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Nutrient intake and brain biomarkers of Alzheimer's disease in at-risk cognitively normal individuals: A cross-sectional neuroimaging pilot study

Authors:

Abstract

Objective There is increasing evidence to suggest that diet, one of the most important modifiable environmental factors, may play a role in preventing or delaying cognitive decline and Alzheimer's disease (AD). This study examines the relationship between dietary nutrients and brain biomarkers of AD in cognitively normal individuals (NL) with and without AD risk factors. Design As part of an ongoing brain imaging study, participants received clinical and laboratory examinations, a neurocognitive test battery, positron emission tomography (PET) with 11C-Pittsburgh Compound-B (PiB; a measure of amyloid-β (Aβ) load) and 18F-fluorodeoxyglucose (FDG; a proxy of neuronal activity), and completed semiquantitative food frequency questionnaires. Setting Research centre affiliated with the Alzheimer's disease Core Center at New York University School of Medicine. Participants 49 NL individuals (age 25–72 years, 69% women) with dietary information, 11C-PiB and 18F-FDG PET scans were examined. Results Controlling for age and total caloric intake, higher intake of vitamin B12, vitamin D and ω-3 polyunsaturated fatty acid (PUFA) was associated with lower Aβ load in AD regions on PiB-PET, while higher intake of β-carotene and folate was associated with higher glucose metabolism on FDG-PET. β-carotene and folate were associated with reduced glucose metabolism for women, apolipoprotein E epsilon 4 (APOE4) carriers and participants with positive AD family history, but not for their risk-free counterparts. The associations of vitamin B12, vitamin D and ω-3 PUFA with PiB retention were independent of gender, APOE and family history. The identified nutrient combination was associated with higher intake of vegetables, fruit, whole grains, fish and legumes, and lower intake of high-fat dairies, meat and sweets. Conclusions Our data provide a potential pathophysiological mechanism for epidemiological findings showing that dietary interventions may play a role in the prevention of AD. Longitudinal studies are needed to determine whether there is a direct link between nutrient intake, brain biomarkers and risk of AD.
Nutrient intake and brain biomarkers
of Alzheimers disease in at-risk
cognitively normal individuals:
a cross-sectional neuroimaging
pilot study
Lisa Mosconi,
1
John Murray,
1
Michelle Davies,
1
Schantel Williams,
1
Elizabeth Pirraglia,
1
Nicole Spector,
1
Wai H Tsui,
1
Yi Li,
1
Tracy Butler,
1
Ricardo S Osorio,
1
Lidia Glodzik,
1
Shankar Vallabhajosula,
2
Pauline McHugh,
1
Charles R Marmar,
1,3
Mony J de Leon
1
To cite: Mosconi L, Murray J,
Davies M, et al. Nutrient
intake and brain biomarkers
of Alzheimers disease in at-
risk cognitively normal
individuals:
a cross-sectional
neuroimaging pilot study.
BMJ Open 2014;4:e004850.
doi:10.1136/bmjopen-2014-
004850
Prepublication history and
additional material is available
online. To view please visit
the journal (http://dx.doi.org/
10.1136/bmjopen-2014-
004850).
Received 14 January 2014
Revised 7 May 2014
Accepted 9 May 2014
For numbered affiliations see
end of article.
Correspondence to
Dr Lisa Mosconi;
lisa.mosconi@nyumc.org
ABSTRACT
Objective:
There is increasing evidence to suggest
that diet, one of the most important modifiable
environmental factors, may play a role in preventing or
delaying cognitive decline and Alzheimers disease
(AD). This study examines the relationship between
dietary nutrients and brain biomarkers of AD in
cognitively normal individuals (NL) with and without
AD risk factors.
Design: As part of an ongoing brain imaging study,
participants received clinical and laboratory
examinations, a neurocognitive test battery, positron
emission tomography (PET) with
11
C-Pittsburgh
Compound-B (PiB; a measure of amyloid-β (Aβ) load)
and
18
F-fluorodeoxyglucose (FDG; a proxy of neuronal
activity), and completed semiquantitative food
frequency questionnaires.
Setting: Research centre affiliated with the Alzheimers
disease Core Center at New York University School of
Medicine.
Participants: 49 NL individuals (age 2572 years,
69% women) with dietary information,
11
C-PiB and
18
F-FDG PET scans were examined.
Results: Controlling for age and total caloric intake,
higher intake of vitamin B
12
, vitamin D and ω-3
polyunsaturated fatty acid (PUFA) was associated with
lower Aβ load in AD regions on PiB-PET, while higher
intake of β-carotene and folate was associated with
higher glucose metabolism on FDG-PET. β-carotene
and folate were associated with reduced glucose
metabolism for women, apolipoprotein E epsilon 4
(APOE4) carriers and participants with positive AD
family history, but not for their risk-free counterparts.
The associations of vitamin B
12
, vitamin D and ω-3
PUFA with PiB retention were independent of gender,
APOE and family history. The identified nutrient
combination was associated with higher intake of
vegetables, fruit, whole grains, fish and legumes, and
lower intake of high-fat dairies, meat and sweets.
Conclusions: Our data provide a potential
pathophysiological mechanism for epidemiological
findings showing that dietary interventions may play a
role in the prevention of AD. Longitudinal studies are
needed to determine whether there is a direct link
between nutrient intake, brain biomarkers and risk of AD.
INTRODUCTION
We are what we eat: the nutritional content
of what we eat determines the composition
of our cell membranes, bone marrow, blood,
hormones, and is therefore the foundation
on which our body and brain are built.
While the importance of nutrition in health
Strengths and limitations of this study
While the importance of nutrition in health is
well understood, the specific effects of nutrition
on brain ageing and cognitive decline are less
so. This study shows a relationship between
nutrients and Alzheimers disease (AD) biomar-
kers in cognitively intact persons at risk for AD,
suggesting that dietary interventions may play a
role in the prevention of AD.
This was a cross-sectional study whose purpose
was to explore a possible link between dietary
nutrients and brain biomarkers of AD in yet
asymptomatic individuals; further longitudinal
studies are necessary to show causal links.
More studies with larger sample sizes and
plasma nutrient measures are needed to further
elucidate the inter-relationship between dietary
choices, brain physiology and risk of future AD.
Our preliminary findings of interaction effects
between nutrients and AD risk factors such as
gender, apolipoprotein E genotype and family
history need to be replicated with larger
samples.
Mosconi L, Murray J, Davies M, et al. BMJ Open 2014;4:e004850. doi:10.1136/bmjopen-2014-004850 1
Open Access Research
is well understood, the specic effects of nutrition on
brain ageing are less so. There is increasing evidence to
suggest that diet, one of the most important modiable
environmental factors, may play a role in preventing or
delaying cognitive decline and Alzheimers disease
(AD), a major public health problem.
17
However, the
biological mechanisms underlying the relationship
between dietary nutrients, brain ageing and AD are
largely unexplored. Understanding how diet and nutri-
tion promote healthy brain ageing in cognitively normal
(NL) indiv iduals, especially those at increased risk for
AD, is critical prior to implementing dietary recommen-
dations for prevention and treatment of disease.
While it is intuitive to assume a link between nutrient
intake and overall brain functioning exists, to our knowl-
edge there are no studies that examined the relationship
between nutrient intake and brain amyloid-β (Aβ), a
major hallmark of AD pathology, or glucose metabolism,
a proxy for neuronal activity, in NL individuals.
The present brain imaging study examines the rela-
tionship between nutrient intake, brain Aβ load assessed
using
11
C-Pittsburgh Compound-B (PiB) positron emis-
sion tomography (PET), and glucose metabolism
assessed using
18
F-uorodeoxyglucose (FDG) PET in a
cohort of young-to-late middle-aged NL individuals with
or without risk factors for AD. Several studies demon-
strated increased PiB-PET retention in AD and mild cog-
nitive impairment (MCI), often a prodromal AD phase,
compared with controls,
8
as well as in non-demented
elderly at risk for AD.
911
Additionally, FDG-PET meta-
bolic reductions occur prior to dementia onset and cor-
relate with clinical symptoms.
1214
Our goals were to
dene which nutrients are associated with lower AD
burden (as reected in lower brain Aβ and higher
glucose metabolic rates) among NL individuals, and to
test whether the associations are stronger in those with
AD-risk factors, including age, gender, education, family
history of AD and apolipoprotein E (APOE) genotype.
