative stress (Stevenson and Hurst, 2007). Recently, attention has focused on the important role of polyphenols, particularly of flavonoids, in regulating vascular health (Cherniack, 2012; Ghosh and Scheepens, 2009; Patel et al., 2008). Anti-inflammatory mechanisms probably mediate part of this action (Cherniack, 2012). The PAQUID Study was one of the first epidemiological studies to suggest that flavonoids play a protective role against cognitive decline and AD (Commenges et al., 2000; Letenneur et al., 2007; Schaffer et al., 2012). More recent findings from the SU.VI.MAX studies confirm earlier results, showing an association between polyphenols intake and better performance in language and verbal memory tasks (Kesse-Guyot et al., 2012). However, other investigations, in particular the Rotterdam study, did not find an overall association with AD and dementia (Devore et al., 2010), although data from the same study showed that flavonoids were associated to reduced risk of AD among current smokers (Engelhart et al., 2002b). More epidemiological research is warranted on this promising class of nutrients. 2.1.2.2. Unsaturated fatty acids. There are two major classes of unsaturated fatty acids: monounsaturated fats (MUFA) and polyunsaturated fats (PUFA). PUFA can also be classified into two groups: the n-6 class (e.g. linoleic acid and arachidonic acid) and the n-3 class [e.g. a-linolenic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)]. PUFAs could be involved in the maintenance of cognitive function and have a preventive effect against dementia through their antithrombotic and anti-inflammatory properties in addition to their specific effect on neural functions (Gillette-Guyonnet et al., 2013). Indeed, DHA is a key component of membrane phospholipids in the brain, and adequate n-3 PUFA status may help maintain neuronal integrity and function. DHA may be directly involved in enhancing neuronal health in the aging brain via a range of potential mechanisms. DHA may modify the expression of genes that regulate a variety of biological functions potentially important for cognitive health, including neurogenesis and neuronal function (Sydenham et al., 2012). Fatty fish is the primary dietary sources of EPA and DHA, the longer-chain n-3 fatty acids. According to several observational studies, high dietary intake of saturated and trans-unsaturated (hydrogenated) fats may increase the risk of cognitive decline and AD (Kalmijn et al., 2004; Morris et al., 2004) but evidence is conflicting (Engelhart et al., 2002a). The potential effects of dietary intake of fish and omega-3 fatty acids on the risk of dementia or cognitive decline are studied as well. Findings are mixed, but most studies have shown the positive effect of higher fish consumption (Barberger-Gateau et al., 2007; Beydoun et al., 2007; Huang et al., 2005; Morris et al., 2005a) even against the accumulation of white matter abnormalities measured in brain MRI (Virtanen et al., 2008). Some studies that investigated the impact of specific omega-3 fatty acids, especially DHA, have found an association between dietary DHA (in the highest tertile measured at baseline) and lower rates of incident dementia (Lopez et al., 2011; Schaefer et al., 2006). In addition, a growing body of evidence suggests that MUFA, and oleic acid in particular, may also have anti-inflammatory effects (Galland, 2010). Recent longitudinal studies support the hypothesis that MUFA may play a protective role toward the

