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A randomized trial (VITACOG) in people with mild cognitive impairment (MCI) found that B vitamin treatment to lower homocysteine slowed the rate of cognitive and clinical decline. We have used data from this trial to see whether baseline omega-3 fatty acid status interacts with the effects of B vitamin treatment. 266 participants with MCI aged ≥70 years were randomized to B vitamins (folic acid, vitamins B6 and B12) or placebo for 2 years. Baseline cognitive test performance, clinical dementia rating (CDR) scale, and plasma concentrations of total homocysteine, total docosahexaenoic and eicosapentaenoic acids (omega-3 fatty acids) were measured. Final scores for verbal delayed recall, global cognition, and CDR sum-of-boxes were better in the B vitamin-treated group according to increasing baseline concentrations of omega-3 fatty acids, whereas scores in the placebo group were similar across these concentrations. Among those with good omega-3 status, 33% of those on B vitamin treatment had global CDR scores >0 compared with 59% among those on placebo. For all three outcome measures, higher concentrations of docosahexaenoic acid alone significantly enhanced the cognitive effects of B vitamins, while eicosapentaenoic acid appeared less effective. When omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. A clinical trial of B vitamins combined with omega-3 fatty acids is needed to see whether it is possible to slow the conversion from MCI to AD.
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Journal of Alzheimer’s Disease 50 (2016) 547–557
DOI 10.3233/JAD-150777
IOS Press
547
Omega-3 Fatty Acid Status Enhances
the Prevention of Cognitive Decline
by B Vitamins in Mild Cognitive
Impairment
Abderrahim Oulhaj
a,
, Fredrik Jerner
´
en
b
, Helga Refsum
b,c
, A. David Smith
b
and Celeste A. de Jager
d,
a
Institute of Public Health, College of Medicine and Health Sciences, United Arab Emirates University,
United Arab Emirates
b
OPTIMA, Department of Pharmacology, University of Oxford, Oxford, UK
c
Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo,
Oslo, Norway
d
Division of Geriatric Medicine, Department of Medicine, Faculty of Health Sciences,
University of Cape Town, South Africa
Accepted 26 October 2015
Abstract. A randomized trial (VITACOG) in people with mild cognitive impairment (MCI) found that B vitamin treatment to
lower homocysteine slowed the rate of cognitive and clinical decline. We have used data from this trial to see whether baseline
omega-3 fatty acid status interacts with the effects of B vitamin treatment. 266 participants with MCI aged 70 years were
randomized to B vitamins (folic acid, vitamins B6 and B12) or placebo for 2 years. Baseline cognitive test performance, clinical
dementia rating (CDR) scale, and plasma concentrations of total homocysteine, total docosahexaenoic and eicosapentaenoic
acids (omega-3 fatty acids) were measured. Final scores for verbal delayed recall, global cognition, and CDR sum-of-boxes were
better in the B vitamin-treated group according to increasing baseline concentrations of omega-3 fatty acids, whereas scores in
the placebo group were similar across these concentrations. Among those with good omega-3 status, 33% of those on B vitamin
treatment had global CDR scores >0 compared with 59% among those on placebo. For all three outcome measures, higher
concentrations of docosahexaenoic acid alone significantly enhanced the cognitive effects of B vitamins, while eicosapentaenoic
acid appeared less effective. When omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive
decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. A clinical
trial of B vitamins combined with omega-3 fatty acids is needed to see whether it is possible to slow the conversion from MCI
to AD.
Keywords: Alzheimer’s disease, B vitamins, clinical dementia rating scale, cognition, omega-3 fatty acids
Correspondence to: Celeste de Jager, PhD, Division of Geriatric
Medicine, Department of Medicine, IAA, L51, Old Main Building,
Groote Schuur Hospital, Observatory, 7925, Western Cape, South
Africa. Tel.: +27 21 406 6538; Fax: +27 0 21 406 6846; E-mail:
Celeste.DeJager@uct.ac.za. and Abderrahim Oulhaj, PhD, Institute
of Public Health, College of Medicine and Health Sciences, United
Arab Emirates University, United Arab Emirates. Tel.: +971 3 713
7461; Fax: +971 3 767 2022; E-mail: aoulhaj@uaeu.ac.ae.
INTRODUCTION
Trials to delay or prevent cognitive decline and
Alzheimer’s disease with nutrients are increasingly rel-
evant due to the lack of new drugs to treat older persons
with cognitive impairment. It is likely that the earlier
treatment or preventative measures are introduced, the
better the resulting efficacy of intervention for those
ISSN 1387-2877/16/$35.00 © 2016 – IOS Press and the authors. All rights reserved
This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License.
548 A. Oulhaj et al. / Omega-3 and B Vitamin Interactions on Cognition
with memory impairment, since the loss of neural net-
works is not as great at early stages of cognitive decline
as it is when dementia has become established.
Nutrients involved in different metabolic pathways
that have shown some positive effects on cognition
include B vitamins and omega-3 fatty acids [1–3].
Inadequate B vitamin status results in accumula-
tion of homocysteine, a non-essential amino acid.
Elevated plasma total homocysteine (tHcy) is a recog-
nized modifiable risk factor for cognitive impairment,
Alzheimer’s disease [4], and other dementias [5].
Treatment trials with B vitamins have given conflict-
ing results on cognitive outcomes [6–8], but some trials
carried out specifically on people with elevated tHcy
concentrations have shown positive outcomes. The
FACIT (Folate after Coronary Intervention Trial) trial
[9] of folate treatment for those with baseline tHcy con-
centrations >13 mol/L showed a slowing of decline in
several cognitive domains and improved performance
in episodic memory tests in healthy older people.
The VITACOG trial showed that a B vitamin supple-
ment (folic acid, vitamins B6 and B12) in older adults
with mild cognitive impairment (MCI) slowed the rate
of global [10] and regional brain atrophy [11] and
maintained verbal episodic memory, semantic mem-
ory, and global cognitive performance (Mini-Mental
State Examination, MMSE), but only for those with
high baseline tHcy concentrations. After 2 years on B
vitamins, more than half of those with elevated tHcy
reverted from MCI back to control status, assessed by
the Clinical Dementia Rating (CDR) scale [12].
Eating fish rich in long-chain polyunsaturated fatty
acids, such as the omega-3 fatty acids eicosapentaenoic
acid (EPA) and docosahexaenoic acid (DHA), protects
against the onset of dementia [5]. DHA constitutes
30%–40% of long-chain polyunsaturated fatty acids
in grey matter cerebral cortex [13]. Intervention trials
with DHA and EPA supplements have, like B vitamin
trials, given conflicting results on cognitive outcomes
[14, 15]. Some trials suggest that older adults with
mild cognitive deficits may benefit more from omega-3
fatty acid supplements than those with Alzheimer’s dis-
ease [16–19]. Benefits in visuospatial episodic memory
were seen after 6 months of supplementation with
DHA alone in older adults with mild age-related cog-
nitive decline [18]. Furthermore, in subjects with MCI,
EPA plus DHA improved general cognitive perfor-
mance [17] and letter fluency [20]. A meta-analysis
of ten omega-3-fatty acid randomized controlled trials
reported a benefit for attention and processing speed
in those with cognitive impairment but no dementia
[21], while a more recent meta-analysis of studies on
the memory domain (episodic, sematic, and working
memory) showed that DHA, with or without EPA, con-
tributes to improved memory function in older adults
with mild memory complaints [19].