METHODS
Participants
From among a larger pool of participants who under-
went PET examinations, this study included 49 prospect-
ively recruited, clinically and cognitively normal (NL)
individuals participating in longitudinal PET studies at
NYU School of Medicine, who completed clinical,
PiB-PET and FDG-PET examinations and dietary ques-
tionnaires within 6 months of each other. Participants
were derived from multiple community sources, includ-
ing individuals interested in research participation,
family members and caregivers of impaired patients. All
participants provided written informed consent to par-
ticipate in this IRB approved study.
Individuals with medical conditions or history of condi-
tions that may affect brain structure or function, that is,
stroke, diabetes, head trauma, any neurodegenerative dis-
eases, depression, hydrocephalus, intracranial mass and
infarcts on MRI, and those taking psychoactive medica-
tions were excluded. Participants were 2572 years of age,
with education 12 years, Clinical Dementia Rating=0,
Global Deterioration Scale (GDS) 2, Mini-Mental State
Examination 28, Hamilton depression scale <16,
Modied Hachinski Ischaemia Scale <4 and had a normal
cognitive test performance for age and education.
14
A
family history of late-onset AD that included at least one
rst-degree relative whose AD onset was after age 60 was
elicited using standardised questionnaires.
14
APOE geno-
types were determined using standard quantitative PCR.
15
Individuals with at least one copy of the ε4 allele were
grouped as APOE ε4 carriers (APOE4+) and compared
with ε4 non-carriers (APOE4).
Dietary assessments
Dietary data regarding average food consumption over
the prior year were obtained using the 116-item version
of Willetts semiquantitative food frequency question-
naire (SFFQ).
1620
The 116-food items were categorised
into 30 food groups based on similarities in food and
nutrient composition, and intake (g/day) of each food
group was calculated by summing the intakes of
member food items. The daily intake of nutrients was
then computed by multiplying the consumption fre-
quency of each portion of every food by the nutrient
content of the specied portion.
19
Similar to previous reports, we focused on 10 nutrients
that have been related to AD or cognitive function
21 22
including saturated fatty acids, monounsaturated fatty
acids, ω-3 polyuns aturated fatty acid (PUFA), ω-6 PUFA,
β-carotene, vitamin B
12
, vitamin C, vitamin D, vitamin E
and folate. As moderate alcohol drinking may be pro-
tective against dementia,
23
alcohol intake (g/day) was
also calculated.
The nutrient intakes from foods and from supple-
ments were separately estimated. The nutrient intake
from foods was the main focus of this analysis. A total of
29/49 (59%) participants reported taking no supple-
ments for >1 year prior to PET, and the remaining
20/49 (41%) participants reported taking a multivitamin
at least three times a week, for >1 year prior to PET. Of
these 20 participants, 8 (16%) reported taking add-
itional sh oil supplements, 5 (10%) reported taking
vitamin D (3001000 IU) and/or vitamin E (>600 IU)
and 2 (4%) reported taking vitamin B
12
(500 μg) regu-
larly. Twelve participants reported taking vitamin C
(1000 mg) and vitamin D (3001000 IU) on a seasonal
basis only, and mostly occasionally. None of the partici-
pants were taking saturated fats or monounsaturated
fatty acid supplementation. As some participants
reported taking supplements consistently, we addition-
ally looked at nutrient intake from supplements, and the
combined nutrient intake from food and supplements.
Brain imaging
All participants received PiB-PET and FDG-PET scans
using standardised procedures.
10 14 24
Briey,
2 Mosconi L, Murray J, Davies M, et al. BMJ Open 2014;4:e004850. doi:10.1136/bmjopen-2014-004850
Open Access
participants were positioned in the scanner 60 min after
injection of 15 mCi of
11
C-PiB, and scanned for 30 min
in three-dimensional mode on an LS Discovery or
BioGraph PET/CT scanner. The FDG scan was per-
formed 30 min after completion of the PiB scan or on a
separate day. After an overnight fast, participants were
injected with 5 mCi of
18
F-FDG, positioned in the
scanner 35 min after injection and scanned for 20 min.
All images were corrected for photon attenuation,
scatter and radioactive decay and smoothed for uniform
resolution.
25
For each participant, summed PET images corre-
sponding to 4060 min of FDG data and 6090 min of
PiB data were coregistered to corresponding MRI using
the Normalised Mutual Information routine implemen-
ted in Statistical Parametric Mapping.
26
MRI were spa-
tially normalised to Montreal Neurological Institute
space by high-dimensional warping (DARTEL).
26
MRI-coregistered FDG and PiB scans were spatially nor-
malised using participant-specic transformation
matrixes from MRI and sampled using automated
regions-of-interest ROI.
27 28
We focused on preselected,
AD-vulnerable ROI including inferior parietal lobe
(IPL), lateral temporal lobe (LTL), medial frontal gyrus,
posterior cingulate cortex (PCC) and prefrontal cortex.
Standardised uptake value ratios were generated for
each ROI by normalising PiB uptake by cerebellar grey
matter uptake
29
and FDG by pons activity.
30
A composite
cortical PiB retention mask (AVG
PiB
) was created by
combining parietotemporal, frontal and PCC regions,
and an FDG mask (AVG
FDG
) by combining parietotem-
poral and PCC regions.
24
Statistical analysis
Clinical and demographical measures were examined
with descriptive statistics. Stepwise forward and backward
linear regressions were used to evaluate the associations
between FDG and PiB ROI measures (independent vari-
ables), nutrients (dependent variables) and covariates.
We rst focused on nutrients from foods only. As nutri-
ent levels are also affected by participants intake of sup-
plements, analyses were repeated for the combined
nutrient intake from foods and supplements, and for
nutrients from supplements only. All regression models
were tested for violations of the model assumptions.
Variables that were not normally distributed were log-
transformed which normalised the distributions.
For all analyses, we regressed each nutrient by age
(years) and caloric intake (kilocalories) to calculate
age-adjusted and caloric intake-adjusted residuals.
31
We
then examined gender,
32
education, ethnicity, body mass
index (BMI), alcohol consumption, family history
33
and
APOE status
34
as covariates. Education and BMI were mod-
elled as continuous variables. Gender (male vs female),
FH (positive vs negative) and APOE status (APOE4+ vs
APOE4) were examined as dichotomous variables. Ethnic
group was based on self-report using the format of the
1990 census. Ethnicity was used as a dichotomous variable
(White/non-Hispanic vs other ethnic groups). Alcohol
intake was used as a dichotomous variable (mild-moderate
(030 g/day) vs no (0 g/day) or more than moderate
(30 g/day) consumption).
23
If one or more covariates showed signicant effects on
the association between nutrients and biomarkers, those
covariates were separately examined for interaction
effects in adjusted models by rst entering the main
effects, then the two-way interactions between each
nutrient and the covariate(s) in the next step. Only sig-
nicant interaction terms were retained in the models.
The food sources of nutrients associated with PiB
retention and FDG uptake were examined by testing for
correlations between food sources (g/day) and nutrient
intake.
3 4 21 22
Results were considered signicant at p<0.05 (2-sided
tests). SPSS V.21 (SPPS Inc, 2013) was used for all
analyses.
RESULTS
Participants characteristics are found in table 1. None
of the participants were diabetics, smokers or met cri-
teria for obesity.
FDG-PET
Among all nutrients examined, β-carotene and folate
from food sources were positively associated with brain
glucose metab olism in several ROIs (p0.05; gure 1,
table 2). Results remained unchanged using the com-
bined nutrient intake from food and supplements.
There were no associations between nutrients from sup-
plements only and glucose metabolism in any ROI. As
supplements did not appear to have signicant effects,
and less than half of our participants were taking multi-
vitamins at the time of the examination, results from
β-carotene and folate from food sources are presented
in what follows.
Adjustment for education, ethnicity, BMI and alcohol
consumption did not attenuate the relationshi ps
between β-carotene, folate and glucose metabolism,
while gender, family history and APOE status showed sig-
nicant interaction effects with β-carotene and folate.