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development of cognitive decline and dementia (Naqvi et al., 2011; Vercambre et al., 2010). In particular, a large RCT study on long term supplementation with extra-virgin olive oil (EVOO)—a good source of MUFA—showed significant improvement in verbal fluency and episodic memory, and reduced incidence of MCI, in the supplemented group as compared to controls (MartinezLapiscina et al., 2013b). However, the interpretation of these findings is not unequivocal, considering that EVOO is not only rich in MUFA but also rich in polyphenols with a proven antinflammatory and antioxidant action, which alone could explain the beneficial impact of EVOO consumption on the brain (Bullo et al., 2011; Cicerale et al., 2012). 2.2. Dietary patterns and cognitive decline Accumulating evidence supports the hypothesis that, rather than single nutrients, what is most beneficial for the brain (as well as for overall health) is a balanced diet with an ideal combination of different vital compounds. Even among the generally unsuccessful RCTs on the effect of antioxidant vitamin supplementation and cognitive decline, trials including supplementation that consisted of an antioxidant blend were proportionally the most successful (Kesse-Guyot et al., 2012; Summers et al., 2010). Indeed, epidemiological studies that focused on consumption of groups of antioxidant-rich foods such as vegetables and fruit were far more successful than studies that focused on single compounds (see Section 2.1.1 on antioxidants). A recent systematic review (Loef and Walach, 2012) identified nine longitudinal studies that investigated the development of MCI/dementia or cognitive decline in relation to fruit and vegetables consumption. Altogether 44,004 participants were followed over time and in eight out of nine of the included studies reported an association of fruit and vegetables (Barberger-Gateau et al., 2007; Hughes et al., 2010; Ritchie et al., 2010) or of vegetables alone (Engelhart et al., 2002b; Kang et al., 2005; Morris et al., 2006a; Sachdev et al., 2013) with the development of MCI/dementia or cognitive decline. Indeed most of the studies found that vegetables, rather than fruit intake, is associated with decreased risk of MCI/dementia or cognitive decline. The authors speculate that the consumption of vegetables is generally coupled with the consumption of condiments (such as vegetable oils, butter and margarine), which are generally rich of vitamin E (Loef and Walach, 2012). However, not all studies agree regarding the beneficial effects of vegetables consumption on cognitive functioning, and one report showed a decline in executive functioning in people in the highest category of vegetable intake (Peneau et al., 2011). It has been suggested that the generally agreed on protective effect of vegetables toward cognitive decline may also be mediated by polyphenolic compounds found in vegetables that have insulin-potentiating effects and may therefore reduce diabetes risk (see following section). Vegetables may also have a neuroregulatory role by inducing satiety and ultimately reducing the risk of obesity (Panickar, 2013), another major risk factor for accelerated cognitive decline and dementia (see the following section on adiposity). Vegetables could also positively influence gut microbiota, which have been found associated to insulin regulation and obesity (Esteve et al., 2011). Specific dietary patterns may be even more beneficial than a high consumption of individual food items. The Mediterranean diet (MeDi) is by far the most studied dietary pattern in relation to the maintenance of brain health (Chao et al., 2013; Matthews et al., 2013; Norton et al., 2013; Wu et al., 2013). The MeDi includes most of the individual nutrients and food items that have been repeatedly associated to reduced rates of cognitive decline and MCI/dementia (see Table 1), such as fruit and vegetables (rich in anti-oxidants and polyphenols), olive oil (rich of unsaturated fatty

Please cite this article in press as: Caracciolo, B., et al., Cognitive decline, dietary factors and gut–brain interactions. Mech. Ageing Dev. (2013), http://dx.doi.org/10.1016/j.mad.2013.11.011

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Table 1 Major nutrition-related factors investigated in relation to cognitive decline, according to classic etiological pathways. Oxidative stress Possible protective effect

Inflammation Possible protective effect

Atherosclerosis Possible risk effect

Nutrients Vitamin E b-Carotene (vitamin A) Vitamin C

Unsaturated fats Polyphenols

Saturated fats Cholesterol Vitamin B12 (deficiency)

Food items Fruit and vegetables Ginkgo biloba Herbs and spices Green tea Cocoa Red wine

Fruit and vegetables Fish Herbs and spices Green tea Cocoa Red wine

Animal fats

Dietary patterns Mediterranean diet

Mediterranean diet

High calorie diets

Polyphenols

acids, vitamin E and polyphenols), and fish (rich in fatty acids and also vitamin B12 and selenium); MeDi is also poor in animal fats (Table 1). Several observational studies have investigated the association between the MeDi and cognitive decline (Feart et al., 2009; Gu et al., 2010; Kesse-Guyot et al., 2013; Psaltopoulou et al., 2008; Roberts et al., 2010; Samieri et al., 2013; Scarmeas et al., 2006; Tangney et al., 2011). In a recent systematic review, higher adherence to Mediterranean diet was associated with better cognitive function, lower rates of cognitive decline, and reduced risk of Alzheimer disease in nine out of 12 eligible studies, whereas results for mild cognitive impairment were inconsistent (Lourida et al., 2013). A large long-term randomized controlled trial (PREDIMED) of individuals at high cardiovascular risk, confirmed previous results from observational studies regarding possible beneficial effects of the MeDi on cognitive functioning (MartinezLapiscina et al., 2013a). Another large randomized controlled trial of dietary patterns and health based on the MeDi approach is ongoing. New dietary strategies addressing the specific needs of the elderly population for healthy aging in Europe (NU-AGE) is an European multicenter study focused on older adults and includes in-depth cognitive assessments (Santoro et al., 2013). 3. Vascular risk factors/diseases Vascular and related factors that have been associated with dementia and cognitive decline include hypertension and elevated blood pressure (Qiu et al., 2005), total cholesterol (Anstey et al., 2008), obesity and diabetes mellitus (Luchsinger and Gustafson, 2009). Since several dietary factors affect the risk of cardiovascular disease, it can be assumed that they may also influence the risk of dementia (Coley et al., 2008; Frisardi et al., 2010; Luchsinger and Gustafson, 2009; Luchsinger and Mayeux, 2004; Luchsinger et al., 2007a). This hypothesis is further supported by recent evidence that certain diets are associated with a lower incidence of AD. 3.1. Hypercholesterolemia An association between midlife elevated serum cholesterol and increased risk of late-life AD is reported in some studies (Alonso et al., 2009; Kivipelto et al., 2002; Whitmer et al., 2005b) but not confirmed by others (Kalmijn et al., 2000; Tan et al., 2003). Conflicting findings are also reported with regard to serum cholesterol in late life. Several cohort studies with relatively short periods of follow-up found no association between late-life total cholesterol level and risk of AD and dementia (Hayden et al., 2006;