Differences in trial design may account for some
of the inconsistency in results [8, 14]. Nutritional
interventions to remediate cognition are influenced by
factors such as the stage of cognitive decline, the extent
of nutritional deficiency of the investigated population,
the applied nutrient and its dose, and the duration of the
intervention [22, 23]. Effects will likely be smaller in
healthy adults or those with advanced cognitive impair-
ment [24]. It has also been proposed that combinations
of different nutrients might be more effective than sup-
plementation with single nutrients [3, 25].
In this regard, it is noteworthy that links between
omega-3 fatty acids and homocysteine have been sug-
gested [26]. Homocysteine has a role in regulating
phospholipid metabolism and omega-3 distribution via
the methionine cycle. In turn, B vitamins are important
for the synthesis of phospholipids. The question arises:
is there a beneficial effect of omega-3 fatty acids on the
disease-modifying actions of B vitamins in MCI? We
have already shown that in VITACOG a good omega-
3 fatty acid status enhances the protective effect of B
vitamins on brain atrophy, the primary trail outcome
[27]. In this report, we analyze the VITACOG trial
data to see if there is an interaction between baseline
omega-3 fatty acid status and B vitamin treatment on
the secondary cognitive and clinical outcomes of the
trial.
MATERIALS AND METHODS
The recruitment methods and consent process for the
VITACOG trial, the inclusion and exclusion criteria,
and the neuropsychological tests have been described
previously [10, 12]. 266 participants 70 years and over
with MCI [28] were randomized either to high dose
B vitamins (n = 133) or placebo for 2 years. Baseline
demographics (age, gender, education) and blood lev-
els of tHcy, vitamin B12, serum folate, vitamin B6,
DHA, and EPA were measured, and repeated at the
end of the trial period. APOE allele status, depressive
symptoms with the geriatric depression scale, and other
risk factors for Alzheimer’s disease were also assessed
[10].
Cognitive testing
Cognitive tests were administered at baseline and
at the 2-year end-point as secondary trial outcomes.
A. Oulhaj et al. / Omega-3 and B Vitamin Interactions on Cognition 549
Some cognitive tests were conducted at more than two
time-points during the trial to allow for longitudinal
analyses. These included the Hopkins verbal learn-
ing test (for verbal episodic memory) with delayed
recall (HVLT-DR) using six different versions of the
wordlists [29] to minimize a learning effect, and
the telephone inventory for cognitive status-modified
(TICS-M) [30], which assesses general cognition. The
HVLT-DR was conducted face-to-face at baseline and
two-year endpoint, but by telephone at 3, 6, 12, and
18 month time points. The TICS-M was assessed at
baseline, 15, and 27 months; the latter test was done
three months after the treatment ceased. The CDR [31]
was administered as a clinical and functional measure
to both the participant and informant at baseline and
two-year follow-up. See supplement in de Jager et al.
[12] for detailed descriptions of the tests and scoring.
Biochemical assays
Plasma total DHA and EPA were quantified by gas
chromatography-mass spectrometry (Focus GC-DSQ
II GC-MS system, Thermo Scientific, Hemel Hemp-
stead, UK) as described [27]. The method measures the
combined pool of DHA and EPA in plasma, including
the free fractions, and those esterified into phospho-
lipids, triglycerides, and cholesteryl esters. In short,
30 L non-fasting plasma was transmethylated using
methanolic-HCl (3 N)at95
C for 2 h. Fatty acid methyl
esters were extracted with hexane, and separated on a
BPX70 column (25 m × 0.22 mm, 25 m film, SGE,
Weiterstadt, Germany). DHA and EPA were quantified
by comparison with calibrations curves, corrected for
the presence of internal standard, and absolute concen-
trations were expressed in mol/L. APOE genotype,
plasma tHcy, folate, and vitamin B12 were assayed as
previously described [32].
Statistical methods
The main objective in this study is to show how the
baseline concentration of omega-3 fatty acids modifies
the effect of B vitamin treatment on cognitive function.
The baseline concentrations of combined long-chain
omega-3 fatty acids (DHA and EPA), of DHA alone
and of EPA alone were divided into tertiles for the
placebo group and for the B vitamin group separately.
The concentration split-points and numbers in each
subgroup are shown in Supplementary Table 4. Inter-
action terms were tested using the likelihood ratio test
and were considered significant if their correspond-
ing p values were <0.1. In addition to quantitative
interactions, we also statistically investigated for the
presence of cross-over interactions. This type of inter-
action occurs when one treatment is superior for some
subgroup(s) of patients and the alternative treatment is
superior for another subgroup(s). Please refer to the fol-
lowing papers for examples of cross-over interactions
[33, 34].
For each of the cognitive scores, the last follow up
measure (24 months or, for TICS-M, 27 months) was
statistically modeled as a function of B-vitamin treat-
ment code, baseline omega-3 level (in tertiles) and an
interaction term between both. The model adjusted for
baseline cognitive score, age, gender, APOE4 status,
education, and baseline tHcy. A multiple linear regres-
sion model was used for HVLT-DR, TICS-M, and
CDR-sum-of-boxes (CDRsob). The CDR overall score
was dichotomized into CDR = 0 (normal) or CDR >0
(equivalent to MCI and mild Alzheimer’s disease) and
then used in multiple logistic regression. Longitudinal
changes in HVLT-DR, with the six repeated measures
(using alternate versions) from baseline through to
last follow-up, were analyzed by a linear mixed effect
(LME) model. The LME model included main effects
of treatment, time, and combined omega-3 levels and
two and three-way interactions between these factors.
A random intercept and a random slope were included
in the LME model. We compared the distribution,
across tertiles of omega-3, of demographic and clinical
variables at baseline to identify potential confounders
that might distort the modifying effect of omega-3 on
B vitamin treatment. We dealt with the issue of con-
founding by using adjusted analysis in the multiple
linear regression models [35].
No adjustment procedure for multiplicity was used
when testing for multiple hypothesis testing. All anal-
yses were performed using ‘R’ software version 3.0.3.
RESULTS
Demographics
The B vitamin treated and placebo groups showed
no differences in most demographic variables at
baseline, including age, gender ratio, total years of
education, APOE4 allele status, smoking, blood pres-
sure, BMI, creatinine, tHcy, folate and vitamin B12
concentrations, DHA, EPA and combined omega-
3 concentrations, MMSE, HVLT-DR, TICS-M, and
CDR scores. The treated group had lower baseline
geriatric depression scores than the placebo group
(Table 1). Self-reported use of B vitamin supplements
and fish oils did not differ between the groups.
