New Perspectives on Alzheimer’s Disease and Nutrition

Journal of Alzheimer’s Disease 46 (2015) 1111–1127
DOI 10.3233/JAD-150084
IOS Press
1111
Meeting Report
New Perspectives on Alzheimer’s Disease
and Nutrition
Deborah R. Gustafsona,b
, Martha Clare Morrisc
, Nikolaos Scarmeasd,e
, Raj C. Shahf
, John Sijbeng
,
Kristine Yaffeh,∗
and Xiongwei Zhui
aDepartment of Neurology, State University of New York - Downstate Medical Center, Brooklyn,
New York, NY, USA
bSection for Psychiatry and Neurochemistry, Neuropsychiatric Epidemiology Unit,
Sahlgrenska Academy at University of Gothenburg, Institute for Neuroscience and Physiology,
NeuroPsychiatric Epidemiology Unit, Wallinsgatan, Gothenburg, Sweden
cSection on Nutrition and Nutritional Epidemiology, Department of Internal Medicine,
Rush University Medical Center, Chicago, IL, USA
dTaub Institute for Research in Alzheimer’s Disease and the Aging Brain,
the Gertrude H. Sergievsky Center, Department of Neurology, Columbia University, New York, NY, USA
eDepartment of Social Medicine, Psychiatry and Neurology, National and Kapodistrian,
University of Athens, Athens, Greece
fDepartment of Family Medicine and Rush Alzheimer’s Disease Center, Rush University Medical Center,
Chicago, IL, USA
gNutricia Research, Nutricia Advanced Medical Nutrition, Utrecht, Netherlands
hDepartment of Psychiatry and Department of Neurology, University of California San Francisco;
and San Francisco VA Medical Center, San Francisco, CA, USA
iDepartment of Pathology, Case Western Reserve University, Cleveland, OH, USA
Accepted 6 April 2015
Abstract. Accumulating evidence shows nutritional factors inﬂuence the risk of developing Alzheimer’s disease (AD) and its
rate of clinical progression. Dietary and lifestyle guidelines to help adults reduce their risk have been developed. However, the
clinical dementia picture remains complex, and further evidence is required to demonstrate that modifying nutritional status
can protect the brain and prevent, delay, or reduce pathophysiological consequences of AD. Moreover, there is a pressing need
for further research because of the global epidemic of overweight and obesity combined with longer life expectancy of the
general population and generally observed decreases in body weight with aging and AD. A new research approach is needed,
incorporating more sophisticated models to account for complex scenarios inﬂuencing the relationship between nutritional
status and AD. Systematic research should identify and address evidence gaps. Integrating longitudinal epidemiological data
with biomarkers of disease, including brain imaging technology, and randomized controlled interventions may provide greater
∗Correspondence to: Kristine Yaffe, MD, Roy and Marie Scola
Endowed Chair in Psychiatry, Vice Chair for Clinical & Transla-
tional Research, Professor, Department of Psychiatry, Neurology,
and Epidemiology and Biostatistics, University of California, San
Francisco, Chief, Geriatric Psychiatry, San Francisco VAMC, 4150
Clement St, San Francisco, CA 94121, USA. Tel.: +1 415 221
4810 x3985; Fax: +1 415 750 6641; E-mail: kristine.yaffe@
ucsf.edu.
ISSN 1387-2877/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved

1112 D.R. Gustafson et al. / Alzheimer’s Disease and Nutrition
insights into progressive and subtle neurological changes associated with dietary factors in individuals at risk for or living with
AD. In addition, greater understanding of mechanisms involved in nutritional influences on AD risk and progression, such as
oxidative stress and loss of neuronal membrane integrity, will better inform possible interventional strategies. There is consensus
among the authors that nutritional deficits, and even states of excess, are associated with AD, but more work is needed to
determine cause and effect. Appropriately designed diets or nutritional interventions may play a role, but additional research is
needed on their clinical–cognitive effectiveness.
Keywords: Alzheimer’s disease, cognition disorders, diet therapy, neuronal membrane, nutrition
INTRODUCTION
Alzheimer’s disease (AD) has a complex, multi-
factorial pathophysiology involving amyloid plaques,
neurofibrillary tangles, and decreased number of
synapses [1]. A broad range of studies, from preclin-
ical to epidemiological, point to an important role
for diet and nutritional status in AD (reviewed in
[2, 3]). While AD is not the result of a single spe-
cific nutrient deficiency, accumulating evidence shows
that nutritional factors can influence both the risk of
developing AD and subsequently its rate of clinical
progression [2, 4]. As a result, dietary and lifestyle
guidelines have been proposed to help adults reduce
their risk [5]. However, further evidence is required to
demonstrate that modification of an individual’s nutri-
tional status can protect the brain and prevent, delay,
or reduce the pathophysiological consequences of AD
[6]. With this challenge in mind, the authors convened a
roundtable discussion, with support provided by Nutri-
cia, to examine the role of nutrition in AD and to
discuss proposals for raising awareness of nutrition as
an important topic for future research projects in AD.
Indeed, the authors have formed a new Professional
InterestArea(PIA)withintheAlzheimer’sAssociation
Society to Advance Alzheimer’s Research (ISTAART)
to improve the quality of studies in this field. This paper
summarizes the proceedings from the roundtable meet-
ing and includes a synopsis of individual presentations
together with a summary of the roundtable discussion.