Gender × β-carotene interaction effects on brain
glucose metabolism were observed in PCC and AVG
FDG
(p0.03, table 3). In these regions, women showed sig-
nicant positive associations between β-carotene and
glucose metabolism (p<0.05) while men showed no asso-
ciations (table 3), resulting in steeper regression slopes
of glucose metabolism on β-carotene in women com-
pared with men (egure 1). Interaction effects of
gender × folate on glucose metabolism were observed in
all ROIs (p0.05), with women showing signicant posi-
tive associations between folate and glucose metabolism
(p<0.05) and men showing no associations (table 3,
egure 1). Additionally, marginally signicant gender ×
saturated fats interaction effects were observed on PCC
and AVG
FDG
glucose metabolism (p0.08), as women
Mosconi L, Murray J, Davies M, et al. BMJ Open 2014;4:e004850. doi:10.1136/bmjopen-2014-004850 3
Open Access
showed signicant negative associations between satu-
rated fats and glucose metabolism (p<0.05) while men
showed no associations (table 3).
Family history × β-carotene interaction effects on
glucose metabolism were observed for all ROIs
(p0.05). In these regions, participants with positive
family history showed signicant associations between
β-carotene and glucose metabolism (p<0.05), while
those with negative family history showed no associations
(table 3). Interaction effects of gender × family
history×β-carotene on glucose metabolism were observed
(p<0.05), as women with a positive family history showed
signicant associations between β-carotene and glucose
metabolism in PCC, LTL and AVG
FDG
(p<0.05) whereas
the other groups (ie, men with positive family history,
men and women with negative family history) did not
show signicant associations (table 3), resulting in sig-
nicant interaction effects (p<0.05, egure 2).
Interaction effects of APOE × β carotene were marginally
signicant (p0.08), with APOE4+ participants showing
steeper regression slopes vs APOE4. Nonetheless, there
were signicant gender × APOE × β carotene interaction
effects, as women APOE4+ had the steepest regression
slopes of PCC and AVG
FDG
glucose metabolism on
β-carotene as compared with the other groups (ie, APOE4
+men,APOE4 men and women; p<0.05; table 3,egure
2). Additionally, there were signicant gender × APOE ×
saturated fat interactions in glucose metabolism, as APOE4
+ women showed signicant negative associations between
saturated fats and glucose metabolism (p<0.05), whereas
the other groups (ie, APOE4+ men, APOE4 men and
women) did not (table 3).
Correlations between nutrients associated with FDG
uptake and food groups showed that β-carotene was
mainly from dark leaf, green leafy and cruciferous vege-
tables and fresh fruit, with correlation coefcients of
0.82, 0.77, 0.69 and 0.53, respectively, (p0.001). Folate
was from grains, legumes, cruciferous vegetables and
fresh fruit (0.44, 0.34, 0.32 and 0.30; p0.04), and satu-
rated fats were from high fat dairies, salad dressing, fried
potatoes, sweets and processed meat (0.65, 0.52, 0.5,
0.45, 0.41, p0.003).
PiB-PET
Among all nutrients examined, vitamin B
12
and vitamin D
levels from food sources were negatively associated with
PiB retention in all ROIs (p<0.05; table 2, gure 2). There
were marginally signicant negative associations between
PiB retention and ω-3 PUF A (p0.10), which prompted
exploratory analyses of three major ω-3 PUF As subtypes
(ie, eicosapentaenoic acid 20 : 5, EPA; docosahexaenoic
acid 22 : 6, DHA; α-linolenic acid 18 : 3, ALA). PiB reten-
tion was negatively associated with EPA (β range 0.37 in
IPL to 0.31 in PCC, SE 0.490.43, p<0.04; gure 2), but
not with DHA or ALA (p>0.20, n.s.).
Analy sis of nutrients from food and supplements attenu-
ated the rela tionships between PiB retention and vitamin D,
Table 1 Demographic and clinical characteristics
N49
Age, year, mean (SD) 54 (11), range 2572
Female gender, % 69
Education, year, mean (SD) 16 (2)
Family history of LOAD, % positive 69
APOE ε4 status*, % positive 39
Ethnicity, %
White 82
Black 8
Hispanic 6
Other 4
Body mass index (unitless),
mean (SD)
26 (4)
Hip-to-waist ratio (unitless),
mean (SD)
1.2 (0.2)
Blood pressure (mm/Hg), mean (SD)
Systolic 118 (15)
Diastolic 71 (9)
Glucose (mg/dL) 78 (12)
Cholesterol (mg/dL) 200 (38)
HDL (mg/dL) 62 (19)
LDL (mg/dL) 119 (33)
Triglycerides (mg/dL) 91 (40)
Homocystein (μmol/L) 10 (2)
Neuropsychological tests, mean (SD)
Mini-Mental State Examination 29 (1)
Digit symbol substitution 62 (10)
Paired associates delayed recall 7 (2)
Paragraph delayed recall 10 (3)
Designs 8 (2)
Object naming 55 (12)
WAIS-vocabulary 65 (14)
Nutrients levels, mean (SD), range
β-carotene (μg)
Foods 6556 (8593), 82525 451
Foods and supplements 7438 (8447), 133125 957
ω-3 polyunsaturated fatty acid (g)
Foods 0.19 (0.14), 0.050.82
Foods and supplements 0.23 (0.18), 0.081.09
ω-6 polyunsaturated fatty acid (g)
Foods 19.7 (17.3), 5.275.5
Foods and supplements 20.1 (17.2), 5.375.5
Folate (μg)
Foods 486.6 (345.1), 181.41674.2
Foods and supplements 648.1 (335.9), 187.61759.9
Monounsaturated fats (g)
Foods 38.7 (31.5), 10.8164.5
Foods and supplements n.a.
Saturated fats (g)
Foods 23.5 (13.0), 8.661.3
Foods and supplements n.a.
Vitamin B
12
(μg)
Foods 4.5 (2.7), 1.312.1
Foods and supplements 15.4 (9.9), 2.658.3
Vitamin C (mg)
Foods 129 (100), 35521
Foods and supplements 305 (267), 691565
Vitamin D (μg)
Foods 4.7 (2.9), 1.116.3
Foods and supplements 729 (445), 1.81806
Vitamin E (mg)
Foods 13.2 (11.5), 3.657.4
Foods and supplements 697 (37), 632797
*APOE genotyping was obtained from 41/49 participants.
APOE, apolipoprotein E; HDL, high-density lipoprotein; LDL,
low-density lipoprotein.
4 Mosconi L, Murray J, Davies M, et al. BMJ Open 2014;4:e004850. doi:10.1136/bmjopen-2014-004850
Open Access
while those with vitamin B
12
and ω-3 PUFA EPA remained
signicant (p0.05). There were no associations between
nutrients from supplements only and PiB retention in any
ROI. Since supplements did not appear to have signicant
effects other than to attenuate the relationship between
nutrients and PiB retention, and only 41% of our partici-
pants were taking supplements at the time of the examin-
ation, results using nutrients from food sources only are
presented in what follows.
Including education, ethnicity, BMI, alcohol consump-
tion, gender, family history and APOE status as covariates
in the model did not attenuate the relationships
between vitamin B
12
, vitamin D, ω-3 PUFA EPA and PiB
retention. There were no interaction effects between
possible AD-risk factors and nutrient intake on PiB
retention in any ROI (egure 3).
Correlations between nutrients associated with PiB
and food groups showed that vitamin B
12
was mainly
from meat, eggs and butter with correlation coefcients
of 0.35, 0.31 and 0.36, respectively, (p<0.04). Vitamin D
was mostly from low-fat dairies and sh (0.64 and 0.55,
p<0.001), and ω-3 PUFA EPA from sh and other vegeta-
bles (0.36 and 0.31, p<0.01).
DISCUSSION
This brain imaging study shows that higher intake of
vitamin B
12
, vitamin D and ω-3 PUFA EPA from food
Figure 1 Associations between brain glucose metabolism in AD regions, β-carotene, folate and saturated fats. Nutrient values
are age and caloric intake-adjusted residuals. Unadjusted values (minimum, mean, maximum) are provided for reference
purposes. The mean value is in italic. FDG values are regional standardised uptake value ratios to pons activity (SUVR, unitless).
Corresponding p values are found in table 2. AD, Alzheimers disease; FDG,
18
F-fluorodeoxyglucose; PCC, posterior cingulate
cortex; SUVR, standardised uptake value ratios.
Mosconi L, Murray J, Davies M, et al. BMJ Open 2014;4:e004850. doi:10.1136/bmjopen-2014-004850 5
Open Access
sources was associated with lower Aβ load, and higher
β-carotene and folate intake was associated with higher
brain glucose metabolism in NL individuals. Higher con-
sumption of saturated fats was associated with lower
brain glucose metabolism, albeit weakly. These data indi-
cate that a healthy diet rich in natural folate, β-carotene,
ω-3 PUFA, vitamin B
12
and vitamin D might be particu-
larly useful to support healthy brain ageing. The identi-
ed AD-protective nutrients were associated with
higher intake of vegetables, fruit, whole grains, sh and
legumes, and with lower intake of high-fat dairies, pro-
cessed meat and sweets. A signicant impact of risk
factors such as gender, APOE status and family history of
late-onset AD was noted on the associations between
nutrients and glucose metabolism in AD regions.