550 A. Oulhaj et al. / Omega-3 and B Vitamin Interactions on Cognition
Table 1
Demographic variables at baseline for treatment and placebo groups
Variables B vitamins (n = 133) Placebo (n = 133) p-value
Mean ± SD Mean ± SD
Age 76.86 ± 4.89 76.77 ± 4.90 0.872
School Total 14.29 ± 3.35 14.77 ± 3.38 0.242
Gender, n (%)
Male 86 (65) 85 (63) 0.935
Female 47 (35) 49 (37)
APOE4+
Yes 50 (38) 38 (28) 0.140
No 83 (62) 96 (72)
Ever Smokers, n (%)
Yes 58 (44) 68 (51) 0.294
No 74 (56) 65 (49)
Systolic Blood Pressure 147.20 ± 22.41 146.80 ± 19.82 0.876
Diastolic Blood Pressure 80.44 ± 11.19 80.22 ± 10.87 0.875
Body Mass Index (kg/m
2
) 25.76 ± 3.81 26.27 ± 4.17 0.302
tHcy 11.84 ± 3.40 12.14 ± 4.03 0.511
Vitamin B12 364.86 ± 166.52 336.73 ± 105.31 0.101
Serum Folate 27.37 ± 17.96 27.23 ± 18.80 0.951
Creatinine 95.92 ± 16.82 97.91 ± 16.42 0.332
DHA 309.60 ± 117.66 319.35 ± 126.04 0.514
EPA 206.38 ± 131.10 218.68 ± 147.03 0.471
Sum DHA + EPA 515.98 ± 235.01 538.02 ± 363.44 0.471
Vitamin B supplement use, n (%)
Yes 21 (16) 25 (19) 0.647
No 112 (84) 109 (81)
GDS (0 – 30) 6.08 ± 4.43 7.37 ± 4.94 0.025
TICS-M (0 – 39) 24.77 ± 2.88 24.92 ± 2.77 0.663
MMSE (0 – 30) 28.14 ± 1.84 28.21 ± 1.52 0.716
HVLT-DR (0 – 12) 7.72 ± 2.91 7.37 ± 3.20 0.356
tHcy, total homocysteine, DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HVLT-DR,
Hopkins Verbal Learning Test delayed recall score; GDS, geriatric depression scale; TICS-M, Telephone
Inventory for Cognitive status-modified.
Subjects in the different tertiles of omega-3 showed
no differences in most demographic variables at base-
line, including age, total years of education, smoking,
blood pressure, BMI, and vitamin B12 concentra-
tions (Supplementary Table 1). The highest tertiles of
omega-3 were more likely to have a higher proportion
of men, lower levels of tHcy, higher levels of folate,
and lower levels of creatinine.
Linear regression analyses of final cognitive test
performance
Episodic memory (HVLT-DR) at last follow-up
The scores for HVLT-DR at the last follow-up
(24 months) increased in the B vitamin treated
group across increasing tertiles of combined omega-3
fatty acids, whereas the scores in the placebo group
showed negligible change (Fig. 1). The likelihood
ratio test showed a significant interaction between
Fig. 1. Episodic memory score after 2 years according to baseline
omega-3 fatty acid concentration. The interaction between omega-3
tertiles and B vitamin treatment was significant (p = 0.028). In the
third tertile of the combined omega-3 fatty acid concentration, the
memory score in the B vitamin group was higher than in placebo
(p = 0.047). In the B vitamin group, memory score in the 3rd tertile
of omega-3 was higher than in the 1st tertile (p = 0.01). See Table 2.
Columns show mean scores and error bars indicate SEM.
A. Oulhaj et al. / Omega-3 and B Vitamin Interactions on Cognition 551
B-vitamin treatment and plasma combined omega-3
fatty acids (p
interaction
= 0.028) (Table 2). This finding
is mainly due to the 2.08 point difference between
scores (p = 0.010) in the 1st and 3rd tertile of com-
bined omega-3 fatty acids. The HVLT-DR score was
also significantly higher (p = 0.047) in the B vitamin
group compared with the placebo group for those
with combined omega-3 fatty acids in the 3rd ter-
tile (>579 mol/L), while at lower omega-3 levels
there was no significant difference in performance
by treatment code. When HVLT-DR was assessed in
relation to tertiles of baseline plasma concentrations
of DHA and of EPA separately, similar results were
obtained and were particularly significant for DHA
(Supplementary Fig. 1 and Supplementary Tables 2
and 3). Thus, for DHA the interaction was significant
at p = 0.003; in the 3rd tertile the average HVLT-DR
score was 1.7 points higher in the B vitamin treated
group compared with placebo group (p = 0.002). A
marked concentration-dependent effect of DHA was
found in the B vitamin treated group: in the 3rd tertile
the average HVLT-DR score was 1.96 points higher
than in the 2nd tertile (p = 0.015) and 2.53 points
higher than in the 1st tertile (p = 0.001) (Supplementary
Table 2).
Global cognition (TICS-M) at last follow-up
The TICS-M scores at the last follow-up (27 months)
increased in the B vitamin treated group across increas-
ing tertiles of combined omega-3 fatty acids, whereas
the scores in the placebo group were not affected
(Fig. 2). The likelihood ratio test showed a significant
interaction between B vitamin treatment and combined
omega-3 fatty acids (p
interaction
= 0.09). There was also
a significant difference in the treatment effects between
the 3rd and the 1st tertile of combined omega-3 fatty
acids (difference = 2.85 points, p = 0.035) with higher
scores for those in the 3rd tertile (Fig. 2 and Supple-
mentary Table 1).
When TICS-M was assessed in relation to tertiles
of baseline plasma concentrations of DHA and EPA
separately, only higher concentrations of DHA signif-
icantly enhanced the cognitive effects of B vitamins,
p
interaction
= 0.098 (Supplementary Fig. 2 and Supple-
mentary Tables 2 and 3). In the 3rd DHA tertile, there
was a significant effect of B vitamin treatment on
TICS-M (p = 0.041) and in the B vitamin treatment
group there was a concentration-dependent effect of
DHA with a 2.78 point higher TICS-M score in the
3rd tertile compared with the 1st tertile (p = 0.039)
(Supplementary Table 2).
Table 2
Results of the fit of the linear regression model for cognitive and clinical outcomes and concentrations of combined omega-3 fatty acids
(DHA + EPA)
Treatment Effect
1
Overall interaction
3
Tertiles pairwise comparisons
Crude Adjusted p value
2
p value
45
p
1st vs 2nd
p
1stvs3rd
p
2nd vs 3rd
HVLT-DR 0.028
Tertile 1 –0.7 –0.94 0.097 diff = 1.36 diff = 2.08 diff = 0.72
Tertile 2 0.4 0.42 0.44 p = 0.087 p = 0.010 p = 0.37
Tertile 3 2 1.14 0.047
TICS-M 0.09
Tertile 1 –1.6 –1.07 0.25 diff = 1.62 diff = 2.85 diff = 1.23
Tertile 2 0.4 0.55 0.56 p = 0.22 p = 0.035 p = 0.36
Tertile 3 2.8 1.78 0.062
CDR (OR & 95% CI) 0.13
Tertile 1.99 (0.64,6.44) 1.50 (0.48, 4.79) 0.48 diff in diff in log diff in log
Tertile 2 0.41 (0.12, 1.31) 0.43 (0.13, 1.36) 0.15 log OR = –1.25 OR = –1.57 OR = – 0.32
Tertile 3 0.35 (0.11, 1.08) 0.31 (0.10, 0.95) 0.043 p = 0.13 p = 0.053 p = 0.69
CDRsob 0.35
Tertile 1 0.26 –0.03 0.92 diff = – 0.36 diff = –0.50 diff = –0.14
Tertile 2 –0.34 –0.38 0.16 p = 0.34 p = 0.17 p = 0.69
Tertile 3 –0.66 –0.53 0.040
1
Defined as the average score in treated minus the average score in placebo for HVLT-DR, TICS-M and CDRsob. For CDR it is the OR ratio for
a worse outcome comparing treated to placebo. The crude estimate uses the raw data without any statistical modeling. The adjusted treatment
effect was obtained by using statistical modeling and adjusting for baseline cognitive score, age, gender, APOE4 status, education, and baseline
tHcy.
2
This is the p-value for testing the null hypothesis of no treatment effect within a fixed tertile. This applies to adjusted analysis only.