OVERWEIGHT, OBESITY, AND THE BODY
WEIGHT LOSS TRAJECTORY IN AD
Deborah Gustafson
Some epidemiological studies show that being over-
weight or obese in midlife, measured as body mass
index (BMI) or central adiposity (waist circumference
or waist-to-hip ratio), may increase the risk of AD
and other dementias decades later, although conflict-
ing results have been reported [7–11]. Studies using
traditional anthropometric cut-points for BMI, waist
circumference, and waist-to-hip ratio have shown that
in adult midlife (reported as approximately mid-30 s to
60 years), being overweight or obese increases the risk
of late-onset dementia [12]. However, after midlife,
these anthropometric measures of body weight and
BMI tend to decrease and subsequently higher levels of
body weight, BMI, and/or overweight and obesity are
associated with a lower risk of dementia. Data suggest
that individuals who are underweight and/or experi-
ence a decrease in BMI in late-life have a higher risk
of dementia than individuals whose BMI is in the nor-
mal range or stable [8, 13]. In addition to increasing
the risks of developing dementia and AD, being over-
weight or obese is associated with cognitive decline,
brain atrophy, white matter changes, and disturbances
of blood-brain barrier integrity [9, 12, 13]. There is
one study of two million people suggesting that under-
weight measured at any time from age 40 years and
older, is a risk factor for dementia [11]. Given the
observed trajectory of BMI over the life course and
in relation to dementia described below, these data are
difficult to interpret.
The association between adiposity and dementia is
complicated by the natural BMI trajectory over an indi-
vidual’s life course [8]. In a longitudinal study among
Swedish women followed over 37 years, BMI trajec-
tories as a function of age differed between women
who did versus those who did not develop demen-
tia. There was a smaller increase in BMI from age 38
to 70 years in women who developed dementia com-
pared with those who did not. After age 70 years, the
BMI slope decreased at a similar rate irrespective of
whether dementia occurred. Furthermore, the associa-
tion between BMI trajectory and risk of dementia was
significantlyinfluencedbythepresenceoftheAPOE␧4
allele (Bäckman, et al, unpublished). The rate of BMI
decline after midlife was greater in individuals with
the APOE␧4 allele compared with those without the
allele. However, the greatest decline was evident in
individuals with the APOE␧4 allele who were diag-
nosed with dementia. Although compelling, it is not

D.R. Gustafson et al. / Alzheimer’s Disease and Nutrition 1113
known whether these data can be extrapolated to other
populations.
Changes in BMI also appear to be associated with
clinical progression of dementia [13]. The effects of
baseline BMI and 1-year body weight change on clin-
ical progression were assessed in 2,268 individuals
with amnestic mild cognitive impairment (MCI) and
1,506 with early-stage AD. In individuals with MCI,
high BMI (≥27.5 kg/m2) was associated with higher
baseline cognitive impairment compared with moder-
ate BMI (20.0 to <27.5 kg/m2). However, high BMI
was associated with slower clinical progression than
moderate BMI. In addition, >4% weight loss in 1 year
showed a borderline association with faster clinical
progression compared with no weight change over
the same period. In AD, high BMI was associated
with higher baseline impairment, although no signifi-
cant differences were observed in clinical progression
by baseline BMI or weight change. In addition to
the aforementioned study, no decrease in BMI among
those with AD was also observed in an observational
cohort study and a clinical study [14]. These find-
ings are in accord with other studies showing that
weight loss is associated with AD risk and faster clin-
ical progression of cognitive decline [15–17]. Of note,
the association between BMI and clinical progression
varied significantly by APOE␧4 status in AD. In indi-
viduals without APOE␧4, high BMI was associated
with a slower rate of clinical progression compared
with a moderate BMI (p = 0.010). Apolipoprotein E,
the gene product of APOE, plays a central role in the
distribution and metabolism of cholesterol and triglyc-
erides, and individuals carrying the APOE␧4 allele
may have higher total and low-density lipoprotein
(LDL) cholesterol [18, 19]. This finding may help to
shine some light on the link between lipid metabolism,
adipose tissue, and risk for dementia.
The mechanistic basis underlying the association
between BMI and AD may be linked to the endocrine
function of adipose tissue, mediated by adipose tissue
hormones and adipokines [12]. Accumulating evi-
dence suggests that adipose tissue may play multiple
roles in the aging brain, including disease processes
leading to dementia-related pathologies [20]. Adipose
tissue produces and releases a variety of proin-
flammatory and anti-inflammatory factors, including
the adipokines leptin, adiponectin, resistin, and vis-
fatin, as well as cytokines and chemokines, such as
tumor necrosis factor-␣, interleukin-6, and monocyte
chemoattractant protein 1 [12, 21]. It is hypothesized
that inflammatory cytokines produced in midlife may
increase the risk of AD [12]. However, the picture is
complex and extensive research is required to deter-
mine the role of adipokines in relation to clinical
dementia outcomes (reviewed in [12]). Ongoing stud-
ies in this context include imaging-based measures
of brain volume, structure, and function in humans
and preclinical models of clinical dementia [12].
Adipokines, leptins, and inflammatory cytokines also
show promise as biomarkers in the development of new
nutritionally based approaches to modify the risk of
developing AD [22].
In summary, apparently conflicting evidence for the
association between adiposity, estimated using anthro-
pometric measures, and risk of AD has not yet been
fully resolved. There is a pressing need for further
research because of the global epidemic of overweight
and obesity combined with longer life expectancy of
the general population. Future research in MCI and
AD needs to embrace the importance of nutritional
factors in the design of studies. Longitudinal studies
with sufficient follow-up are required to understand
how BMI trajectory, and the role of the APOE␧4
and other AD alleles, influence AD risk and pro-
gression in diverse populations. In addition, studies
should include standardized measurements of adipos-
ity beyond anthropometry, and should account for
multiple confounding factors in statistical analyses.
Finally, studies are required to test biological hypothe-
ses proposed to explain the complex epidemiological
phenomena and to differentiate between ‘cause and
effect’ in relation to nutritional status in AD.