Specically, women, individuals with positive family
history and APOE ε4 carriers showed the strongest asso-
ciations between β-carotene, folate and saturated fats on
glucose metabolism as compared with their risk-free
counterparts. These effects were not evident on PiB
retention, as the associations between Aβ load and
intake of vitamin B
12
, vitamin D and ω-3 PUFA EPA were
independent of these risk factors for late-onset AD.
Some studies have shown that higher intakes of
vitamin B
12
and folate are related to better cognitive
functioning or lower AD risk in the elderly,
3541
possibly
due to their ability to reduce homocysteine levels,
although results are not conclusive.
41
β-Carotene (a
major precursor to vitamin A) might have benecial
effects via its antioxidant or Aβ antioligomerisation
effects.
4247
Vitamin D has been associated with reduced
risk of AD and cerebrovascular disease through several
mechanisms including vasculoprotective and synaptic
plasticity-enhancing effects, modulation of vascular
endothelial factor expression, angiogenin and advanced
glycation end products.
4850
On the other hand, higher
intake of saturated fats is known to have negative effects
on cognitive functions,
51 52
while intake of polyunsatur-
ated fatty acids, especially ω-3 PUFA, is known to
decrease risk of decline.
21 22 53 54
A distinction must be made between diet and nutri-
tion, where nutrition refers to the components of the
foods which one may absorb while diet refers to patterns
of foods eaten. Knowledge of AD-protective nutrients is
important to identify the food sources of these nutrients
in order to develop and implement dietary recommen-
dations. Several epidemiological studies have identied
dietary patterns (ie, food combinations) that are protect-
ive against AD. Despite differences in the analytic
approaches, high adherence to dietar y patterns charac-
terised by higher intakes of fr uits, vegetables, sh, nuts
and legumes, and lower intake of meat, high-fat dairies
and sweets, is consistently associated with reduced risk
for AD.
3 4 21 5559
The food sources associated with the
nutrients identied as being AD protective using brain
PET in this study are consistent with prior epidemio-
logical ndings. Other studies are needed to test for spe-
cic associations between PET biomarkers, specic food
groups and risk for AD.
A community-based study of NL elderly showed that
ω-3 PUFA was associated with lower peripheral plasma
Aβ levels.
22
Our PiB-PET results in a younger NL cohort
show associations between brain Aβ and ω-3 PUFA EPA,
further reinforcing the connection between ω-3 PUFA
and AD pathology. Other studies with larger samples
and a wider age range are needed to assess whether
other ω-3 PUFA markers are also associated with brain
Aβ load in the elderly.
Table 2 Associations between nutrients and AD biomarkers
AVG IPL LTL MFG PCC PFC
FDG glucose metabolism
β-carotene β 0.31
a
0.25
c
0.33
a
0.31
a
0.32
a
0.27
c
SE 0.001 0.001 0.001 0.001 0.001 0.001
Folate β 0.35
b
0.33
a
0.31
a
0.31
a
0.36
b
0.27
c
SE 0.001 0.001 0.001 0.001 0.001 0.001
Saturated fats β 0.20
c
0.16 0.15 0.24
c
0.13 0.16
SE 0.006 0.006 0.007 0.007 0.006 0.005
PiB retention
Vitamin B
12
β 0.32
a
0.37
b
0.29
a
0.33
a
0.37
a
0.27
c
SE 0.006 0.01 0.009 0.008 0.001 0.008
Vitamin D β 0.26
c
0.21 0.28
a
0.13 0.28
a
0.27
c
SE 0.006 0.009 0.009 0.007 0.006 0.007
ω-3 PUFA β 0.18
c
0.28
a
0.07 0.24
c
0.09 0.16
SE 0.01 0.04 0.04 0.01 0.03 0.01
ω-3 PUFA EPA β 0.33
a
0.37
b
0.32
a
0.20 0.31
a
0.28
c
SE 0.32 0.49 0.47 0.40 0.42 0.39
Standardised β and SE estimates from linear regression using age-residual nutrients and caloric intake-residual nutrients from food sources.
a
p0.05,
b
p0.01,
c
p=0.060.10.
AVG, average cortical ROI; EPA, eicosapentaenoic acid 20 : 4; FDG,
18
F-fluorodeoxyglucose; IPL, inferior parietal lobe; LTL, lateral temporal
lobe; MFG, medial frontal gyrus; PUFA, polyunsaturated fatty acids; PCC, posterior cingulate cortex; PFC, prefrontal cortex.
6 Mosconi L, Murray J, Davies M, et al. BMJ Open 2014;4:e004850. doi:10.1136/bmjopen-2014-004850
Open Access
While SFFQs are fairly comprehensive and
SFFQ-derived dietary patterns remain broadly stable over
time,
21
the method may be subject to faulty recall of
dietary intake. Plasma nutrient studies might obviate this
issue. Bowman et al
60
showed that higher levels of
plasma antioxidants, vitamin B, D and ω-3 PUFA were
associated with more favourable cognitive and MRI
white matter hyperintensity measures in an elderly popu-
lation (mean age 87 years). Analysis of plasma nutrients
would be very valuable in younger NL at risk for AD. In
our data set, none of the nutrients were associated with
neuropsychological measures, possibly because our parti-
cipants were relatively young and all high-school gradu-
ates, which resulted in a ceiling-effect. Longitudinal
studies with larger samples are warranted to assess
whether the relationship between protective nutrients,
AD biomarkers and cognitive per formance varies with
age and disease.
In our data set, gender, family history and APOE status
affected the relationships between brain glucose metab-
olism, β-carotene and to a lesser extent folate levels. To
our knowledge, there are no previous studies that exam-
ined the interaction between nutrients and AD-risk
factors on glucose metabolism in normal ageing. Our
results were in the expected direction, as at-risk indivi-
duals showed stronger effects of nutrient levels on
glucose metabolism. Several studies have shown that
female gender, a rst-degree family history of late-onset
AD and the APOE ε4 genotype are all associated with
reduced glucose metabolism in NL individuals.
13 14 61
Table 3 Effects of gender and family history on the relationship between nutrients and brain glucose metabolism
AVG
FDG
IPL LTL MFG PCC PFC
Gender (women, n=33 vs men=16)
β-carotene
Women β 0.33
a
0.29 0.32
a
0.33
a
0.34
a
0.28
SE 0.001 0.001 0.001 0.001 0.001 0.001
Men β 0.01 0.01 0.08 0.08 0.06 0.02
SE 0.001 0.001 0.001 0.001 0.001 0.001
Folate
Women β 0.31
a
0.34
a
0.24 0.28 0.38 0.24
SE 0.001 0.001 0.001 0.001 0.001 0.001
Men β 0.29 0.25 0.18 0.22 0.31 0.28
SE 0.001 0.001 0.001 0.001 0.001 0.001
Saturated fats
Women β 0.35
a
0.30 0.32
a
0.38
a
0.37
a
0.34
a
SE 0.008 0.009 0.007 0.01 0.01 0.009
Men β 0.15 0.16 0.17 0.12 0.09 0.12
SE 0.004 0.005 0.004 0.008 0.005 0.007
Family history (FH+, n=33 vs FH=16)
β-carotene
FH+ β 0.42
b
0.35
a
0.42
b
0.43
b
0.45
b
0.42
b
SE 0.001 0.001 0.001 0.001 0.001 0.001
FH β 0.10 0.10 0.17 0.12 0.06 0.2
Gender×family history (FH+ women, n=23 vs other participants=26)
β-carotene
FH+ women β 0.48
a
0.43
a
0.46
a
0.49
b
0.50
b
0.47
a
SE 0.001 0.001 0.001 0.001 0.001 0.001
Other β 0.04 0.006 0.08 0.09 0.04 0.05
SE 0.001 0.001 0.001 0.001 0.001 0.001
Gender×APOE genotype (APOE4+ women, n=13 vs other participants=36)
β-carotene
APOE4+ women β 0.52
a
0.46
a
0.48
a
0.54
a
0.53
a
0.48
a
SE 0.001 0.001 0.001 0.001 0.001 0.001
Other β 0.10 0.10 0.10 0.08 0.03 0.08
SE 0.001 0.001 0.001 0.001 0.001 0.001
Saturated fats
APOE4+ women β 0.66
b
0.60
a
0.59
b
0.57
b
0.68
b
0.57
a
SE 0.02 0.03 0.02 0.03 0.03 0.03
Other β 0.11 0.11 0.16 0.18 0.08 0.19
Standardised β and SE estimates from linear regression using age-residual nutrient values and caloric intake-residual nutrient values.
a
p<0.05,
b
p0.01.