3
Overall interaction tests the null hypothesis that treatment effects in 1st, 2nd and 3rd tertiles are all the same.
4
This is the p-value for testing
the null hypothesis of no overall interaction.
5
p
1st vs 2nd
is the p-value for testing the null hypothesis that treatment effects in 1st and 2rd tertiles
are the same. The same applies for p
1st vs 3rd
and p
2nd vs 3rd
.
552 A. Oulhaj et al. / Omega-3 and B Vitamin Interactions on Cognition
Clinical dementia rating: CDR (binary variable)
at last follow-up
The proportion of participants who had a CDR over-
all score of >0 (worse outcome) at the 24 month
follow-up is shown in Fig. 3A. In the 3rd tertile of
baseline combined omega-3 fatty acids only 33% of
those on B vitamin treatment had CDR scores >0 com-
pared with 59% in the placebo group. Also, in the 3rd
tertile, B vitamins markedly reduced the risk of hav-
ing CDR scores >0 (adjusted OR 0.31, 95% CI 0.10,
0.95; p = 0.043) (Table 2). There was a trend for a
Fig. 2. Global cognition after 2 years according to baseline omega-3
fatty acid concentration. The interaction between omega-3 tertiles
and B vitamin treatment was significant (p = 0.09). In the B vitamin
group, global cognition score in the 3rd tertile of omega-3 was higher
than in 1st tertile (p = 0.035). See Table 2. Columns show mean
scores and error bars indicate SEM.
concentration-dependent effect of combined omega-3
fatty acids: the proportion scoring >0 in the B vitamin
group declined from 70% to 33% from the 1st tertile
to the 3rd tertile (p = 0.053).
Significant interaction effects were also found for
DHA (p
interaction
= 0.097), with an adjusted odds ratio
of 0.26 (95% CI 0.08, 0.81) for a worse CDR, com-
paring B vitamin treated versus placebo in the 3rd
tertile of DHA (p = 0.022) (Supplementary Table 2 and
Supplementary Fig. 3A). There was a concentration-
dependent effect of DHA in the B vitamin group with
a greater improvement in the 3rd than in the 1st ter-
tile (p = 0.034) (Supplementary Table 2). The effects
of EPA on the CDR showed similar patterns but did
not reach significance (Supplementary Table 3 and
Supplementary Fig. 3B).
Clinical dementia rating: CDR-sum-of-boxes at
last follow-up
The average scores for CDRsob are shown in
Fig. 3B. The likelihood ratio test failed to show a sig-
nificant overall interaction at level 10% between
B-vitamin treatment and plasma combined omega-3
fatty acids on CDRsob (p
interaction
= 0.35). However,
there was a significant difference in the average
CDRsob score in the 3rd omega-3 tertile between
B vitamin and placebo groups: average difference=–
0.53, p = 0.040 (Table 2). For DHA alone there was a
significant effect of B vitamin treatment on CDRsob
in the third tertile of DHA (p = 0.03). For EPA alone,
Fig. 3. (A) Clinical Dementia Rating score after 2 years according to baseline omega-3 fatty acid concentration. The interaction between
omega-3 tertiles and B vitamin treatment did not reach significance (p = 0.13). In the 3rd tertile of combined omega-3 fatty acids, the percent
of subjects with CDR >0 was lower in the B vitamin group than in the placebo group (p = 0.043). See Table 2. Columns show mean scores and
error bars indicate SEM. (B) Clinical Dementia Rating sum of boxes score after 2 years according to baseline omega-3 fatty acid concentration.
The interaction between omega-3 tertiles and B vitamin treatment was not significant (p = 0.35). In the 3rd tertile of combined omega-3 fatty
acids, the CDRsob score was lower in the B vitamin group than in the placebo group (p = 0.040). See Table 2. Columns show mean scores and
error bars indicate SEM.
A. Oulhaj et al. / Omega-3 and B Vitamin Interactions on Cognition 553
Fig. 4. Longitudinal scores of episodic memory (HVLT-DR) across tertiles of combined omega-3 fatty acids. Solid line: B vitamin group;
dashed line: placebo group. Ranges of the tertiles are given in Supplementary Table 4. The likelihood ratio test for interaction between B vitamin
treatment and combined omega-3 tertiles was significant at an alpha level 10% (p = 0.086, Supplementary Table 6). In the 3rd tertile of combined
omega-3, the average HVLT-DR significantly increased in the B vitamin group by 0.46 points per year of follow-up (p = 0.013) compared to no
significant change in the placebo group (Supplementary Table 6). Error bars represent SEM.
the pattern was similar but did not reach significance
(Supplementary Tables 2 and 3; Supplementary
Fig. 4A, B).
Longitudinal analysis of episodic memory
(HVLT-DR)
The results of fitting the linear mixed effects model
on the repeated measures of HVLT-DR showed that the
effect of B-vitamin treatment depended on the base-
line plasma concentration of combined omega-3 fatty
acids and DHA alone (Fig. 4, Supplementary Fig. 6A,
Supplementary Table 6). The likelihood ratio test for
interaction between B vitamin treatment and com-
bined omega-3 was significant at an alpha level 10%
(p = 0.086) and also for interaction between B vita-
min treatment and DHA (p = 0.025), but did not reach
significance for EPA (Supplementary Table 6). The
modifying effect of omega-3 was mainly characterized
by different slopes in placebo and B vitamin group in
the 3rd tertile compared to the 1st tertile. For example,
in the 3rd tertile of combined omega-3, the average
HVLT-DR significantly increased in the B vitamin
group by 0.46 points per year of follow-up (p = 0.013)
compared to no significant change in the placebo group
(p = 0.91). However, in the 1st tertile, there were no
significant changes in HVLT-DR in either placebo
(p = 0.36) or B-vitamin groups (p = 0.44). The same
pattern occurred for the third tertile of DHA (Sup-
plementary Fig. 5A) with an increase in HVLT-DR
score of 0.46 points per year in the B vitamin group
(p = 0.009), but no significant change in the placebo
group (Supplementary Table 6). The pattern for EPA
was similar to that for DHA (Supplementary Fig. 5B)
but did not reach significance (Supplementary Table 6).
Testing for qualitative or cross-over interactions
We observed a consistent trend for subjects in the
lowest tertile of omega-3: B-vitamin treatment, com-
pared with placebo, appeared to be associated with
lower cognitive scores. However, there is no evidence
for any cross-over interactions as shown in Supple-
mentary Table 5. This means that treatment effects are
not in opposite directions across tertiles of omega-3.
Although this observation was not significant on anal-
ysis of cross-over interactions, it will be important to
examine this possibility in other observational stud-
ies and clinical trials. Residual confounding cannot be
excluded.
DISCUSSION
This study revealed significant beneficial effects of
higher baseline omega-3 fatty acid concentrations on
certain cognitive and clinical outcomes of B vitamin
treatment in older persons with MCI, both cross-
sectionally at the study end, and longitudinally for
episodic memory, over the 2-year intervention period.
The cross-sectional regression analyses for all cog-
nitive and clinical outcomes tested showed similar
patterns. For participants with high baseline levels
of omega-3 fatty acids, the B vitamin treated group
performed better than placebo, while those with low
baseline omega-3 fatty acids did not benefit from B
vitamin supplementation. In general, the effects were
554 A. Oulhaj et al. / Omega-3 and B Vitamin Interactions on Cognition
more significant for DHA alone than for EPA or com-
bined omega-3 fatty acids, especially for the HVLT-DR
and TICS-M. However, due to the small number of
participants and a considerable co-variation between
DHA and EPA, the present data set is not ideal for sep-
arating effects between the two fatty acids. Overall,
DHA and EPA showed similar patterns on all cog-
nitive outcomes (see Supplementary Figures). These
results should be used for hypothesis generation and
optimization of future trials.