IS ALZHEIMER’S A NUTRITIONAL
DISEASE?
Raj C. Shah
The World Health Organization (WHO) broadly
defines a nutritional disease as one ‘caused by an
insufficient intake of food or of certain nutrients, by
an inability of the body to absorb and use nutrients,
or by overconsumption of certain foods’ [23]. While
this broad definition works well for obesity caused by
excess energy intake, anemia caused by insufficient
intake of iron, and impaired sight because of inad-
equate intake of vitamin A, the situation for AD is
far more complex. While a large body of evidence
demonstrates links between nutrition and AD [2],
understanding the true nature of relationships between
AD and multiple nutrients is challenging because of a
multitude of confounding and inter-dependent factors.
First, AD has a long asymptomatic phase that con-
founds understanding the nature of physiologic and

Fig. 1. Schematic illustration of the relationship between disease and nutritional factors. The top panel shows that a disease process may lead
to a nutrient deficiency, a relative insufficiency, for example caused by resistance to the effect of the nutrient, or an overabundance of a nutrient.
Conversely, nutrient levels may influence the disease process. The lower panels illustrate how the relationship between AD and nutritional status
is confounded by many variables, including complex feedback loops, the involvement of multiple inter-related nutrients, and the presence of
comorbid diseases.
nutritional changes that occur before symptoms appear
and AD is clinically diagnosed [24, 25]. Indeed, mod-
eling of biomarker changes over the course of AD
suggests that important pathophysiological changes
during the preclinical phase may account for about
half of the total duration of disease in an individ-
ual [25]. This is an important observation because
measurements of cognitive decline are most imprecise
during the preclinical phase [25]. Second, the relation-
ship between disease and nutrient status is complex
and multi-dimensional, in that AD can influence nutri-
ent status and nutrient status may contribute to AD
pathophysiology. In other words, it is challenging to
discriminate between ‘cause’, i.e., the effect of a spe-
cific nutrient on AD, and ‘effect’, i.e., the effect of
AD on the levels of a specific nutrient. It is, therefore,
difficult to delineate the relationship between disease
and nutritional factors (Fig. 1). The challenge of deter-
mining causality is confounded because patients with
AD often have multiple comorbidities that may influ-
ence or be influenced by nutritional status, and multiple
nutrients may be involved in complex inter-related pro-
cesses (Fig. 1).
Changes in the levels of one particular nutrient can-
not be viewed in isolation because levels of other
nutrients may be altered by compensatory mecha-
nisms. Such complexity means that modeling in AD
needs to discriminate between ‘cause and effect’ and
to quantify nutritional status in terms of ‘deficiency or
insufficiency’. Moreover, deficiency or insufficiency
cannot be seen simply in terms of dietary input because
nutritional status may be influenced by the pathologic
processes, such as synapse loss, that characterize AD
[26, 27].
Standard modeling techniques for determining
causality may be inadequate to describe the role of
nutritional status in the onset and progression of AD.
Classically, the relationship between a disease and
causal factors may be assessed using Bradford Hill cri-
teria [28]. The strength of causal relationships between
AD and nutrient status should be tested using the
criteria of consistency, specificity, temporality, bio-
logic gradient, plausibility, coherence, experiment,
and analogy. However, in the setting of AD, most
studies conducted to date have not systematically col-
lected nutritional data to generate a sufficiently robust
dataset to allow causal relationships to be definitively
described.
Determination of a specific nutritional need,
amenable to intervention with a medical food, may
provide new management options for patients with
AD. According to FDA guidance, a medical food is
intended for the specific dietary management of a
disease or condition for which distinctive nutritional

requirements, based on recognized scientific prin-
ciples, are established by medical evaluation [29].
Following this guidance, is it possible to characterize
AD as a disease with distinctive nutritional require-
ments? Other contributing authors in this manuscript
summarize the growing body of evidence showing that
nutritional factors are important in the risk of develop-
ing AD and the rate of clinical progression. However,
the challenge of characterizing the specific nutritional
requirement remains.
A new approach is required to improve the mod-
els used to determine causality. New models need to
take into account the complex scenarios influencing
the relationship between nutritional status and AD in
the clinical setting. In this regard, it is important that
candidate effects of AD on nutrient requirements are
driven by data from human studies and are clearly
characterized by disease stage. In addition, Mendelian
randomization should be used to integrate genetic
information into traditional epidemiologic methods in
studies looking at the importance of nutritional fac-
tors over time. Such an approach recently has been
used to investigate genetic predisposition to increased
levels of blood lipids and the risk of late-onset AD
[30]. The design of nutritional-based research in AD
could be enriched by conducting neuropathology-wide
association studies looking at brain/plasma levels of
specific nutrients of interest [31]. Finally, systems biol-
ogy and/or efficient modeling approaches are needed
to characterize disease-related perturbations in nutrient
homeostasis.
In conclusion, a systematic plan will help to iden-
tify and address gaps in the evidence needed to state
that AD is associated with nutrient changes. Until such
research efforts are undertaken, significant resources
may be invested in studies with minimal chance for sig-
nificant impact. With current approaches, a significant
finding may be likely due to luck or chance. There-
fore, in the near term, replication studies are required
to confirm such findings before any changes to clinical
practice or health policy guidelines are implemented.
The evidence base guiding health management deci-
sions must be robust.