Li et al., 2004) and a few investigations even found an association between high total cholesterol and decreased AD risk (Mielke et al., 2005; Reitz et al., 2004; Romas et al., 1999). The importance of the pattern of change in cholesterol levels after midlife was recently highlighted by two studies with long follow-ups. These studies reported that a decline in plasma total cholesterol after midlife may be associated with the risk of cognitive decline, dementia, and AD in late life (Solomon et al., 2009; Stewart et al., 2007). The findings suggest a bidirectional relationship between serum total cholesterol and dementia: high total serum cholesterol in midlife seems to be a risk factor for dementia and AD in advanced age, whereas decreasing serum cholesterol after midlife may reflect ongoing disease processes and represent a marker of early stages in the development of dementia and AD. The relationship between use of statins (cholesterol-lowering drugs) and dementia has been investigated in several community studies, but with mixed findings. Some observational studies suggested a protective effect, whereas others did not, and clinical trials on the use of statins for prevention of cognitive decline or dementia have for the most part reported no effects. 3.2. Adiposity A large body of literature demonstrates that cognitive aging adversely impacts frontal-subcortical brain functioning and promotes declines in abilities such as processing speed and executive functioning (Sellbom and Gunstad, 2012). Evidence indicates that brain changes related to normal aging processes may be exacerbated by obesity. Much current research has suggested that adiposityrelated brain changes are independent of those due to normal aging; however, few studies to date have specifically examined the possible interaction of body composition and age on neurocognitive performance. Substantial evidence links obesity in adulthood with elevated dementia risk in later life. One study found that both overweight and obese adults exhibit up to three times greater risk of Alzheimer’s disease and up to four times greater risk of vascular dementia (Xu et al., 2011). Several other studies have demonstrated similar risks for obesity, even independently of key medical variables that are established as risk factors for dementia, including hypertension, diabetes, cardiovascular disease, stroke, and hyperlipidemia (Hassing et al., 2009; Kivipelto et al., 2005; Whitmer et al., 2005a, 2007). Altered body composition indices are also independently associated with longitudinal decline in the cognitive performance of older adults without dementia (Elias et al., 2003, 2005; Sabia et al., 2009; Wolf et al., 2007). A recent meta-analysis reported that, compared to normal weight, midlife obesity nearly doubles the risk of dementia later in life (Loef and Walach, 2013). Whereas obesity in midlife may confer an increased risk of later dementia, many studies have found an opposite effect in older adults (Atti et al., 2008; Chu et al., 2009; Dahl et al., 2008; Fitzpatrick et al., 2009; Hughes et al., 2009; West and Haan, 2009). Lower BMI has been associated with the development of Alzheimer’s disease (Johnson et al., 2006) and a higher degree of AD pathology (Buchman et al., 2006). Weight loss may result from pre-dementia apathy, reduced olfactory function, difficulty in eating, or inadequate nutrition due to cognitive impairment or incipient dementia. In this context, low BMI and weight loss in advanced age can be interpreted as markers of preclinical dementia. Thus, BMI is not linearly association with dementia and AD (Luchsinger and Mayeux, 2007). As measures of central obesity, particularly waist to hip ratio, seem to be better predictors of cardiovascular outcomes compared to BMI, central obesity has been related to high risk of dementia (Luchsinger et al., 2012; Luchsinger and Mayeux, 2007). In summary, evidence suggests that prevention and management of adiposity in mid-life may provide a means of preventing cognitive decline and dementia.