APOE, apolipoprotein E; AVG, average cortical ROI; IPL, inferior parietal lobe; LTL, lateral temporal lobe; MFG, medial frontal gyrus; PCC,
posterior cingulate cortex; PFC, prefrontal cortex.
Mosconi L, Murray J, Davies M, et al. BMJ Open 2014;4:e004850. doi:10.1136/bmjopen-2014-004850 7
Open Access
Nutritional studies have shown that women need fewer
calories than men, but in many cases, they have higher
vitamin and mineral needs.
62 63
particularly of vitamin
D/calcium and folic acid, as women are susceptible to
hormonal changes associated with menstruation, child-
bearing and osteoporosis. While limited by the small
sample, APOE4+ women with a positive family histor y
showed the strongest associations between glucose
metabolism and β-carotene ( p<0.04). These descriptive
observations warrant replication in larger samples.
Additionally, nutrientbiomarker associations were stron-
ger using nutrients from foods only, which reinforces
the general recommendations of a lifelong diversied
diet that includes an abundance of nutrient-rich foods,
and is consistent with ndings that nutritional supple-
mentation is not equivalent to obtaining nutrients from
whole foods,
64
especially for women.
65
While family
history and APOE status have been associated with
increased Aβ load in NL,
10 11
the effects of vitamin B
12
,
vitamin D
12
and ω-3 PUFA EPA on PiB retention were
not exacerbated in the presence of these risk factors or
female gender. Overall, our data suggest that nutritional
interventions aimed at preserving brain activity might be
particularly useful if instituted in young adulthood in
Figure 2 Associations between brain amyloid-β load in AD regions, as measured with
11
C-PiB, vitamin B
12
, vitamin D and ω-3
PUFA (EPA 20 : 4). Nutrient values are age and caloric intake-adjusted residuals. Unadjusted values (minimum, mean,
maximum) are provided for reference purposes. The mean value is in italic. PiB values are regional standardised uptake value
ratios to cerebellar uptake (SUVR, unitless). Corresponding p values are found in table 2. AD, Alzheimers disease;
11
C-PiB,
11
C-Pittsburgh Compound-B; EPA, eicosapentaenoic acid; PCC, posterior cingulate cortex; PUFA, polyunsaturated fatty acid;
SUVR, standardised uptake value ratios.
8 Mosconi L, Murray J, Davies M, et al. BMJ Open 2014;4:e004850. doi:10.1136/bmjopen-2014-004850
Open Access
NL at risk for AD, before irreversible neuronal loss.
Second, these results indicate a genetic component to
dietary needs, as genetic risk in conjunction with
unhealthy eating habits may boost genetic predispos-
ition,
66
and support the view that AD is a multifactorial
disease resulting from genetic, lifestyle and environmen-
tal interactions.
67
Third, nutrient effects on Aβ load
were independent of AD-risk factors, but this may differ
in older populations with more substantial Aβ depos-
ition. Nutrients may have an impact on Aβ oligomers,
which are not detectable with PiB-PET, prior to plaque
formation.
68
A low saturated fat/glycaemic index diet
was shown to improve Aβ composition in cerebrospinal
uid in MCI,
69
suggesting that diet is a power ful envir-
onmental factor that modulates AD risk through its
effects on brain Aβ and associated neuronal injury.
This study has several limitations. The NL population
selected in our s tudy consists of a gr oup with a high a
priori risk of preclinical AD changes, and results were
found in small numbers of carefully scr eened participants
under controlled clinical conditions. While a sample of 49
participants with FDG and PiB-PET scans is quite sizeable
from a neur oimaging perspective, larger samples are war -
ranted to re plica te these preliminary studies. The small
sample led us to examine predictors and confounds in sep-
arate analyses rather than simultaneously so as to avoid
overtting. Simultaneous sta tistical control of potential
confounds would be informa tive because of conjoint con-
founding that stepwise approaches do not capture.
Nonetheless, only gender, family history and AP OE geno-
type had a signicant impact on the associations between
nutrient levels and glucose metabolism, yielding signicant
interaction effects even in this small sample. The sample
size also may have decreased the lik elihood of a wide dis tri-
bution of nutrient intak e to fully test for potential associa-
tions. For instance, we did not report associations between
biomarkers and vitamin E, possibly because vitamin E
intake in our healthy popula tion did not include the level
below or abo ve which an association may be observed.
Lik e wise, we observed positiv e associations betw e en folate
and brain glucose metabolism in an NL, albeit a t risk popu-
lation, although folate lev els were gener ally moder a te. The
literature indicates that whereas higher food intak e of
folate may be benecial, high intake levels of folic acid (the
synthetic form of folate) may be harmful, particularly in
individuals with low vitamin B
12
status,
41
as high dosages of
folic acid may mask vitamin B
12
deciencies.
Second, the sample size was not large enough to detect
non-linear associations that may be present for nutrients
and imaging biomarker measures. An interesting
approach would be to analyse indicator variables of quan-
tiles (ie, tertiles and quartiles) of the nutrients to test for
quadratic, rather than linear associations. Third, dietary
intake assessments may lead to incorrect quantication of
bioavailable nutrient levels. For instance, vitamin B
12
intake may be challenging to characterise by dietary intake
assessment as its serum level can be affected by gastrointes-
tinal malabsorption syndromes, such as those seen with
pernicious anaemia, Crohns disease or gastric bypass
surgery; by excessive alcohol intake or by common medica-
tions, including antacids and antidiabetic agents, among
others. Although none of our participants showed vitamin
B
12
deciencies in plasma on standard blood tests, we
cannot exclude that intake may have been underestimated
in some participants. Moreover, a signicant component
of vitamin D serum levels is sunlight exposure as well as
dietary intake; residents of large cities have been shown to
be particularly at risk for vitamin D deciency due to a
chronic lack of sunlight exposure. Malabsorption syn-
dromes may also affect vitamin D bioavailability regardless
of sunlight exposure or dietary intake, as well as conditions
such as obesity or renal insufciency, which may interfere
with vitamin D extraction or conversion to its active form.
A few participants reported taking vitamin D on a seasonal
basis. Overall, our preliminary results using SFFQs warrant
replication by direct quantication of nutrient levels from
plasma to better address these potential confounds, as well
as conrmation on medical screening that medical condi-
tions or medications that may interfere with vitamin bio-
availability are not present. Finally, replication of these
preliminary research ndings in community-based popula-
tions with more diversied socioeconomic and medical
status is warranted and clinical application is not yet
justied.
In conclusion, we identied specic nutrients asso-
ciated with healthy brain ageing, which provides support
for further exploration of nutritional status in the pre-
vention of AD.
Author affiliations
1
Department of Psychiatry, New York University School of Medicine,
New York, USA
2
Department of Radiology, Citigroup Biomedical Imaging Center (CBIC), Weill
Cornell Medical College, New York, New York, USA
3
Steven and Alexandra Cohen Veterans Center for PTSD and TBI, New York,
New York, USA
Contributors LM, PMcH and CM participated in study concept and design.
LM, JM, MD, SW, NS, RSO, PMcH and SV participated in acquisition of data.
LM, EP, TB, RSO, LG, PMcH and CM participated in analysis and
interpretation of data. LM and PMcH participated in drafting of the
manuscript. LM, TB, RSO, LG, SV, PMcH, CM and MJdL participated in
critical revision of the manuscript for important intellectual content. LM and
EP participated in statistical analysis. LM and MJdL obtained funding. LM and
MJdL participated in administrative, technical and material support. LM
participated in study supervision.
Funding This study was supported by NIH/NIA grants AG035137, AG13616,
Alzheimers Association IIRG-09-132030, and an anonymous foundation.
Competing interests LM, WHT and MJdL have a patent on a technology that
was licensed to Abiant Imaging Inc by NYU and, as such, have a financial
interest in this license agreement and hold stock and stock options on the
company. LM, YL and MJdL have received compensation for consulting
services from Abiant Imaging. MJdL and LG have received honoraria from the
French Alzheimer Foundation.