MEDITERRANEAN-TYPE DIET: DIETARY
PATTERNS AND COGNITIVE FUNCTION
Nikolaos Scarmeas
Unravelling the complexity of nutritional fac-
tors in AD may be facilitated by the systematic
study of dietary patterns. Such an approach could
capturethemultidimensionalityofnutrient-relatedfac-
tors by reducing confounding factors and integrating
complex or subtle interactions between dietary compo-
nents [32]. In addition, studies of dietary patterns may
reduce methodological flaws, such as multiple testing
and co-linearity, and are useful when well-developed
hypotheses for particular dietary elements do not exist.
Studies of the influence of the Mediterranean-type
diet (MeDi) on the risk of AD, MCI, and AD mor-
tality have contributed to our understanding of the
importance of nutritional factors [33–36]. The MeDi
is characterized by high intake of vegetables, legumes,
fruits, and cereals, a high intake of unsaturated fatty
acids, but low intake of saturated fatty acids, a moder-
ately high intake of fish, a low-to-moderate intake of
dairy products, a low intake of meat and poultry, and
a regular but moderate consumption of alcohol. These
studies showed that dietary patterns have a significant
association with risk for AD. Among community-
based individuals without dementia, higher adherence
to a MeDi was associated with a lower risk for AD
(hazard ratio [HR], 0.91; 95% confidence interval
[CI], 0.83–0.98; p = 0.015) [33]. Data also showed that
higher adherence to a MeDi is associated with reduced
risk for developing MCI and with reduced risk for MCI
conversion to AD [34]. Furthermore, it was shown that
higher adherence to a MeDi is associated with lower
mortality in AD [35]. The mean duration of survival
was 6.6 years for patients with AD with the lowest
adherence, 7.9 years for those with middle adherence,
and 10.5 years for those with the highest adherence to
a MeDi.
It is important to consider nutritional status as a
whole in the context of AD [37–40]. When a study
demonstrates an association between a dietary pattern
and a particular health outcome, although important
for public health, it is hard to know which particular
nutrient or food or food group, or any other aspect
of nutrition, is responsible for the noted relation. For
example, statistical analysis showed that in adjusted
models, none of the individual components of a MeDi
was a significant AD predictor, suggesting that the
effect of the whole may be more than its individual
constituents [33].
The validity of the MeDi–cognition relation is
another related issue. Confidence in scientific find-
ings is higher when associations are shown to be
reliable in multiple studies, settings, and populations.
The replicability of the initial findings relating a
MeDi with cognitive performance was addressed in
a meta-analysis of relevant studies that addressed sim-
ilar questions [41]. High adherence to a MeDi was

consistently associated with reduced risk for stroke
(relative risk [RR] 0.71, 95% CI 0.57–0.89), depres-
sion (RR 0.68, 95% CI 0.54–0.86), and cognitive
impairment (RR 0.60, 95% CI 0.43–0.83). Moderate
adherence was similarly associated with reduced risk
for depression and cognitive impairment, whereas the
protective trend for stroke was only marginal [41].
Additionally, a dose-response effect for a MeDi on
outcomes was evident. Based on these findings, the
authors concluded that high adherence to a MeDi,
seems to have beneficial effects on several central ner-
vous system (CNS)-related functions.
Regarding future research, in view of the inherent
limitations of cross-sectional epidemiological stud-
ies, prospective, longitudinal, cohort designs with
adequate follow-up and meticulous data collection
(potentially considered together after appropriate har-
monization and/or in the form of a meta-analytic
approach) would strengthen the current state of knowl-
edge. It is also important to consider other potentially
confounding factors that may influence the effect of
diet on AD. For example, in a study of community-
dwelling elders without dementia, both higher MeDi
adherence and higher physical activity were inde-
pendently associated with reduced risk for AD [42].
Individuals adhering to the diet and participating in
physical activity had a lower risk of AD than those
neither adhering to the diet nor participating in phys-
ical activity (HR 0.65 [95% CI 0.44–0.96]; p = 0.03
for trend). Other such potential confounders should be
considered in future studies.
Despite the apparent advantages of studying dietary
patterns, the limitations of observational studies
remain. Therefore, randomized controlled intervention
studies are clearly needed to investigate experimental
manipulation of dietary exposure. The design of future
studies should also consider using a range of methods
to determine how nutrient and dietary status modifies
different pathologic processes and biological pathways
within the CNS [43]. For example, magnetic resonance
imaging (MRI) was employed successfully to show
that higher adherence to MeDi was associated with
reduced cerebrovascular disease burden, specifically
MRI infarcts [44] and white matter hyperintensities
[43]. Such studies may be useful for strengthening our
biological understanding of the relation between diet
and pathologic processes in the CNS.
Inconclusion,integratinglongitudinalepidemiolog-
ical data with biomarkers of disease, including brain
imaging technology, together with randomized con-
trolled interventions may provide greater insights into
progressiveandsubtleneurologicalchangesassociated
with dietary factors in individuals at risk for AD. This
approach will help to determine the effect of MeDi
and other dietary patterns on the occurrence and course
of AD.
ROLE OF OXIDATIVE STRESS AND
ANTIOXIDANTS IN AD
Xiongwei Zhu
Agreaterunderstandingofthemechanismsinvolved
in nutritional influences on AD risk and progression
will help to better inform possible interventional strate-
gies. This point is clearly illustrated by studies of
oxidative stress and antioxidants in AD, which have
helped to refine how vitamin E is viewed as a potential
therapeutic in this setting [45].