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3.3. Diabetes mellitus Dietary factors appear to play a relevant role in the development of diabetes and impaired glucose tolerance. The association between diabetes and cognitive changes is now well established (Arvanitakis et al., 2006b; Cheng et al., 2012; Exalto et al., 2012). Over the last decade, many population-based longitudinal studies have found a relationship between diabetes and an increased risk of dementia and VaD, although the results concerning the association of diabetes with the Alzheimer type of dementia are inconsistent. In fact, some prospective studies have shown an association between diabetes and an increased risk of AD, or observed such an association only in specific subgroups while others did not. Since 2000, twenty population-based studies have examined the longitudinal relation between diabetes, prediabetes, and AD. Thirteen studies found that the incidence of AD was approximately 1.4- to 3.0-fold higher in people with diabetes or prediabetes than in those without the conditions (Ahtiluoto et al., 2010; Akomolafe et al., 2006; Arvanitakis et al., 2006a; Becker et al., 2009; Borenstein et al., 2005; Hassing et al., 2002; Hayden et al., 2006; Irie et al., 2008; Kimm et al., 2011; Luchsinger et al., 2005; MacKnight et al., 2002; Muller et al., 2007; Ohara et al., 2011; Peila et al., 2002; Raffaitin et al., 2009; Tyas et al., 2001; Wang et al., 2012; Xu et al., 2007, 2009b). In a recent meta-analysis based on 14 cohorts the aggregate relative risk of AD for people with diabetes was 1.57 (95% CI: 1.41–1.75) based on 14 cohorts (Vagelatos and Eslick, 2013). The risk effect seems to be stronger when diabetes occurs at midlife than in late-life (Xu et al., 2009a). Borderline diabetes (pre-diabetes) or impaired glucose tolerance is also linked to an increased risk of dementia and AD in very old people independently of future development of type 2 diabetes mellitus (Xu et al., 2007). Such an association may reflect the direct effect of hyperglycemia on neurodegenerative changes in the brain or an effect of hyperinsulinemia or diabetes-related comorbidities such as hypertension and dyslipidemia. Other pathophysiological mechanisms through which diabetes could increase the risk of dementia include increased oxidative stress, advanced glycation end-products, and inflammatory cytokines. 3.4. Hypertension In the past decade, longitudinal studies have shown a close association between high blood pressure in middle age, cognitive decline and dementia, including AD, in the late life (Wysocki et al., 2012). A possible relationship between HTN and cognitive impairment has been the focus of increased attention in recent years because lifestyle factors associated with HTN (such as alcohol, tobacco, and sodium consumption, as well as obesity and amount of exercise) are potentially modifiable. Reducing these lifestyle risk factors, in conjunction with early detection and pharmacological treatment of HTN, may reduce the risk or severity of cognitive impairment and rate of decline. Although the amount of research examining the relationship between HTN and cognitive function has increased recently, findings have been inconsistent (Reitz et al., 2007). Several studies have found that a diagnosis of HTN is predictive of late life cognitive impairment. Importantly, this association is not limited to midlife HTN, because late life HTN has also been associated with dementia (Wysocki et al., 2012). Individuals with increased diastolic blood pressure (BP) at age 70 were significantly more likely to develop AD by age 75 (Ballard et al., 2011). The pathophysiological mechanisms underpinning this link have not yet been clearly established although the summation of cerebrovascular and degenerative lesions appears to contribute to early expression of as yet sub-clinical AD reaching the dementia threshold earlier. Longitudinal studies examining the possible benefit of anti-hypertensive treatments on cognitive