As mentioned in the Introduction, trials of both
omega-3 fatty acids and, separately, of B vitamins
have given conflicting results regarding cognitive
outcomes. Nevertheless, some previous studies have
shown benefits of omega-3 fatty acid treatment alone
on various types of memory [14, 19], attention and
processing speed [21], as well as global cognition [17],
while trials with B vitamins have shown benefits on
episodic memory, verbal fluency, and global cognition
in people with high baseline tHcy [9, 12]. We find
here that this beneficial effect of B vitamin treatment
on cognition only clearly occurs in those with a
good omega-3 fatty acid status. A similar interaction
between omega-3 fatty acid status and B vitamin
treatment was found in VITACOG for the slowing of
brain atrophy rate [27]. Our previous findings revealed
that cognitive scores including the HVLT-DR and
TICS-M decline more rapidly in those with the most
brain atrophy [36]. We discuss below the likely causal
links between cognitive scores and regional brain
atrophy.
On the whole, trials on the efficacy of B vitamin sup-
plementation for cognitive impairment have produced
variable and sometimes negative results (see Introduc-
tion). Our results lead us to suggest that the variable
outcomes might in part be related to different omega-3
fatty acid status in the trial participants, either due to
diet or supplement intake. If intake is not monitored at
baseline and controlled for in the randomization of par-
ticipants to treatment, omega-3 status may confound
the results. Future trials of B vitamin treatment should
accordingly control for omega-3 fatty acid status. The
different cognitive outcomes used may also account for
variable outcomes in clinical trials. Manders et al. [24]
found that general cognitive tests such as the MMSE
often did not show effects for nutrients. But positive
results were obtained when domain-specific tests were
used, especially for fluid rather than crystallized ability,
such as information processing. We found significant
results for the episodic memory domain (HVLT-DR)
and for general cognition with the TICS-M. However,
the TICS-M contains more memory items than the
MMSE and is a more sensitive test for cognitive decline
[30].
There has been one randomized trial with a com-
bination of B vitamins and omega-3 fatty acids in
which cognition was assessed [37]. This was a sec-
ondary prevention trial in patients with cardiovascular
disease, but only one cognitive assessment was done,
at the end of the trial, and so it was not possible to
study the effect of the treatment upon cognitive decline.
Overall, no significant treatment effects were found
on the final cognitive test scores, apart from a higher
score in temporal orientation in those with a history of
ischemic stroke and a lower score in semantic mem-
ory in those with a history of heart disease. This trial
was not designed to study cognitive decline, and used
doses of nutrients at dietary levels rather than pharma-
cological levels; it is thus not suitable for answering
the question of whether omega-3 fatty acids enhance
the slowing effect of B vitamins on cognitive decline.
A randomized trial should now be performed with
high dose combinations of these supplements in peo-
ple who will experience cognitive decline during the
trial period, such as those with MCI.
The findings from VITACOG, here on cognition
and earlier on brain atrophy [27], are evidence of an
interaction between two different classes of nutrients,
B vitamins and omega-3 fatty acids, in people with
MCI. Possible mechanisms for this interaction have
been discussed in our earlier report [27] and include
the hypothesis that B vitamins facilitate the forma-
tion of phosphatidylcholine (PC) enriched in omega-3
fatty acids from phosphatidylethanolamine (Fig. 5)
and hence the transport of omega-3 fatty acids into
the brain [26, 38]. PC synthesized by this B vitamin-
Fig. 5. Metabolic interactions in the homocysteine methy-
lation cycle with omega-3 fatty acids. Hcy, homocysteine;
PEMT, phosphatidylethanolamine N-methyl transferase; SAH, S-
adenosylhomocysteine; SAM, S-adenosylmethionine; THF, tetrahy-
drofolate.
A. Oulhaj et al. / Omega-3 and B Vitamin Interactions on Cognition 555
dependent pathway has been shown to contain higher
levels of polyunsaturated fatty acids, including omega-
3, compared with the alternative CDP-choline pathway
[39, 40]. Selley [26] found that the raised plasma S-
adenosylhomocysteine in patients with Alzheimer’s
disease was associated with decreased erythrocyte
concentrations of PC and with increased concen-
trations of phosphatidylethanolamine; he therefore
suggested that raised homocysteine inhibits phos-
phatidylethanolamine methyltransferase. Selley [26]
also found that the PC in Alzheimer’s disease erythro-
cytes was relatively depleted in DHA. It is noteworthy
that decreased levels of polyunsaturated fatty acids
in PC occur in the brain in Alzheimer’s disease [38].
Also, low levels of omega-3 fatty acids (DHA and
EPA) in plasma PC are a risk factor for dementia [41]
and have been found in plasma PC in patients with
Alzheimer’s disease [42]. Animal experiments are con-
sistent with the above hypothesis: rats made deficient
in folate had impaired spatial memory performance
and showed a halving in brain PC concentration and
an increase in brain phosphatidylethanolamine [43].
Notably, the memory deficit and the decline in brain
PC were both reversed by treatment of the rats with
methionine. It remains to be shown whether the deple-
tion of brain PC in folate deficiency is associated with
a loss of polyunsaturated fatty acids.
The striking agreement between the results on the
rate of brain atrophy and on cognitive decline in
VITACOG raises the question of whether the two
outcomes are causally linked. We have previously
addressed this question by mediation analysis [11].
We found associations between cognitive decline and
loss of gray matter in specific brain regions. Worsen-
ing of CDRsob and MMSE scores was associated with
gray matter loss, most pronounced bilaterally in the
amygdalo-hippocampal complex and entorhinal cor-
tex. Decreases in HVLT-delayed recall and category
fluency scores were associated with increased gray
matter loss in the left hippocampus and entorhinal cor-
tex. These gray matter regions involved in cognitive
decline also showed a marked reduction of atrophy
with B-vitamin treatment in subjects with high tHcy
levels. We found that the optimal Bayesian network
model explaining our data indicated the following
causal chain of events: B vitamin treatment (mainly
vitamin B12) caused a fall in tHcy levels, which
reduced the rate of gray matter atrophy, which, in turn,
delayed cognitive decline (HVLT-DR, category flu-
ency, CDRsob) [11]. It would be of interest to see what
the effect would be of the inclusion of omega-3 fatty
acid status in these analyses.
A limitation of our study is that omega-3 fatty acids
were not supplemented during the trial, so the find-
ings only relate to baseline levels. Another limitation,
which may account for the variability between sub-
groups, was the small number of participants in some
of the subgroups. The small numbers also prevented us
from looking for modifying factors, such as the pos-
sible interaction between the effects of omega-3 fatty
acids and APOE4 status [44].
In conclusion, when plasma omega-3 fatty acid con-
centrations are low, B vitamin treatment does not slow
cognitive decline in people with MCI. In contrast, when
omega-3 fatty acid levels are in the upper range of nor-
mal, the slowing effects of B vitamins on both brain
atrophy [27] and cognitive decline are enhanced. We
suggest that the effects of this interaction between the
two nutrients on brain atrophy and cognition is con-
sistent with the view that they slow down the disease
process in MCI. These results may have public health
implications. It will be important to test in a clinical
trial whether the administration of these two nutrients
will delay the conversion from MCI to dementia.