Oxidative stress occurs when the intracellular capac-
ity for removing free radicals is exceeded, leading
to modification of DNA, lipids, polysaccharides, and
proteins, and to changes in redox homeostatic bal-
ance. Oxidative stress is a prominent and early feature
in AD pathology [46]. A study involving individu-
als with Down syndrome showed that oxidative stress
occurs earlier than neurofibrillary abnormalities and
precedes amyloid pathology by decades [47]. The
authors concluded that increased levels of oxidative
damage occur prior to the onset of both tau- and
amyloid-␤ deposition. The same authors also showed
that increased oxidative damage is an early event in
AD that in fact decreases after lesion formation. In
addition, other studies have shown that oxidative stress
mediates amyloid-␤ production: both amyloid-␤ pro-
tein precursor and amyloid-␤ increased by 3-4-fold
after an oxidative insult [48, 49]. Oxidative stress also
causes increased tau phosphorylation, facilitates the
conformational conversion and assembly of tau fibrils,
and impairs the proteasomal and lysosomal activity
that may lead to progressive accumulation of protein
deposits. Indeed it has been proposed that oxidative
stress, rather than amyloid-␤ or tau, precipitates the
pathogenesis of AD, especially the most abundant spo-
radic forms [50, 51].
Interestingly, many of the pathogenic factors such
as oxidative damage, mitochondrial dysfunction, and
accumulationofamyloid-␤arefoundatsynaptictermi-
nals in AD brain and models, and are associated with
synaptic dysfunction [49]. This is important because
synaptic damage is a critical factor in cognitive decline
during aging and progression of AD [49]. Studies
have shown levels of presynaptic and postsynaptic pro-
teins are decreased in patients with AD compared with

Fig. 2. Schematic showing prevention or amelioration of oxidative
stress as potential therapeutic targets in AD.
age-matched controls and that brain regions known to
be affected in AD suffer the greatest loss of synapses
and synaptic proteins [49].
There is good evidence linking oxidative stress with
synaptic dysfunction and loss [49, 52, 53]. For exam-
ple, a mouse model of AD showed loss of postsynaptic
proteins was associated with increased oxidation [53].
This effect may involve loss of the omega-3 fatty acid
docosahexaenoic acid (DHA), which is highly vulner-
able to oxidative damage [53]. Extrapolation of these
findings suggests that dietary deficiency of DHA may
be a relevant and modifiable risk factor in AD [53].
Studies using human postmortem frontal cortex from
individuals with MCI or AD have also shown a correla-
tion between markers of oxidative stress and a decline
in Mini-Mental Status Examination scores, suggesting
a role for oxidative stress in AD-related synaptic loss
[52]. Of note, oxidative stress was more localized to the
synapses. Levels of endogenous antioxidants appear to
decline to levels that are insufficient to neutralize rising
antioxidant levels. These findings suggest increasing
brain levels of antioxidants may be helpful in slow-
ing or preventing synaptic damage caused by oxidative
stress (Fig. 2).
Evidence supporting a key role for oxidative stress
in AD pathology has provided a compelling rationale
to investigate the therapeutic potential of antioxi-
dants, including Gingko biloba, vitamin E, estrogen,
lipoic acid, non-steroidal anti-inflammatory drugs,
tenilsetam, acetyl-L-carnitine, and selegilene, for the
protection of neuronal membranes and maintenance of
metabolic control. Antioxidant therapy is purported to
reduce amyloid-␤ and tau protein and their deposits,
and synaptic changes by limiting oxidative stress-
related damage, but at present evidence for clinical
benefit is limited [54, 55]. Among these antioxidants,
vitamin E is perhaps the most extensively studied.
Vitamin E is a term to describe eight, fat-soluble
derivatives of tocopherol and tocotrienol. Of these,
alpha-tocopherol is most commonly used in supple-
ment form and the only form used in trials of patients
with AD or MCI. However, a systematic review found
noconvincingevidencethatalpha-tocopherolisofben-
efit in the treatment of AD or MCI [56], although
none of the completed trials targeted individuals with
marginal vitamin E status, who may be the population
most likely to benefit from vitamin E supplementa-
tion. It should be emphasized that the oxidative stress
hypothesis in the pathogenesis of AD is far from
being extensively tested and further studies are still
urgently needed to determine how and where antiox-
idants should be used in the prevention and treatment
of AD. Furthermore, genome-wide association stud-
ies point to the need to consider multiple aspects of
AD pathology in the design of future research [57]. Of
note, genetic variation in the clusterin (apolipoprotein
J) gene appears to be associated with the pathogene-
sis of AD via various pathways, including amyloid-␤
aggregation and clearance, lipid metabolism, and neu-
roinflammation [58]. Such findings may provide new
opportunities for therapeutic and nutritional interven-
tions in AD.
In conclusion, oxidative stress contributes to loss of
neuronalintegrityinAD.Dietarynutrientswithantiox-
idant properties may have positive effects in AD and
thoseatriskforADbyreducingoxidativestress,partic-
ularly when used in combination. The preventive and
therapeutic potential of antioxidants in AD remains to
be fully defined.
NUTRITIONAL NEEDS FOR
MAINTAINING MEMBRANE INTEGRITY,
INCLUDING NEW DIETARY APPROACHES
Martha Clare Morris
In the CNS, phospholipid bilayers integrate with
lipids (e.g., choline) and proteins to form neuronal
membranes [59]. Neuronal functioning is profoundly
affected by degeneration and changes affecting the
dynamic neuronal membrane structure [59–61]. Pre-
clinical experiments have provided evidence to show
that lowering the availability of key nutrients can have
an adverse effect on neuronal structure and function;
for example, synaptic proteins involved in learning
and memory are down-regulated in the DHA-deficient
mouse brain [62] and neurite growth and synapto-
genesis in cultured hippocampal neurons are inhibited

Table 1
Evidence for the role of specific nutrients required to maintain a healthy brain
Nutrient Food sources
Strong evidence Dietary tocopherols – low deleterious Nuts, oils, seeds, green leafy vegetables,
whole grains
DHA – low deleterious Fish
Folate – low deleterious Vegetables, whole grains
Saturated fat – high deleterious
Unsaturated fat – high beneficial
Commercial products, baked goods, red
meats, high fat dairy
Moderate/limited evidence Carotenoids (␤-carotene, lutein,
lycopene)
Green leafy vegetables, bright-colored fruit,
vegetables
Flavonoids Berries
Vitamin D Fish, dairy
Trans fat Commercial products, baked goods
Monosaturated fat Olive oil
Polyphenols Olive oil, red wine, teas, vegetables, fruit
by prenatal depletion of DHA [63]. Moreover, many
studies in humans have shown that brain structure and
function are influenced by nutrients obtained from the
diet [64, 65]. It follows therefore, that the CNS requires
specific nutrients to maintain neuronal integrity and
to support everyday brain functions, including cogni-
tion [61].