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decline have produced promising results. There are only a few randomized, placebo-controlled trials, some of which show positive results (Duron and Hanon, 2008). The results of recent meta-analyses however remain relatively inconclusive because of the heterogeneous nature of the studies which they have included and because of methodological difficulties. In summary, there is convincing evidence to support an association between hypertension, particularly in midlife, and the development of cognitive disorders and dementia, including AD, though once the disease has become apparent a fall in blood pressure may be seen (Duron and Hanon, 2008). 3.5. Serum homocysteine and B vitamins Experimental research suggests that B vitamins (i.e., folic acid, B12, and B6) may protect against cognitive deterioration and dementia (Morris et al., 2006c). However, epidemiologic evidence supporting the association between B vitamins and dementia is still not strong (Fratiglioni et al., 2010; Luchsinger and Mayeux, 2004). Some follow-up studies have suggested an association between low serum vitamin B12 and folate and a high risk of dementia and AD (Maxwell et al., 2002; Wang et al., 2001). However, the beneficial effects of B vitamins supplementation with regard to dementia are yet not supported by follow-up studies (Luchsinger et al., 2007b; Nelson et al., 2009). Furthermore, meta-analyses of RCTs indicate that B vitamins supplementation does not appear to benefit cognitive function in individuals with or without cognitive impairment (Dangour et al., 2010; Ford and Almeida, 2012). It remains unclear whether prolonged treatment with B vitamins can reduce the risk of dementia. Hyperhomocysteinaemia is a risk factor for cardiovascular diseases. Thus, increased serum homocysteine, which may occur as a result of B vitamins deficiency, could contribute to dementia via vascular mechanisms or neurotoxic effects. An association between high serum homocysteine and an increased risk of dementia has been suggested in several cohort studies (Ravaglia et al., 2005; Schafer et al., 2005; Seshadri et al., 2002), but not in others (Luchsinger et al., 2004; Morris et al., 2006b). Meta-analyses support the positive association between high homocysteine and dementia, but the causal relationship is uncertain (Ho et al., 2011; Wald et al., 2011). In addition, high-doses of B vitamins may reduce homocysteine levels and slow AD progression (Aisen et al., 2003). However, a Cochrane review of RCTs showed that supplemental folic acid and vitamin B12 had no positive impacts on cognitive function, although they might be effective in reducing serum homocysteine level (Eussen et al., 2006; Malouf et al., 2003; McMahon et al., 2006). 4. The role of gut health in brain functioning Evidence of a direct link between gastrointestinal function and the brain is increasing. The gastrointestinal tract is sterile in utero but is rapidly colonized at birth, primarily via maternal contact. The number and diversity of bacteria increases throughout early childhood, and it is estimated that by adulthood the colon contains 1012 bacteria per gram of colonic content (Dominguez-Bello et al., 2011). This highly organized and complex ecosystem, known as the intestinal microbiome, plays a critical role in imprinting the mucosal immune system and in maintaining normal gut physiology. It is now evident that the intestinal microbiome influences host function well beyond the gut, and it has been implicated in a variety of diseases, including obesity, diabetes, non-alcoholic fatty liver disease, autism, multiple sclerosis, and cardiovascular disease (de Vos and de Vos, 2012). The notion that the intestinal microbiome influences brain function is based on the longstanding observation that orally administered antibiotics improve the

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decline in cognitive function in patients with hepatic encephalopathy (Riordan and Williams, 1997). Recent work has found that cognitive decline in hepatic encephalopathy is associated with the presence of specific bacteria, although causality has not been established (Bajaj et al., 2012). 4.1. Studies in mice on microbiome–brain interactions The first demonstration of a causal link between the intestinal microbiome and brain function was the identification of an exaggerated hypothalamic-pituitary response to mild restraint stress in germ-free mice and the normalization of this response following intestinal colonization with specific pathogen free (SPF) bacteria (Sudo et al., 2004). This was followed by several studies showing changes in behavioral phenotype and brain chemistry in germ-free mice. Germ-free mice demonstrate a risk-taking or anxiolytic behavioral profile that is corrected by early colonization with SPF bacteria (Diaz Heijtz et al., 2011; Neufeld et al., 2011). Changes in brain chemistry in germ-free mice include a decrease in the Nmethyl-D-aspartate (NMDA) receptor subunit NR2BmRNA expression in amygdala, up-regulation of brain-derived neurotrophic factor (BDNF) and decreased expression of the serotonin receptor 1A (5HT1A) in the hippocampus (Neufeld et al., 2011). Another study demonstrated the same behavioral phenotype in germ-free mice and similar changes in brain chemistry but also showed reduced expression of the synaptic plasticity-related genes PSD-95 and synaptophysin in the striatum (Diaz Heijtz et al., 2011). Together these findings indicate that the presence of commensal bacteria in the gut is critical for normal brain development and raise the possibility that bacteria may influence brain plasticity later in life. Upon completion of the postnatal colonization and expansion of the intestinal microbiome, the microbial composition of the gut remains generally stable under normal conditions, with transient variations induced by diet and antimicrobial drugs (DominguezBello et al., 2011). However, animal studies reveal that a mild shift in the microbial composition of the gut, induced by diet or antimicrobials, is sufficient to cause changes in brain chemistry and function (Bercik et al., 2011; Li et al., 2009). The oral administration of antimicrobials resulted in an increase in BDNF in the hippocampus and a reduction in anxiety like behavior. As these changes were not seen following intra-peritoneal administration of the antimicrobial drugs, the changes in brain chemistry and function were attributed to the shift in the intestinal microbial community. Confirmation of the microbial influence on the brain was obtained by showing that brain chemistry and behavioral phenotype could be adoptively transferred across mouse strains via the intestinal microbiota (Bercik et al., 2011). Dietary change was used to demonstrate the effect of the microbiome on cognitive function. Mice fed a diet consisting of 50% lean ground-beefenriched chow had a significantly more diverse microbiome than mice fed a standard rodent chow and exhibited improved performance in a hole-board open field test (Li et al., 2009). These results indicate that diet-induced changes in the intestinal microbiome improve learning and memory in mice, although the contribution of a direct effect of host protein metabolism on brain function could not be excluded. In another study, mice deficient in interleukin-10 placed on a western-style diet exhibited anxiety-like behavior and impaired memory, and these changes were prevented by treatment with the probiotic bacterium Lactobacillus helveticus (Ohland et al., 2013). A recent study showed that probiotic bacteria improved impaired spatial memory in diabetic rats (Davari et al., 2013). The effects of probiotic bacteria in these studies imply a role for the microbiome–gut–brain axis in the behavioral abnormities seen in these models. Mechanisms underlying microbiome-to-brain signaling include microbial metabolites acting directly or indirectly on the brain; immune