ACKNOWLEDGMENTS
We are grateful for contributions from the OPTIMA
team, in particular the nurses, and to a principal inves-
tigator for the study, Professor Robin Jacoby, and to
all the volunteers who took part in the trial. We thank
Carole Johnston, Cynthia Prendergast and Cheryl
Turner for laboratory analyses. This study was sup-
ported by grants from UK MRC, Charles Wolfson
Charitable Trust, Norman Collisson Foundation and
Norwegian Research Council.
Authors’ disclosures available online (http://j-alz.
com/manuscript-disclosures/15-0777r1).
SUPPLEMENTARY MATERIAL
The supplementary material is available in the
electronic version of this article: http://dx.doi.org/
10.3233/JAD-150777.
REFERENCES
[1] G
´
omez-Pinilla F (2008) Brain foods: The effects of nutrients
on brain function. Nat Rev Neurosci 9, 568-578.
[2] Gillette-Guyonnet S, Secher M, Vellas B (2013) Nutrition and
neurodegeneration: Epidemiological evidence and challenges
for future research. Br J Clin Pharmacol 75, 738-755.
[3] Barberger-Gateau P (2014) Nutrition and brain aging: How
can we move ahead? Eur J Clin Nutr 68, 1245-1249.
556 A. Oulhaj et al. / Omega-3 and B Vitamin Interactions on Cognition
[4] Hooshmand B, Polvikoski T, Kivipelto M, Tanskanen M,
Myllykangas L, Erkinjuntti T, Makela M, Oinas M, Paetau
A, Scheltens P, van Straaten EC, Sulkava R, Solomon A
(2013) Plasma homocysteine, Alzheimer and cerebrovascu-
lar pathology: A population-based autopsy study. Brain 136,
2707-2716.
[5] Beydoun MA, Beydoun HA, Gamaldo AA, Teel A, Zonder-
man AB, Wang Y (2014) Epidemiologic studies of modifiable
factors associated with cognition and dementia: Systematic
review and meta-analysis. BMC Public Health 14, 643.
[6] Ford AH, Almeida OP (2012) Effect of homocysteine lower-
ing treatment on cognitive function: A systematic review and
meta-analysis of randomized controlled trials. J Alzheimers
Dis 29, 133-149.
[7] Clarke R, Bennett D, Parish S, Lewington S, Skeaff M, Eussen
SJ, Lewerin C, Stott DJ, Armitage J, Hankey GJ, Lonn E,
Spence JD, Galan P, de Groot LC, Halsey J, Dangour AD,
Collins R, Grodstein F, on behalf of the BVTTC (2014) Effects
of homocysteine lowering with B vitamins on cognitive aging:
Meta-analysis of 11 trials with cognitive data on 22,000 indi-
viduals. Am J Clin Nutr 100, 657-666.
[8] McCaddon A, Miller JW (2015) Assessing the association
between homocysteine and cognition: Reflections on Brad-
ford Hill, meta-analyses and causality. Nutr Rev 73, 723-735.
[9] Durga J, van Boxtel MP, Schouten EG, Kok FJ, Jolles J, Katan
MB, Verhoef P (2007) Effect of 3-year folic acid supple-
mentation on cognitive function in older adults in the FACIT
trial: A randomised, double blind, controlled trial. Lancet 369,
208-216.
[10] Smith AD, Smith SM, de Jager CA, Whitbread P, John-
ston C, Agacinski G, Oulhaj A, Jacoby R, Refsum H (2010)
Homocysteine-lowering by B vitamins slows the rate of
accelerated brain atrophy in mild cognitive impairment. A
randomized controlled trial. PLoS One 5, e12244.
[11] Douaud G, Refsum H, de Jager CA, Jacoby R, Nichols TE,
Smith SM, Smith AD (2013) Preventing Alzheimer’s disease-
related gray matter atrophy by B-vitamin treatment. Proc Natl
Acad SciUSA110, 9523-9528.
[12] de Jager CA, Oulhaj A, Jacoby R, Refsum H, Smith AD
(2012) Cognitive and clinical outcomes of homocysteine-
lowering B-vitamin treatment in mild cognitive impairment:
A randomized controlled trial. Int J Geriatr Psychiatry 27,
592-600.
[13] Lauritzen L, Hansen HS, Jorgensen MH, Michaelsen KF
(2001) The essentiality of long chain n-3 fatty acids in rela-
tion to development and function of the brain and retina. Prog
Lipid Res 40, 1-94.
[14] Dacks PA, Shineman DW, Fillit HM (2013) Current evidence
for the clinical use of long-chain polyunsaturated n-3 fatty
acids to prevent age-related cognitive decline and Alzheimer’s
disease. J Nutr Health Aging 17, 240-251.
[15] Chew EY, Clemons TE, Agron E, Launer LJ, Grodstein F,
Bernstein PS, Age-Related Eye Disease Study 2 Research
G (2015) Effect of omega-3 fatty acids, Lutein/Zeaxanthin,
or other nutrient supplementation on cognitive function: The
AREDS2 randomized clinical trial. JAMA 314, 791-801.
[16] Freund-Levi Y, Eriksdotter-Jonhagen M, Cederholm T, Basun
H, Faxen-Irving G, Garlind A, Vedin I, Vessby B, Wahlund
LO, Palmblad J (2006) Omega-3 fatty acid treatment in 174
patients with mild to moderate Alzheimer disease: OmegAD
study: A randomized double-blind trial. Arch Neurol 63, 1402-
1408.
[17] Chiu CC, Su KP, Cheng TC, Liu HC, Chang CJ, Dewey
ME, Stewart R, Huang SY (2008) The effects of omega-3
fatty acids monotherapy in Alzheimer’s disease and mild cog-
nitive impairment: A preliminary randomized double-blind
placebo-controlled study. Prog Neuropsychopharmacol Biol
Psychiatry 32, 1538-1544.
[18] Yurko-Mauro K, McCarthy D, Rom D, Nelson EB, Ryan AS,
Blackwell A, Salem N Jr, Stedman M (2010) Beneficial effects
of docosahexaenoic acid on cognition in age-related cognitive
decline. Alzheimers Dement 6, 456-464.
[19] Yurko-Mauro K, Alexander DD, Van Elswyk ME (2015)
Docosahexaenoic acid and adult memory: A systematic
review and meta-analysis. PLoS One 10, e0120391.
[20] Sinn N, Milte CM, Street SJ, Buckley JD, Coates AM,
Petkov J, Howe PR (2012) Effects of n-3 fatty acids, EPA v.
DHA, on depressive symptoms, quality of life, memory and
executive function in older adults with mild cognitive impair-
ment: A 6-month randomised controlled trial. Br J Nutr 107,
1682-1693.
[21] Mazereeuw G, Lanctot KL, Chau SA, Swardfager W, Her-
rmann N (2012) Effects of omega-3 fatty acids on cognitive
performance: A meta-analysis. Neurobiol Aging 33, 1482
e1417-1429.
[22] Morris MC, Tangney CC (2011) A potential design flaw of
randomized trials of vitamin supplements. JAMA 305, 1348-
1349.
[23] de Jager CA, Dye L, de Bruin EA, Butler L, Fletcher J, Lam-
port DJ, Latulippe ME, Spencer JP, Wesnes K (2014) Criteria
for validation and selection of cognitive tests for investigating
the effects of foods and nutrients. Nutr Rev 72, 162-179.