Ethics approval New York University School of Medicine Ethics Committee/
Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement No additional data are available.
Mosconi L, Murray J, Davies M, et al. BMJ Open 2014;4:e004850. doi:10.1136/bmjopen-2014-004850 9
Open Access
Open Access This is an Open Access article distributed in accordance with
the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license,
which permits others to distribute, remix, adapt, build upon this work non-
commercially, and license their derivative works on different terms, provided
the original work is properly cited and the use is non-commercial. See: http://
creativecommons.org/licenses/by-nc/3.0/
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Open Access
... The significant impact of vegetables [12,[71][72][73][74][75] and dairy [72,[76][77][78] on WMH burden aligns with previous findings [30]. Some nutrients mainly found in vegetables, such as dietary fiber and vitamins B, C, D, and E, have been reported to be associated with white matter integrity [12,[71][72][73][74][75]. ...
... Some nutrients mainly found in vegetables, such as dietary fiber and vitamins B, C, D, and E, have been reported to be associated with white matter integrity [12,[71][72][73][74][75]. Dairy products, which are rich in saturated fatty acids (SFAs), were reported to be associated with higher volume of white matter damage [72,[76][77][78]. Fiber may help regulate the gut microbiota and glucose metabolism and further enhance insulin resistance in the brain [71]; B-vitamins may assist in regulating energy by supplying homocysteine metabolism [74]; vitamins C and E may provide antioxidant properties [73]; and vitamin D may be involved in the regulation of neurotransmitters and neurotrophin and may have anti-inflammatory and antioxidant neuroprotective capacities [75]. ...
Article
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Current evidence on the impact of Mediterranean diet (MeDi) on white matter hyperintensity (WMH) trajectory is scarce. This study aims to examine whether greater adherence to MeDi is associated with less accumulation of WMH. This population-based longitudinal study included 183 cognitively intact adults aged 20–80 years. The MeDi score was obtained from a self-reported food frequency questionnaire; WMH was assessed by 3T MRI. Multivariable linear regression was used to estimate the effect of MeDi on WMH change. Covariates included socio-demographic factors and brain markers. Moderation effects by age, gender, and race/ethnicity were examined, followed by stratification analyses. Among all participants, WMH increased from baseline to follow-up (mean difference [follow-up-baseline] [standard deviation] = 0.31 [0.48], p < 0.001). MeDi adherence was negatively associated with the increase in WMH (β = −0.014, 95% CI = −0.026–−0.001, p = 0.034), adjusting for all covariates. The association between MeDi and WMH change was moderated by age (young group = reference, p-interaction[middle-aged × MeDi] = 0.075, p-interaction[older × MeDi] = 0.037). The association between MeDi and WMH change was observed among the young group (β = −0.035, 95% CI = −0.058–−0.013, p = 0.003), but not among other age groups. Moderation effects by gender and race/ethnicity did not reach significance. Greater adherence to MeDi was associated with a lesser increase in WMH over time. Following a healthy diet, especially at younger age, may help to maintain a healthy brain.
... High levels of serum vitamin D may protect against physical frailty and reduce its occurrence (34). In addition, vitamin D (25(OH)D3), a neurosteroid hormone required for normal brain regulation and development, is strongly associated with cognitive decline and neuron-degenerative diseases (36,37). Epidemiological evidence has identified vitamin D as a valid predictor of cognitive decline or dementia in older people (38)(39)(40). ...
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Background Physical frailty and cognitive aging have important influences on poor clinical outcomes in older adults. Many studies have investigated the association between frailty and cognitive function, but whether vitamin D mediates the association between frailty and cognitive function is unclear. We explored the mediating role of vitamin D on the cross-sectional association between physical frailty and cognitive function using data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Methods We analyzed data from 1944 subjects aged 60 years and older from the 2011 CLHLS cohort. Frailty status was identified by the Osteoporotic Fracture Study (SOF) index. The Chinese version of the Mini-Mental State Examination (MMSE) was used to assess cognitive function. Linear regression models were used to examine the association between frailty, vitamin D, and cognition, adjusted for a range of covariates. Mediation analyses tested the indirect effects of vitamin D on physical frailty and cognitive function. Result Physical frailty was negatively associated with vitamin D levels and scores on the MMSE, and vitamin D levels were positively associated with scores on the MMSE. Linear regression analysis showed that physical frailty and serum vitamin D concentration were significant predictors of cognitive function. Importantly, mediation analysis showed that serum vitamin D concentration significantly mediated the relationship between physical frailty and cognitive function. Conclusion The association between physical frailty and cognitive function appears to be mediated by vitamin D. Future studies should explore whether serum vitamin D concentrations may mediate the association between physical frailty and cognitive decline and whether this mediating role is moderated by other factors.
... Pomegranate, for example, was demonstrated to have neuroprotective effects that are attributed to its containing urolithins, which have been shown to prevent Aβ fibrillation in vitro [75]. A study that used principal component analysis to assess the correlation between nutrient patterns consumed by patients and risk of developing AD found that diets with greater proportions of fruit, vegetables, whole grains, fish, and low-fat dairy were associated with lower risk than diets comprised of more sweets, fried foods, high-fat dairy products, processed meat, and butter [76], findings that were corroborated by an additional study [77]. The diet recommended by these studies closely resembles the Mediterranean diet thought to be neuroprotective against the development of PD. ...
Article
The process of neuroinflammation contributes to the pathogenic mechanism of many neurodegenerative diseases. The deleterious attributes of neuroinflammation involve aberrant and uncontrolled activation of glia, which can result in damage to proximal brain parenchyma. Failure to distinguish self from non-self, as well as leukocyte reaction to aggregation and accumulation of proteins in the CNS, are the primary mechanisms by which neuroinflammation is initiated. While processes local to the CNS may instigate neurodegenerative disease, the existence or dysregulation of systemic homeostasis can also serve to improve or worsen CNS pathologies, respectively. One fundamental component of systemic homeostasis is the gut microbiota, which communicates with the CNS via microbial metabolite production, the peripheral nervous system, and regulation of tryptophan metabolism. Over the past 10-15 years, research focused on the microbiota-gut-brain axis has culminated in the discovery that dysbiosis, or an imbalance between commensal and pathogenic gut bacteria, can promote CNS pathologies. Conversely, a properly regulated and well-balanced microbiome supports CNS homeostasis and reduces the incidence and extent of pathogenic neuroinflammation. This review will discuss the role of the gut microbiota in exacerbating or alleviating neuroinflammation in neurodegenerative diseases, and potential microbiota-based therapeutic approaches to reduce pathology in diseased states.
... 25~72岁成年人膳食营养素和脑生物学标记的关系, 结果发现, β-胡萝卜素和叶酸与顶下小叶、外侧颞 叶、内侧前额叶以及后扣带的葡萄糖代谢呈显著正相 关 [156] . 追踪研究表明, 对地中海饮食模式依从性较低 的中年人, 其后扣带和额叶皮层的葡萄糖代谢率下降 更快 [157] . ...
... Of these, 89 studies were excluded: 20 did not assess dietary patterns and 69 did not evaluate the outcome "Alzheimer's disease". In addition, 6 studies were excluded as they did not determine an effect size (Gustaw-Rothenberg, 2009;Mosconi et al., 2014;Berti et al., 2015;Liu et al., 2016;Pase et al., 2017;Calil et al., 2018). In total, 21 eligible studies were identified (Fig. 1). ...
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A healthy diet has long been indicated to be protective against Alzheimer's diseases (AD). We carried out a systematic review and meta-analysis of published observational studies to explore the relationship between healthy and unhealthy diets and risk of ADs. We screened PubMed, Scopus, Web of Sciences, Google Scholar, Science Direct, and Em-base, and screened manually to identify relevant articles published in English and non-English until Jun 2020. We classified the studied dietary patterns into two groups: healthy and unhealthy diets. The pooled weighted mean difference and 95% confidence interval (95% CI) was used to analyze the data using a random-effects model. The data were extracted manually and the preferred reporting items for systematic review and meta-analysis checklist was used to appraise the risk of bias and quality of data. Of the 1,813 articles identified, 21 met the inclusion criteria and were included in the quantitative analysis. A healthy diet was related to a lower risk of AD [odds ratio (OR): 0.45, 95% CI: 0.23 to 0.86, I 2 =99.7%; n=17 studies]. Moreover, high adherence to an unhealthy diet was not associated with increased risk of AD (OR: 0.99, 95% CI: 0.98 to 0.99, I 2 =0.0%; n=6 studies). However, the etiology of AD is uncertain and it is difficult draw conclusions about dietary healthy patterns. We concluded that adherence to a healthy diet is associated with a lower risk of AD, but were unable to find evidence that an unhealthy diet increases the risk of AD.