activation; and endocrine and neural pathways, including vagal afferents—for review, see Collins et al. (2012). 4.2. Human studies on microbiome–brain interactions Impaired cognitive function in patients with hepatic encephalopathy is associated with alterations in the intestinal microbiome. Pyrosequencing-based characterization of the intestinal microbiome has revealed altered bacterial composition, endotoxemia, and increases in inflammatory cytokines in people with cirrhosis and cognitive decline compared to people with cirrhosis and normal cognitive function. Specifically, the families Alcaligeneceae and Porphyromonadaceae were positively correlated with cognitive impairment (Bajaj et al., 2012). Strong objective evidence of a linkage between gut bacteria and brain function was recently provided by Tillisch et al., who demonstrated that brain activity and connectivity in healthy women following an emotive task could be attenuated by administering a 4-week course of a fermented milk beverage containing several probiotic bacterial strains (Tillisch et al., 2013). 4.3. The intestinal microbiome in the elderly There is growing interest in the putative role of the intestinal microbiome in the fragility and vulnerabilities associated with the aging process. Several studies have now shown that whereas the microbial composition of the gut changes with age, this is not a linear process. Marked changes appear later than originally expected, and longevity, as reflected by centenarians, appears to be associated with a markedly different microbiome (Biagi et al., 2010; Claesson et al., 2011, 2012). There is agreement that microbial diversity is reduced in elderly people but there is temporal stability. The two dominant phyla in younger age groups, Bacteroides and Firmicutes, remain prominent in older age, but possible changes in the ratio of these phyla are still under debate. There is a trend toward a more prominent presence of potentially pathogenic bacteria (pathobionts) at the expense of beneficial bacteria (symbionts). This is reflected in the increased relative abundance of proteobacteria and a reduction in bifidobacteria species. There is an age-related reduction in short-chain fatty acid production, and the fatty acid butyrate is particularly important in this regard in view of its critical role in the maintenance of colonic epithelial integrity and inflammation. The changes in microbial composition and metabolism are consistent with the concept of inflamm-aging (Franceschi et al., 2000) which implicates chronic low-grade inflammation as a common basis for a broad spectrum of age-related pathologies, including cognitive decline. Whereas most studies have involved healthy elderly populations, a recent study from Ireland segregated subjects into those living in the community and those institutionalized for short or long terms. A reduction in the frequency of genes encoding shortchain fatty acid production was prominent among the institutionalized elderly people, as were increases in circulating proinflammatory cytokines tumor necrosis factor-alpha, interleukins6 and -8, and a C-reactive protein (Claesson et al., 2012). Significant correlations were found between microbiome profiles and indices of frailty and poor health among long-term institutionalized elderly people. Changes in dietary composition and diversity were considered the main drivers of the shifts in microbiome structure and activity seen in this well designed study (Claesson et al., 2012). 4.4. The aging microbiome and declining cognitive function As discussed earlier in this review, inflammation is now considered a prime suspect in promoting cognitive decline, not only in the context of normal aging, but also in neurological disorders and sporadic Alzheimer’s disease (Griffin, 2013).