Table 1 summarizes the strength of evidence for
the role of specific nutrients in brain functions. The
level of evidence is strong for dietary tocopherols,
where a low intake has been shown to be deleteri-
ous for brain health, DHA (low intake is deleterious),
folate (low intake is deleterious), and fatty acids (a
high intake of saturated fatty acids is deleterious,
whereas, a high intake of unsaturated fatty acids is
beneficial) [66]. A healthy diet is therefore one of
the key principles recommended for AD prevention
[5]. In addition, epidemiological data have shown
an association between adherence to certain healthy
dietary patterns, for example the MeDi or Dietary
Approaches to Stop Hypertension (DASH) diets, and
slower cognitive decline and lower risk of develop-
ing dementia, including AD [33, 67–69]. However,
although a growing number of epidemiological studies
indicate nutrition is related to the development of AD
[70], dietary recommended daily amounts (RDAs) are
not optimized to meet the specific nutritional require-
ments of the brain [71, 72]. The optimal nutrient level
for brain functioning and prevention of neurodegener-
ation may be very different from the level required to
avoid deficiency.
SeveralnutrientsareofspecialinterestinAD,partic-
ularly those required for the maintenance of neuronal
integrity, including antioxidants and fatty acids. As
discussed by Xiongwei Zhu in this article, antiox-
idants, specifically tocopherols, may reduce plaque
formation, neurofibrillary tangles, and synapse loss.
Although there are extensive preclinical data providing
a scientific basis for antioxidant strategies to prevent
AD, epidemiological studies have generated conflict-
ing results. For example, studies have shown that food
sources of tocopherols are protective, whereas vitamin
E supplements (␣-tocopherol) are not [31, 56]. Dif-
ferences in the biological effects between tocopherols
(␣, ␤, ␥, and δ) may explain this discrepancy [31,
73]. Understanding the differences between different
forms of vitamin E may inform future studies in AD
prevention [73–75]. The most common supplemental
form of vitamin E is ␣-tocopherol, which is a potent
antioxidant within cell membranes [73]; however, ␥-
tocopherol, the major form of tocopherol provided by
North American diets, has been shown to have anti-
amyloidogenic, anti-inflammatory, and anti-nitrative
capacities [31, 76]. At least in the preclinical setting,
␣- and ␥-tocopherols work synergistically [77, 78],
so it is important that future randomized trials should
consider the contribution of ␥-tocopherol [31]. Fur-
thermore, for dietary management, vitamin E should
be obtained from foods, rather than taken as separate
supplements [5].
Changes in the composition and levels of fatty acids
also have important implications on neuronal integrity
during aging and the development of AD [79–81].
Polyunsaturated fatty acids (PUFAs), such as DHA, are
essential to support neuronal integrity and brain func-
tion [79]; however, studies have shown that increasing
age is associated with a progressive decline in PUFA
composition, including DHA and arachidonic acid
[80]. Preclinical studies have shown that dietary DHA
increases brain levels of DHA, leading to beneficial
changes in cerebral functions relevant to the patho-
physiology of AD [82–89], including hippocampal
nerve growth, improved fluidity of synaptic mem-
branes, induction of antioxidant enzymes, increased

transcription of transthyretin (an amyloid protein scav-
enger), and greater cerebral blood volume. In addition,
these studies showed that increasing levels of DHA in
the brain leads to decreased oxidation of lipid mem-
branes, less ischemic damage to neurons, decreased
inflammation, lower amyloid burden, reduced synaptic
loss, and mitigation of impaired learning.
The central role of lipids in maintaining neuronal
integrity has clear implications for dietary manage-
ment for AD prevention and management. A high
ratio of saturated/unsaturated fatty acids in the diet
leads to an increase in LDL and a decrease in
high-density lipoprotein cholesterol; this change may
significantly alter the risk of developing AD [70,
79]. Preclinical studies have shown that diets high
in saturated fat/cholesterol level are associated with
impaired memory, amyloid-␤ deposition and plaque
formation, neuroinflammation, neurotoxicity, and an
increase in brain lesions [90–96]. Furthermore, choles-
terol appears to play a central role in AD, and of
particular interest, the most important genetic risk
factor for AD is the APOE␧4 allele, which is prin-
cipally responsible for regulating cholesterol transport
in the brain [70]. Healthy diet regimes, such as DASH
(developed to reduce blood pressure) and the MeDi (a
culturally-based diet), recommend low intake of satu-
rated fats and a high intake of PUFAs [97].
In summary, accumulating evidence suggests that
diet and nutrition status influence neuronal membrane
integrity and risk for AD. Maintaining a healthy diet,
designed to support neuronal membrane integrity, may
reduce the risk of developing AD [5].