[24] Manders M, de Groot LC, van Staveren WA, Wouters-
Wesseling W, Mulders AJ, Schols JM, Hoefnagels WH (2004)
Effectiveness of nutritional supplements on cognitive func-
tioning in elderly persons: A systematic review. J Gerontol A
Biol Sci Med Sci 59, 1041-1049.
[25] Kamphuis PJ, Scheltens P (2010) Can nutrients prevent or
delay onset of Alzheimer’s disease? J Alzheimers Dis 20, 765-
775.
[26] Selley ML (2007) A metabolic link between S-adenosyl-
homocysteine and polyunsaturated fatty acid metabolism in
Alzheimer’s disease. Neurobiol Aging 28, 1834-1839.
[27] Jerner
´
en F, Elshorbagy AK, Oulhaj A, Smith SM, Refsum
H, Smith AD (2015) Brain atrophy in cognitively impaired
elderly: The importance of long-chain omega-3 fatty acids
and B vitamin status in a randomized controlled trial. Am J
Clin Nutr 102, 215-221.
[28] Petersen RC (2004) Mild cognitive impairment as a diagnostic
entity. J Intern Med 256, 183-194.
[29] Brandt J (1991) The Hopkins Verbal Learning Test: Develop-
ment of a new memory test with six equivalent forms. Clin
Neuropsychol 5, 125-142.
[30] de Jager CA, Budge MM, Clarke R (2003) Utility of TICS-m
for the assessment of cognitive function in older adults. Int J
Geriatr Psychiatry 18, 318-324.
[31] Morris JC (1993) The Clinical Dementia Rating (CDR): Cur-
rent version and scoring rules. Neurology 43, 2412-2414.
[32] Vogiatzoglou A, Refsum H, Johnston C, Smith SM, Bradley
KM, de Jager C, Budge MM, Smith AD (2008) Vitamin B12
status and rate of brain volume loss in community-dwelling
elderly. Neurology 71, 826-832.
[33] Gail M, Simon R (1985) Testing for qualitative interactions
between treatment effects and patient subsets. Biometrics 41,
361-372.
[34] Pan G, Wolfe DA (1997) Test for qualitative interaction of
clinical significance. Stat Med 16, 1645-1652.
[35] Maldonado G, Greenland S (1993) Simulation study of
confounder-selection strategies. Am J Epidemiol 138, 923-
936.
A. Oulhaj et al. / Omega-3 and B Vitamin Interactions on Cognition 557
[36] de Jager CA (2014) Critical levels of brain atrophy associated
with homocysteine and cognitive decline. Neurobiol Aging
35(Suppl 2), S35-S39.
[37] Andreeva VA, Kesse-Guyot E, Barberger-Gateau P, Fezeu L,
Hercberg S, Galan P (2011) Cognitive function after sup-
plementation with B vitamins and long-chain omega-3 fatty
acids: Ancillary findings from the SU.FOL.OM3 randomized
trial. Am J Clin Nutr 94, 278-286.
[38] Liu JJ, Green P, John Mann J, Rapoport SI, Sublette ME
(2015) Pathways of polyunsaturated fatty acid utilization:
Implications for brain function in neuropsychiatric health and
disease. Brain Res 1597, 220-246.
[39] DeLong CJ, Shen YJ, Thomas MJ, Cui Z (1999) Molecu-
lar distinction of phosphatidylcholine synthesis between the
CDP-choline pathway and phosphatidylethanolamine methy-
lation pathway. J Biol Chem 274, 29683-29688.
[40] Pynn CJ, Henderson NG, Clark H, Koster G, Bernhard W,
Postle AD (2011) Specificity and rate of human and mouse
liver and plasma phosphatidylcholine synthesis analyzed in
vivo. J Lipid Res 52, 399-407.
[41] Schaefer EJ, Bongard V, Beiser AS, Lamon-Fava S, Robins
SJ, Au R, Tucker KL, Kyle DJ, Wilson PW, Wolf PA (2006)
Plasma phosphatidylcholine docosahexaenoic acid content
and risk of dementia and Alzheimer disease: The Framingham
Heart Study. Arch Neurol 63, 1545-1550.
[42] Whiley L, Sen A, Heaton J, Proitsi P, Garcia-Gomez D, Leung
R, Smith N, Thambisetty M, Kloszewska I, Mecocci P, Soini-
nen H, Tsolaki M, Vellas B, Lovestone S, Legido-Quigley C,
AddNeuroMed C (2014) Evidence of altered phosphatidyl-
choline metabolism in Alzheimer’s disease. Neurobiol Aging
35, 271-278.
[43] Troen AM, Chao WH, Crivello NA, D’Anci KE, Shukitt-
Hale B, Smith DE, Selhub J, Rosenberg IH (2008) Cognitive
impairment in folate-deficient rats corresponds to depleted
brain phosphatidylcholine and is prevented by dietary methio-
nine without lowering plasma homocysteine. J Nutr 138,
2502-2509.
[44] Barberger-Gateau P, Samieri C, Feart C, Plourde M (2011)
Dietary omega 3 polyunsaturated fatty acids and Alzheimer’s
Disease: Interaction with apolipoprotein E genotype. Curr
Alzheimer Res 8, 479-491.

Supplementary resource (1)

... The Smith AD team analyzed the potential role of ω-3 fatty acids in reducing the therapeutic effect of Hcy-lowering B vitamins on brain atrophy rate in the VITACOG trial in 2015 [34] and 2016 [35]. The results showed that in subjects with high baseline levels of ω-3 fatty acids (> 590µmol/L), B vitamin treatment reduced the average brain atrophy rate by 40.0% compared to placebo (P = 0.023), while it had no signi cant effect on brain atrophy rate in subjects with low baseline levels of ω-3 fatty acids (< 390µmol/L). ...
... Therefore, routine Hcy examination is recommended for individuals above 50, and FA and other B-complex vitamins supplementation is advised if Hcy levels exceed 11.3 µmol/L [33]. Besides that, maintaining a good ω-3 fatty acid status (> 590 µmol/L) enhances the brain-protective effect of B-complex vitamins [34,35], hence supplementing ω-3 fatty acids along with FA is recommended, but optimal dosage needs further research. ...
Preprint
Full-text available
Background Homocysteine is a high-risk factor for cognitive decline, and supplementing with B vitamins such as folic acid can lower homocysteine levels. However, current clinical research results are inconsistent, and the effects of B vitamins on homocysteine levels and cognitive function in older people are inconsistent. Methods Systematic searches were conducted in five databases including PubMed, Embase, the Cochrane Library, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL), from inception to March 1, 2023. Randomized controlled trials investigating the effects of folic acid alone or in combination with other nutrients on cognitive function in patients with cognitive disorders were included. The quality of the literature was evaluated using RevMan 5.4. Results 17 articles were reviewed, with 6 focusing on the effects of folic acid alone and 11 examining folic acid in combination with other nutrients. folic acid dosages ranged from 400 µg to 5 mg, and intervention durations varied from 4 weeks to 3 years. The study included 3,100 individuals, aged 60 to 83.2 years, with a relatively equal gender distribution (approximately 51.82%). Conclusion Most studies have shown that folic acid alone or in combination with other nutrients can effectively improve cognitive function in patients with mild cognitive impairment. For patients with Alzheimer's disease and dementia, folic acid alone or in combination with other nutrients can reduce the level of homocysteine, but the improvement in cognitive function is not significant. In healthy older people, high baseline homocysteine levels (> 11.3 µmol/L) and good ω-3 fatty acid status (> 590 µmol/L) can enhance the improvement effect of B vitamins on cognitive function. This trial has been registered on PROSPERO as CRD42023408576.