... Not only does the intestinal microbiome affect absorption potential, but diet can also impact the diversity and metabolic capacity of gut flora and alter body composition [64]. A FH of AD may modify how the brain utilizes ␤-carotene and may be related to other beneficial effects, such as higher regional glucose metabolism in AD-sensitive brain areas [65]. In other words, FH of AD may moderate how diet and cognition are related because it reflects inter-individual differences in the ability to harbor a healthy diversity of gut bacteria, which alters how food is metabolized and which nutrients are extracted. ...
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Background: Fluid intelligence (FI) involves abstract problem-solving without prior knowledge. Greater age-related FI decline increases Alzheimer's disease (AD) risk, and recent studies suggest that certain dietary regimens may influence rates of decline. However, it is uncertain how long-term food consumption affects FI among adults with or without familial history of AD (FH) or APOE4 (ɛ4). Objective: Observe how the total diet is associated with long-term cognition among mid- to late-life populations at-risk and not-at-risk for AD. Methods: Among 1,787 mid-to-late-aged adult UK Biobank participants, 10-year FI trajectories were modeled and regressed onto the total diet based on self-reported intake of 49 whole foods from a Food Frequency Questionnaire (FFQ). Results: Daily cheese intake strongly predicted better FIT scores over time (FH-: β= 0.207, p < 0.001; ɛ4-: β= 0.073, p = 0.008; ɛ4+: β= 0.162, p = 0.001). Alcohol of any type daily also appeared beneficial (ɛ4+: β= 0.101, p = 0.022) and red wine was sometimes additionally protective (FH+: β= 0.100, p = 0.014; ɛ4-: β= 0.59, p = 0.039). Consuming lamb weekly was associated with improved outcomes (FH-: β= 0.066, p = 0.008; ɛ4+: β= 0.097, p = 0.044). Among at risk groups, added salt correlated with decreased performance (FH+: β= -0.114, p = 0.004; ɛ4+: β= -0.121, p = 0.009). Conclusion: Modifying meal plans may help minimize cognitive decline. We observed that added salt may put at-risk individuals at greater risk, but did not observe similar interactions among FH- and AD- individuals. Observations further suggest in risk status-dependent manners that adding cheese and red wine to the diet daily, and lamb on a weekly basis, may also improve long-term cognitive outcomes.
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Background: Diet may be a modifiable factor for reducing the risk of Alzheimer's disease (AD). Western-style dietary patterns are considered to increase the risk, whereas Mediterranean-style dietary patterns are considered to reduce the risk. An association between diet and AD-related biomarkers have been suggested, but studies are limited. Aim: To investigate potential relations between dietary patterns and cerebrospinal fluid (CSF) biomarkers for AD among dementia-free older adults. Methods: Data were derived from the population-based Gothenburg H70 Birth Cohort Studies, Sweden. A total of 269 dementia-free 70-year-olds with dietary and cerebrospinal fluid (CSF) amyloid beta (Aβ42 and Aβ40), total tau (t-tau), and phosphorylated tau (p-tau) data were investigated. Dietary intake was determined by the diet history method, and four dietary patterns were derived by principal component analysis. A Western dietary pattern, a Mediterranean/prudent dietary pattern, a high-protein and alcohol pattern, and a high-total and saturated fat pattern. Logistic regression models, with CSF biomarker pathology (yes/no) as dependent variables, and linear regression models with continuous CSF biomarker levels as dependent variables were performed. The analyses were adjusted for sex, energy intake, body mass index (BMI), educational level, and physical activity level. Results: The odds ratio for having total tau pathology (odds ratio [OR] 1.43; 95% confidence interval [CI] 1.02 to 2.01) and preclinical AD (Aβ42 and tau pathology; OR 1.79; 95% CI 1.03 to 3.10) was higher among those with a higher adherence to a Western dietary pattern. There were no other associations between the dietary patterns and CSF biomarkers that remained significant in both unadjusted and adjusted models. Discussion: Our findings suggest that higher adherence to a Western dietary pattern may be associated with pathological levels of AD biomarkers in the preclinical phase of AD. These findings can be added to the increasing amount of evidence linking diet with AD and may be useful for future intervention studies investigating dietary intake in relation to AD.
Article
Alzheimer’s disease (AD) is a neurodegenerative disease that affects memory and cognitive function. Clinical evidence has put into question our current understanding of AD development, propelling researchers to look into further avenues. Gut microbiota has emerged as a potential player in AD pathophysiology. Lifestyle factors, such as diet, can have negative effects on the gut microbiota and thus host health. A Western-type diet has been highlighted as a risk factor for both gut microbiota alteration as well as AD development. The gut-derived trimethylamine N-oxide (TMAO) has been previously implied in the development of cardiovascular diseases with recent evidence suggesting a plausible role of TMAO in AD development. Therefore, the main goal of the present review is to provide the reader with potential mechanisms of action through which consumption of a Western-type diet could increase AD risk, by acting through microbiota-produced TMAO. Although a link between TMAO and AD is far from definitive, this review will serve as a call for research into this new area of research.
Article
The last decide has witnessed a growing research interest in the role of dietary phytochemicals in influencing the gut microbiota. On the other hand, recent evidence reveals that dietary phytochemicals exhibit properties of preventing and tackling symptoms of Alzheimer's disease, which is a neurodegenerative disease that has also been linked with the status of the gut microbiota over the last decade. Till now, little serious discussions, however, have been made to link recent understanding of Alzheimer's disease, dietary phytochemicals and the gut microbiota together and to review the roles played by phytochemicals in gut dysbiosis induced pathologies of Alzheimer's disease. Deciphering these connections can provide insights into the development and future use of dietary phytochemicals as anti-Alzheimer drug candidates. This review aims at presenting latest evidence in the modulating role of phytochemicals in the gut microbiota and its relevance to Alzheimer's disease and summarizing the mechanisms behind the modulative activities. Limitations of current research in this field and potential directions will also be discussed for future research on dietary phytochemicals as anti-Alzheimer agents.
Article
Milk and dairy (M&D) is a longstanding human food with widespread use. Many studies showed the preventive capacity of M&D in several human health disorders, but its utility in others is under discussion. Aging has been associated to elderly cognitive decline including dementia-Alzheimer syndrome (Dem-AD). The absence of a therapy to impede or postpone Dem-AD determines the need for its prevention, including nutritional factors. To evaluate the preventive capacity of M&D consumption in elderly Dem-AD we performed a systematic review in the main biomedical databases and information resources, but we present this study as a narrative review to discuss better the complexity of this subject. The elderly Dem-AD has a long pre-symptomatic period and the M&D intake has a widespread use. These determinants and the quality flaws of published studies impeach us to answer whether M&D consumption is preventive for Dem-AD. Moreover, two long Japanese cohorts suggest that M&D intake could prevent Dem-AD. Prospective cohorts beginning in midlife (or early life) could answer this question in the future.