NUTRIENT LEVELS IN AD
John Sijben
Two major factors are thought to contribute to a
specific nutritional need in patients with early AD:
increased loss of synapses and a lower nutritional
status. Synapse loss is an early feature in the pro-
gression of AD [26, 98–105] and is associated with
significant functional deficits [106, 107]. Furthermore,
loss of neuronal structure is associated with phospho-
lipid changes in the brain and functional deterioration
[108]. The neuronal membrane is the principal site of
action for many neuronal activities. The biochemical
and biophysical properties of the neuronal membrane
are important determinants of proper neuronal func-
tion, but can be subject to alterations induced by
nutritional compounds [61].
The formation of new neuronal membranes and the
maintenance of membrane composition and structure
are highly dynamic processes that occur continuously
throughout life [109]. These processes rely upon a sus-
tained supply of neuronal membrane precursors and
cofactors, largely provided by the diet. It has been
known for many years that neuronal membrane syn-
thesis is controlled by the availability of rate-limiting
dietary precursors [27, 61, 110]. Preclinical exper-
iments have shown that a combination of specific
dietary precursors and cofactors increase the forma-
tion of neuronal membrane structures [86, 111, 112].
Conversely, lowering the availability of key nutrients
can have an adverse effect on neuronal structure and
function [53, 62, 63, 113].
Patients with AD have lower levels of specific
nutrients required to support the formation of phos-
pholipids and maintain neuronal membrane integrity
[114], which is highlighted by systematic reviews and a
meta-analysis comparing plasma levels of micronutri-
ents and fatty acids in patients with AD and cognitively
intact elderly controls [114–116]. The analyses clearly
demonstrated that levels of circulating folate and vita-
mins (A, B12, C, D, and E), PUFAs (DHA and
eicosapentaenoic acid) and selenium, are significantly
lower in patients with AD than in controls (Fig. 3).
Additional analysis showed that lower nutrient status
in AD is independent of nourishment status [114].
Other studies found lower plasma uridine levels in
patients with AD compared with controls [117–120].
This is a particularly relevant finding in this context
because circulating uridine is the source of brain cyti-
dine triphosphate, which plays an important role in
phospholipid synthesis [27]. While infants obtain uri-
dine from breast or formula milk, adults rely on hepatic
synthesis because dietary uridine provided by RNA
is not readily bioavailable. Circulating uridine crosses
the blood-brain barrier and after entering brain cells it
is phosphorylated, initially to uridine monophosphate,
and retained. Extensive research has shown that uridine
administered with other nutrients (DHA and choline)
enhances the formation and function of synaptic struc-
tures, providing a scientific rationale for nutritional
support for patients with AD (reviewed in [27] and
[121]).
The lower plasma nutrient levels indicate that
patients with AD have impaired systemic availabil-
ity of several nutrients. Consequently, lower systemic
availability of nutrients may reduce levels in the brain.
This appears to be supported by evidence from studies
that have shown reduced availability of nutrients in the
cerebrospinal fluid (CSF) of patients with AD [122].

Fig. 3. Data from a systematic review and meta-analysis comparing plasma levels of micronutrients and fatty acids in AD patients with those
in cognitively intact elderly controls [114–120].
Specifically, the systematic review and meta-analysis
showed lower brain levels of DHA and choline, and
lower CSF levels of folate and vitamin C [123].
Another study reported lower levels of uridine in the
CSF [122]. It has also been shown that lipid-bound
choline homeostasis is shifted toward catabolism in
AD, suggesting a compensatory mechanism triggered
by lower availability of choline [124–127]. This issue
is further compounded because brain uptake of choline
decreases with aging [128]. Overall, lower availability
of these specific nutrients reduces the capacity to form
neuronal membranes and synapses (Fig. 4).
There are several reasons for lower nutrient status
in patients with AD compared with controls. Dietary
intake of nutrients may be affected by worsening of
appetite, taste, and smell, which lead to reduced food
consumption, food neglect, changes in food prefer-
ences, and poor food choice [129–131]. Low nutrient
levels in patients with AD are not only attributable to
changes in dietary intake, and it is now recognized that
metabolic changes also contribute to a worsening nutri-
entstatus.ThismeansthatasADprogresses,apatient’s
abilitytometabolizeorsynthesizekeynutrientsmaybe
diminished, for example, by having a reduced ability to
convert ␣-linolenic acid to DHA [132]. Furthermore,
lower dietary intake of B vitamins (folate, vitamin B12,
and vitamin B6) may lead to high levels of homo-
cysteine in patients with AD [133], which in turn,
reduces the methylation capacity of many methyltrans-
ferases, resulting in lower availability of DHA and
choline synthesized via the phosphatidylethanolamine
N-methyltransferase pathway [61]. Another potential
reason for low nutrient levels in patients with AD is
impaired absorption and uptake of key nutrients [3].
For example, aging is associated with less efficient
absorption of vitamin B12 because of reduced acidity
in the stomach [134–136], and, in AD, tissue availabil-
ity is further reduced because a lower percentage of
B12 is present in the active holotranscobalamin form
[137, 138]. This means that even if dietary intake is
adequate, the availability of nutrients where they are
required, i.e., the brain, may be insufficient at a time
when nutrient requirement is increased because of neu-
ronal membrane degradation [3].
Accumulating evidence suggests there is a specific
nutritional need in AD [3]. Souvenaid®, a dietary
food for special medical purposes, was developed to
address this need based on years of research [61].
Preclinical studies have shown that increasing the sup-
ply of a specific combination of nutrients supports
the formation and function of neuronal membranes
and improves measures of cognitive performance [61].
