Mechanisms of Ageing and Development 136-137 (2014) 59–69

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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
b
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

A R T I C L E I N F O A B S T R A C T

Article history: Cognitive decline in elderly people often derives from the interaction between aging-related changes
Available online 12 December 2013 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
Keywords: that modifiable lifestyle-related factors are associated with cognitive decline, opening new avenues for
Cognitive decline prevention. Diet in particular has become the object of intense research in relation to cognitive aging and
MCI neurodegenerative disease. We reviewed the most recent findings in this rapidly expanding field. Some
Dementia nutrients, such as vitamins and fatty acids, have been studied longer than others, but strong scientific
Diet evidence of an association is lacking even for these compounds. Specific dietary patterns, like the
Gut–brain axis
Mediterranean diet, may be more beneficial than a high consumption of single nutrients or specific food
Nutrients
items. A strong link between vascular risk factors and dementia has been shown, and the association of
Protective factors
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 2014 The Authors. Published by Elsevier Ireland Ltd. Open access under CC BY-NC-ND license.

1. Introduction common cause of dementia in elderly people, accounting for 60–70%

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
* Corresponding author at: Aging Research Center, Gävlegatan 16, 113 30,
Stockholm, Sweden. Tel.: +46 70 3148518.
E-mail address: barbara.caracciolo@ki.se (B. Caracciolo).
of all dementia cases when traditional diagnostic criteria for
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 combina-
tion 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 ß 2014 The Authors. Published by Elsevier Ireland Ltd. Open access under CC BY-NC-ND license.
http://dx.doi.org/10.1016/j.mad.2013.11.011
60 B. Caracciolo et al. / Mechanisms of Ageing and Development 136-137 (2014) 59–69
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 deteriora-
tion 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 modifi-
able 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 nutri-
ents used by the brain (Morris, 2012).
The possible biological effects of dietary nutrients on underly-
ing 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 antioxi-
dant 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 trace-
minerals 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 (Gill-
ette-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 antiox-
idants 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 patholo-
gies and clinical dementia (Gorelick, 2010). Elevated serum C-
reactive 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-inflamma-
tory action on the brain; among these, polyphenols and
unsaturated fatty acids have been widely investigated.
2.1.2.1. Polyphenols. Phenolic compounds are secondary metabo-
lites 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.
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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 contrib-
ute 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-inflam-
matory 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 abnormali-
ties 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
61
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 (Martinez-
Lapiscina 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 antinflamma-
tory 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 com-
pounds 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
62 B. Caracciolo et al. / Mechanisms of Ageing and Development 136-137 (2014) 59–69

Table 1 Li et al., 2004) and a few investigations even found an association

Major nutrition-related factors investigated in relation to cognitive decline,
between high total cholesterol and decreased AD risk (Mielke et al.,
according to classic etiological pathways.
2005; Reitz et al., 2004; Romas et al., 1999). The importance of the
Oxidative stress Inflammation Atherosclerosis pattern of change in cholesterol levels after midlife was recently
Possible protective Possible protective Possible risk effect
highlighted by two studies with long follow-ups. These studies
effect effect
reported that a decline in plasma total cholesterol after midlife
Nutrients may be associated with the risk of cognitive decline, dementia, and
Vitamin E Unsaturated fats Saturated fats
AD in late life (Solomon et al., 2009; Stewart et al., 2007). The
b-Carotene (vitamin A) Polyphenols Cholesterol
Vitamin C Vitamin B12 findings suggest a bidirectional relationship between serum total
(deficiency) cholesterol and dementia: high total serum cholesterol in midlife
Polyphenols seems to be a risk factor for dementia and AD in advanced age,
Food items whereas decreasing serum cholesterol after midlife may reflect
Fruit and vegetables Fruit and vegetables Animal fats ongoing disease processes and represent a marker of early stages in
Ginkgo biloba Fish the development of dementia and AD. The relationship between
Herbs and spices Herbs and spices
use of statins (cholesterol-lowering drugs) and dementia has been
Green tea Green tea
Cocoa Cocoa investigated in several community studies, but with mixed
Red wine Red wine findings. Some observational studies suggested a protective effect,
whereas others did not, and clinical trials on the use of statins for
Dietary patterns
Mediterranean diet Mediterranean diet High calorie diets prevention of cognitive decline or dementia have for the most part
reported no effects.

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 (Martinez-
Lapiscina 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., 2014).
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;
3.2. Adiposity
A large body of literature demonstrates that cognitive aging
adversely impacts frontal-subcortical brain functioning and pro-
motes 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 adiposity-
related 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 hyper-
lipidemia (Hassing et al., 2009; Kivipelto et al., 2005; Whitmer et al.,
2005a, 2007). Altered body composition indices are also indepen-
dently 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 develop-
ment 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
63
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 hyperten-
sion, 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 physiol-
ogy. 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
64 B. Caracciolo et al. / Mechanisms of Ageing and Development 136-137 (2014) 59–69
decline in cognitive function in patients with hepatic encephalop-
athy (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 N-
methyl-D-aspartate (NMDA) receptor subunit NR2BmRNA expres-
sion 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 (Dominguez-
Bello 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-beef-
enriched 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 encepha-
lopathy is associated with alterations in the intestinal microbiome.
Pyrosequencing-based characterization of the intestinal micro-
biome 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 cogni-
tive 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 (patho-
bionts) 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 short-
chain fatty acid production was prominent among the institution-
alized elderly people, as were increases in circulating pro-
inflammatory cytokines tumor necrosis factor-alpha, interleukins-
6 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).
[(Fig._1)TD$IG] B. Caracciolo et al. / Mechanisms of Ageing and Development 136-137 (2014) 59–69
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 pro-
posed 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 assess-
ments of both cognitive and gut health (Santoro et al., 2014;
65
Candela et al., 2014), will be able to answer to many of the above-
mentioned 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 function-
ing and even death (Morris, 2012); 4. several biological interac-
tions 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
66 B. Caracciolo et al. / Mechanisms of Ageing and Development 136-137 (2014) 59–69
components plus other factors; 5. the extreme variability among
individuals in dietary consumption, uptake of individual compo-
nents, 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 inter-
connected 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 inter-
connections.
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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