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Context Higher adherence to a Mediterranean-type diet is linked to lower risk for mortality and chronic diseases, but its association with cognitive decline is unclear. Objective To investigate the association of a Mediterranean diet with change in cognitive performance and risk for dementia in elderly French persons. Design, Setting, and Participants Prospective cohort study of 1410 adults (>= 65 years) from Bordeaux, France, included in the Three-City cohort in 20012002 and reexamined at least once over 5 years. Adherence to a Mediterranean diet ( scored as 0 to 9) was computed from a food frequency questionnaire and 24-hour recall. Main Outcome Measures Cognitive performance was assessed on 4 neuropsychological tests: the Mini-Mental State Examination (MMSE), Isaacs Set Test (IST), Benton Visual Retention Test (BVRT), and Free and Cued Selective Reminding Test (FCSRT). Incident cases of dementia (n=99) were validated by an independent expert committee of neurologists. Results Adjusting for age, sex, education, marital status, energy intake, physical activity, depressive symptomatology, taking 5 medications/d or more, apolipoprotein E genotype, cardiovascular risk factors, and stroke, higher Mediterranean diet score was associated with fewer MMSE errors (beta=-0.006; 95% confidence interval [CI], -0.01 to -0.0003; P=.04 for 1 point of the Mediterranean diet score). Performance on the IST, BVRT, or FCSRT over time was not significantly associated with Mediterranean diet adherence. Greater adherence as a categorical variable (score 6-9) was not significantly associated with fewer MMSE errors and better FCSRT scores in the entire cohort, but among individuals who remained free from dementia over 5 years, the association for the highest compared with the lowest group was significant (adjusted for all factors, for MMSE: beta=-0.03; 95% CI, -0.05 to -0.001; P=.04; for FCSRT: beta=0.21; 95% CI, 0.008 to 0.41; P=. 04). Mediterranean diet adherence was not associated with the risk for incident dementia (fully adjusted model: hazard ratio, 1.12; 95% CI, 0.60 to 2.10; P=.72), although power to detect a difference was limited. Conclusions Higher adherence to a Mediterranean diet was associated with slower MMSE cognitive decline but not consistently with other cognitive tests. Higher adherence was not associated with risk for incident dementia. JAMA. 2009; 302(6):638-648 www.jama.com
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It is not currently known how dietary assessment in older persons is affected by cognition. In a 1997-2000 study, the authors assessed the validity and reproducibility of a modified Harvard self-administered food frequency questionnaire (SFFQ) among 118 Black and 114 White randomly selected participants, aged 68-99 years, of the Chicago Health and Aging Project. Participants completed multiple 24-hour dietary recall interviews (mean = 3.6) over 12 months and two SFFQs in the first and 12th months. The average energy-adjusted intraclass correlation coefficient for 15 nutrients was 0.59 for 1-year reproducibility in nutrient intake levels assessed by the SFFQ. The average energy-adjusted Pearson correlation coefficient was 0.46 for comparative validity between nutrient intake levels on the SFFQ and the dietary recalls. SFFQ reproducibility was higher among men, and comparative validity with the dietary recalls was higher among women. There were no remarkable differences in the correlations by age, race, educational level, presence of chronic conditions, or cognitive ability. The modified Harvard SFFQ is a reasonable method of dietary assessment even in a population of older persons, some of whom are at advanced age, have chronic health conditions, and have cognitive impairment.
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Empirical prediction models that weight food frequency questionnaire (FFQ) food items by their relation to nutrient biomarker concentrations may estimate nutrient exposure better than nutrient intakes derived from food composition databases. Carotenoids may especially benefit because contributing foods vary in bioavailability and assessment validity. Our objective was to develop empirical prediction models for the major plasma carotenoids and total carotenoids and evaluate their validity compared with dietary intakes calculated from standard food composition tables. 4180 nonsmoking women in the Nurses' Health Study (NHS) blood subcohort with previously measured plasma carotenoids were randomly divided into training (n = 2787) and testing (n = 1393) subsets. Empirical prediction models were developed in the training subset by stepwise selection from foods contributing ≥0.5% to intake of the relevant carotenoid. Spearman correlations between predicted and measured plasma concentrations were compared to Spearman correlations between dietary intake and measured plasma concentrations for each carotenoid. Three to 12 foods were selected for the α-carotene, β-carotene, β-cryptoxanthin, lutein/zeaxanthin, lycopene, and total carotenoids prediction models. In the testing subset, Spearman correlations with measured plasma concentrations for the calculated dietary intakes and predicted plasma concentrations, respectively, were 0.31 and 0.37 for α-carotene, 0.29 and 0.31 for β-carotene, 0.36 and 0.41 for β-cryptoxanthin, 0.28 and 0.31 for lutein/zeaxanthin, 0.22 and 0.23 for lycopene, and 0.22 and 0.27 for total carotenoids. Empirical prediction models may modestly improve assessment of some carotenoids, particularly α-carotene and β-cryptoxanthin.
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Carotenoids may help to prevent the ageing of the brain. Previous findings regarding β-carotene alone are not consistent. In the present study, we evaluated the cross-time association between a carotenoid-rich dietary pattern (CDP) and subsequent cognitive performance using a sample of 2983 middle-aged adults participating in the SU.VI.MAX (Supplémentation en Vitamines et Minéraux Antioxydants) study. Cognitive performance was assessed in 2007-9 using six neuropsychological tests, and a composite cognitive score was computed. The cognitive data were related to dietary data obtained by repeated 24 h dietary records (1994-6) and to measurements of baseline plasma concentrations of carotenoids (lutein, zeaxanthin, β-cryptoxanthin, lycopene, α-carotene, trans-β-carotene and cis-β-carotene). DP were extracted using the reduced rank regression method for 381 participants and then extrapolated to the whole sample using plasma carotenoid concentrations as response variables. Associations between a CDP and cognitive function measured 13 years later were estimated with ANCOVA providing mean difference values and 95 % CI across the tertiles of CDP. A correlation between CDP and consumption of orange- and green-coloured fruits and vegetables, vegetable oils and soup was observed. CDP was found to be associated with a higher composite cognitive score (mean difference 1·04, 95 % CI 0·20, 1·87, P for trend 0·02), after adjustment for sociodemographic, lifestyle and health factors. Similar findings were obtained for scores obtained in the cued recall task, backward digit span task, trail making test and semantic fluency task (all P for trend < 0·05). Further studies ought to confirm whether a diet providing sufficient quantity and variety of coloured fruits and vegetables may contribute to the preservation of cognitive function during ageing.
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Associations between intake of specific nutrients and disease cannot be considered primary effects of diet if they are simply the result of differences between cases and noncases in body size, physical activity, and metabolic efficiency. Epidemiologic studies of diet and disease should therefore be directed at the effect of nutrient intakes independent of total caloric intake in most instances. This is not accomplished with nutrient density measures of dietary intake but can be achieved by employing nutrient intakes adjusted for caloric intake by regression analysis. While pitfalls in the manipulation and interpretation of energy intake data in epidemiologic studies have been emphasized, these considerations also highlight the usefulness of obtaining a measurement of total caloric intake. For instance, if a questionnaire obtained information on only cholesterol intake in a study of coronary heart disease, it is possible that no association with disease would be found even if a real positive effect of a high cholesterol diet existed, since the caloric intake of cases is likely to be less than that of noncases. Such a finding could be appropriately interpreted if an estimate of total caloric intake were available. The relationships between dietary factors and disease are complex. Even with carefully collected measures of intake, consideration of the biologic implications of various analytic approaches is needed to avoid misleading conclusions.
Article
Objectives: The in vitro effect of a vitamin complex in generating and reducing oxidative species in peripheral blood mononuclear cells (PBMNC) and plasma of patients with Alzheimer's disease (AD) and healthy subjects (HS) was evaluated. Methods: Two concentrations of a vitamin complex ([A] and [20A]) with ascorbic acid, alpha-tocopherol, and beta-carotene were incubated with either mononuclear cells or plasma. The generation of oxidizing species was measured in a luminol-dependent chemiluminescence assay and the reducing response by the MTT dye reduction assay. The levels of cytokines (interleukin [IL]-1β, IL-6, and IL-4) were measured by sandwich enzyme-linked immunosorbent assay. Results: Our results demonstrated that the increase in the vitamin complex concentration reduced the reactive oxygen species (ROS) production and enhanced cellular reduction capacity in cells of AD patients in concentration [20A]. Plasma reduction capacity rose significantly for both groups (AD and HS). Concentration [A] did not alter the IL-1β production, increased IL-4 production in both groups and lowered IL-6 production in AD cells. Concentration [20A] increased pro-inflammatory cytokines (IL-1β and IL-6) and decreased IL-4 production by PBMNC of HS leading to a pro-inflammatory status. Discussion: The antioxidant vitamin complex was effective in reducing oxidative stress in PBMNC of AD patients by lowering ROS production, improving cellular antioxidant capacities and modifying cytokine induced inflammation.
Chapter
Total energy intake deserves special consideration in nutritional epidemiology for three reasons: firstly, the level of energy intake may be a primary determinant of disease; secondly, individual differences in total energy intake produce variation in intake of specific nutrients unrelated to dietary composition because the consumption of most nutrients is positively correlated with total energy intake; and, thirdly, when energy intake is associated with risk of disease but is not a direct cause, associations with specific nutrients may be distorted (confounded) by total energy intake. Before examining these three issues in detail, this chapter discusses the physiologic aspects of energy utilization and the determinants of variation in energy intake in epidemiologic studies.