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Fig. 1. Schematic representation of the putative link between the intestinal microbiome and cognitive decline in the elderly.

A recent study by vom Berg and co-workers showed that the intraperitoneal administration of a neutralizing p40 antibody reduced the amyloid load in the brain in the APPPS 1 murine model of Alzheimer’s disease (Vom Berg et al., 2012). The authors proposed a central role for activated microglia in promoting neuroinflammation in the APPPS1 model, and it is possible that activation of brain microglia is primed by the intestinal microbiome, as has been shown in a murine model of multiple sclerosis, which exhibits a similar neuroinflammatory profile (Berer et al., 2011). These findings, taken in conjunction with the above-described associations between age-related changes in the intestinal microbiome and low-grade inflammation, should prompt carefully controlled studies of the microbiome in humans with declining cognitive function. The recently proposed microbiome–gut–brain axis (Collins et al., 2012) is gaining recognition for its potential role not only in gastrointestinal disorders, but also in diseases of the central nervous system. Ongoing large dietary intervention studies of the elderly population, such as NU-AGE which includes thourough assessments of both cognitive and gut health (Santoro et al., 2013;

Candela et al., 2013), will be able to answer to many of the abovementioned issues. 5. Conclusions Although there is no doubt about the relevance of diet in health and aging, especially in brain aging, many pieces of this complex puzzle are still missing. Research in this field is complicated by several challenging issues, such as: 1. difficulties in reliably assessing dietary intake both from a qualitative and quantitative aspect; 2. long-term exposure, where diet in previous time periods may be more relevant than current dietary intake; 3. non-linear relations between single nutrient components and cognitive decline, and the more likely U-shape associations in which deficiency or excess of nutrients can lead to suboptimal functioning and even death (Morris, 2012); 4. several biological interactions that could lead to synergistic or counteracting effects at different levels; for example, of various dietary components, different forms of a single compounds (such the different forms of vitamin E complex) (Mangialasche et al., 2010), or dietary

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components plus other factors; 5. the extreme variability among individuals in dietary consumption, uptake of individual components, and their availability at the tissue level; and, finally, 6. methodological difficulties in measuring the correct blood markers of dietary components and/or their biological effects. Some specific nutrients, such as vitamins and fatty acids, have been studied for a longer time than others, but even for these compounds consistent scientific evidence of an association with cognitive decline and dementia is still missing. Specific dietary patterns, like the Mediterranean diet, may be more beneficial than a high consumption of individual food items. The MeDi includes in fact most of the individual nutrients and food items that have been repeatedly associated to reduced rates of cognitive decline and of MCI/dementia and there is evidence that a higher adherence to this dietary pattern can be beneficial for cognitive functioning. A strong link between vascular risk factors and dementia has also been shown, and the association of diet with several vascular and metabolic diseases is well known. Further, more recently, plausible underlying biological mechanisms have been established, such as inflammation and oxidative stress. Classic models have attempted to segregate different etiological pathways (Table 1) but it is becoming increasingly obvious that vital compounds, food items, and dietary patterns act on our organism and on its most complex device, the brain, in several ways so that the main etiological pathways through which nutrients affect the brain are interconnected in a complex fashion. In addition to the traditional etiological pathways, new and promising hypotheses, such as the role of the intestinal microbiome in cognitive function (Fig. 1), are being suggested and need to be further investigated. In the near future, the availability of large cohort studies that include assessment of diet and related biological markers in people from middle age onward will give us the opportunity to better clarify the multifaceted relationship between diet and brain aging and to explore the numerous underlying mechanisms and their interconnections. Acknowledgements This study was supported by the European Union’s Seventh Framework Program under grant agreement n8 266486 (‘NU-AGE: New dietary strategies addressing the specific needs of the elderly population for healthy aging in Europe’). The First Author is the leader of the cognitive assessment task force of NU-AGE.

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Please cite this article in press as: Caracciolo, B., et al., Cognitive decline, dietary factors and gut–brain interactions. Mech. Ageing Dev. (2013), http://dx.doi.org/10.1016/j.mad.2013.11.011