Souvenaid provides nutritional precursors and cofac-
tors (DHA 1200 mg, eicosapentaenoic acid 300 mg,
uridine monophosphate 625 mg, choline 400 mg, folic
acid 400 mcg, vitamin B6 1 mg, vitamin B12 3
mcg, vitamin C 80 mg, vitamin E 40 mg, selenium
60 mcg, and phospholipids 106 mg), at levels that
cannot be achieved by diet alone [61]. Clinical stud-
ies have shown that Souvenaid preserves functional

Fig. 4. Schematic model to show lower availability of nutrients required for membrane and synapse formation in AD.
connectivity and improves memory performance in
patients with early AD [139–141]. Furthermore, Sou-
venaid significantly increases blood levels of nutrients
and phospholipids [140–141; (Rijpma et al, unpub-
lished)]. Interestingly, plasma phospholipids have been
shown to be biomarkers for diagnosis of preclini-
cal AD [142] and most of the phosphatidylcholine
species reported by Mapstone and colleagues in
this context are significantly increased by Souvenaid
[143]. Souvenaid is now being studied in the set-
ting of prodromal AD [144] in the LipiDiDiet
trial [145]. The primary endpoint of the study is
cognitive performance during 24 months of inter-
vention and progression to dementia is a secondary
endpoint.
In summary, data suggest that patients with AD
have distinctive nutritional requirements that may be
addressed by specific dietary management. It is also
apparent that the nutrient requirement cannot easily
be met with diet alone and, therefore, there is a clear
rationale for a specific combination of nutrients that
may be offered as a medical food.
CONCLUSIONS AND VIEWPOINT
Converging lines of scientific, clinical, and epi-
demiological evidence indicate an association between
dietary/nutritional factors and AD. In this proceedings
article, we have discussed several topics that demon-
strate the importance of nutrition in AD and highlight

the need for additional systematic research in this area.
In addition, we have emphasized the complexity of
the task in hand, which is confounded by a multi-
plicity of dynamic and inter-related factors interacting
over a long period of time. At a macroscopic level,
long-term, longitudinal data have demonstrated a rela-
tionship between BMI trajectory and AD risk [10].
Along the same line of evidence, there is an emerging
link between adiposity, metabolic syndromes, and risk
ofdementia[12,20].Theevidencebaseisstrengthened
by epidemiological data showing the impact of partic-
ular dietary patterns and risk of AD. The archetypical
example is adherence to the MeDi, which is associated
withlowerriskforMCIandAD[33].Detailedanalyses
of these data lead to the conclusion that the potentially
beneficial effect of the MeDi could be attributable to a
combination of nutrients, rather than a single one. It is
interesting to note that the levels of nutrients in the cir-
culation and brain are lower in patients with AD than
in age-matched controls [114]. Specifically, new data
have shown that patients with AD have lower levels of
the specific nutrients required to support the formation
of phospholipids and to maintain neuronal integrity.
Furthermore, preclinical models of AD have shown
there is an increased requirement for specific nutrients
to counter synapse loss, however, nutrient availability
in the circulation and brain may be inadequate to meet
this need [3, 61].
Research into possible links between nutritional fac-
tors and risk of AD has been accompanied by the
development of interventional strategies ranging from
single-agent supplements to dietary regimes specif-
ically developed for individuals at risk from AD.
Studies of single-agent nutritional supplements have
produced largely equivocal results and the consensus
is that overall nutritional status should be improved
by providing a combination of specific nutrients [5].
Providing single high-dose nutrient supplements, e.g.,
vitamin E in nutritionally replete individuals, appears
not to be effective and rationally designed combina-
tions of nutrients or use in individuals with marginal
nutritional status may achieve better outcomes. Based
on the available evidence, there appears to be a clini-
cal need to ensure that nutritional intake is optimized
to reduce the risks of AD onset and progression
[5]. Both dietary quality (e.g., a MeDi providing the
right combination of nutrients) and bodyweight tra-
jectory are important considerations in the context of
AD risk and progression. Although RDAs for nutri-
ents are not appropriate as guidance for the specific
needs of the brain, dietary intake is an important
variable.
Overall, it can be concluded that there is a need for
more information on the causes of nutritional changes
in individuals at risk of progression to AD before
clinical symptoms become apparent. It is important,
therefore, that nutritional markers and dietary intake
should be measured in future studies. There is con-
sensus among the authors that nutritional deficits are
associated with AD, but more work is needed to deter-
mine cause and effect. Appropriately designed diets or
nutritional interventions, such as Souvenaid, may have
a role to play to address the specific nutritional need
before or after the clinical onset of AD, but more work
is needed on various aspects of their clinical–cognitive
effectiveness. As a result of this roundtable discussion,
a new PIA on nutrition in dementia was formed within
the ISTAART. The objectives of this initiative include:
to develop and advance clinical and research applica-
tions of nutrition in AD and related disorders; to create
and promote dedicated research sessions on the topic
at scientific conferences; to foster development of con-
sensus criteria for nutrition research and interpretation
of relevant findings; and to facilitate the creation of
multi-study collaborations.
ACKNOWLEDGMENTS
The authors received the following support: Deb-
orah R. Gustafson: Swedish Research Council
for Health, Working Life and Welfare (AGECAP
2013-2300) and EU 7th framework LipiDiDiet
project (FP7/2007-2015) under grant agreement no.
211696; Nikolaos Scarmeas: 189 10276/8/9/2011
from the ESPA-EU program Excellence Grant
(ARISTEIA) which is co-funded by the European
Social Fund and Greek National resources; and
Y2␤/oικ.51657/14.4.2009 from the Ministry for
Health and Social Solidarity (Greece); Raj C Shah:
The Illinois Department of Public Health; Morris MC:
National Institute on Aging and National Institute on
Environmental Health Sciences.
Authors’ disclosures available online (http://j-
alz.com/manuscript-disclosures/15-0084r1).
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