... Especially when combined with environmental enrichment, antioxidants have been shown to improve the learning ability and memory of old dogs [26,37,43,84]. In human medicine, various studies show that deficiencies in vitamin B may lead to cognitive impairment [51,85] and the supplementation of this vitamin can slow cognitive decline [86]. This is because B vitamins play a crucial role in brain metabolism, as they are important cofactors in numerous methylation reactions in the brain [85,87]. ...
Article
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Simple Summary Canine cognitive dysfunction is considered the canine equivalent to human Alzheimer’s disease. It is a growing concern in veterinary medicine, as it affects many aged dogs. Dietary intervention with different diets and supplements may improve clinical signs and prevent further degeneration. Using an online questionnaire, we found that even though few owners were willing to change their dog’s main diet, many of them added supplements such as oils and vitamins. Consulting a veterinary surgeon when using dietary supplements is important as it allows for evidence-based recommendations to be made. Abstract Canine cognitive dysfunction (CCD) is becoming increasingly recognized in veterinary medicine, as dogs live longer and with CCD being highly prevalent among the elderly dog population. Various studies have shown that diet and dietary supplementation can positively influence the clinical signs of CCD, especially if given at an early stage. The aim of this study was to investigate owner use of dietary supplements (DSs) in dogs with age-related behavioral changes. An observational study based on an online questionnaire for owners of dogs with age-related behavioral changes was performed. Out of a total of 394 owners who completed the survey, after noticing age-related behavioral changes, over half of the dogs received DSs (54%), whereas only 8% reported changing their dog’s base diet. The most used DS was fish oil (48%). The use of DSs should be discussed with and monitored by veterinary surgeons since many geriatric patients have multi-morbidities, may have specific nutritional requirements and receive multi-faceted medications.
... These results are consistent with a metaanalysis of 7 randomized clinical trials including 585 healthy individuals showing no significant effects of omega-3 fatty acid supplementation on cognitive function, assessed using MMSE scores, or other cognitive domains such as attention, processing speed, delayed recall or memory among healthy individuals [44]. Post-hoc analyses of two randomized trials suggest potential complementary interactions between omega-3 status and B vitamin status [45,46]; such a possibility requires more study. Prior observational studies also do not provide strong support for beneficial associations of circulating omega-3 PUFA with cognitive impairment or dementia [47][48][49][50][51], although two studies found inverse associations between seafood-derived EPA or DHA, not DPA, and risk of dementia [47,48]. ...
Article
Background: Comprising nearly 35% of brain lipids, polyunsaturated fatty acids (PUFA) are essential for optimal brain function. However, the role of PUFA on cognitive health outcomes later in life is largely unknown. Objective: We investigated prospective associations of plasma phospholipid omega-3 (ALA [18 : 3], EPA [20 : 5], DPA [22 : 5], DHA [22 : 6]) and omega-6 (LA [18 : 2], AA [20 : 4]) PUFA with cognitive decline, risk of cognitive impairment and dementia among adults aged≥65 years in the Cardiovascular Health Study. Methods: Circulating fatty acid concentrations were measured serially at baseline (1992/1993), 6 years, and 13 years later. Cognitive decline and impairment were assessed using the 100-point Modified Mini-Mental State Examination (3MSE) up to 7 times. Clinical dementia was identified using adjudicated neuropsychological tests, and ICD-9 codes. Results: Among 3,564 older adults free of stroke and dementia at baseline, cognitive function declined annually by approximately -0.5 3MSE points; 507 participants developed cognitive impairment and 499 dementia over up to 23 years of follow-up. In multivariable models, higher circulating arachidonic acid (AA) concentrations were associated with slower cognitive decline and lower dementia risk, with associations growing stronger with greater length of follow-up (hazard ratio [HR,95% CI] of dementia per interquintile range, 0.74 [0.56-0.97] at 5 years, and 0.53 [0.37-0.77] at 15 years). Circulating docosapentaenoic (DPA) concentrations were associated with slower cognitive decline and lower risk of cognitive impairment (extreme-quintile HR, 0.72 [95% CI: 0.55, 0.95]). Findings were generally null or inconsistent for other omega-3 or omega-6 PUFA. Conclusion: Circulating AA and DPA, but not other PUFA, are associated with slower rate of cognitive decline and lower risk of dementia or cognitive impairment later in life.
... It is important to understand the effects of such molecules that could have a parallel or adjuvant effect on B vitamins. For example, in a post hoc analysis of results from the VITACOG trial, it was shown that only participants with a better status of omega 3 polyunsaturated fatty acids (PUFAs) at baseline exhibited a beneficial effect of B vitamins treatments, slowing clinical and cognitive decline as well as brain atrophy (Oulhaj, Jerner en, Refsum, Smith, & de Jager, 2016). Polyunsaturated fatty acids appear to interact with one-carbon metabolism, stimulating various enzymes that take part in the Hcy cycle such as methylenetetrahydrofolate reductase, cystathionine-γ lyase, methionine adenosyltransferase, and other enzymes indirectly related to the degradation of Hcy via betaine, such as cholinephosphate cytidylyltransferase and phosphatidylethanolamine N-methyltransferase (Rizzo & Laganà, 2020b). ...
Chapter
B vitamins are crucial nutrients for nervous system functions. This is particularly evident in the case of nutritional B vitamin deficiency (mainly folate and cobalamin), with the onset of neurological dysfunction in the advanced stages of shortage. Homocysteine is a functional marker of B vitamins, and higher blood homocysteine concentrations were seen among people with cognitive disorders, including dementia and Alzheimer's disease. However, it is not so clear if homocysteine can be a marker of dementia or a mere consequence of vitamin deficiency linked to secondary phenomena. Interventional trials with folic acid and cobalamin gave mixed results so it can be crucial to understand if monitoring of B vitamins could prevent or postpone dementia signs. This chapter deepens the link between B vitamins and dementia, focusing on folate, vitamin B12, and their functional marker homocysteine.
... Observational studies associating nutritional factors to better cognitive function have suggested that nutritional supplementation could be a possible intervention pathway to prevent cognitive decline and Alzheimer's disease (AD) (1)(2)(3)(4)(5)(6)(7). While ambiguous results have been found in trials supplementing single nutrients (8), other studies evaluating the combination of several nutrients have suggested that this might be a better strategy (9)(10)(11)(12)(13). The Nolan Study was then designed to test this novel approach, through offering a nutritional blend (NB) developed to serve as a source of multiple nutrients to community dwelling older adults, and previously tested on cats (12) and dogs (13). ...
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Background: Observational studies and some randomized controlled trials have suggested that nutritional supplementation could be a possible intervention pathway to prevent cognitive decline and Alzheimer's disease (AD). As measuring amyloid-β and tau pathophysiology by positron emission tomography (PET) or cerebrospinal fluid (CSF) analyses may be perceived as complex, plasma versions of such biomarkers have emerged as more accessible alternatives with comparable capacity of predicting cognitive impairment. Objectives: This study aimed to evaluate the effect of a 1-year intervention with a nutritional blend on plasma p-tau181 and glial fibrillary acidic protein (GFAP) levels in community-dwelling older adults. Effects were further assessed in exploratory analyses within sub-cohorts stratified according to p-tau status (with the third tertile considered as high: ≥15.1 pg/ mL) and to apolipoprotein E (APOE) ε4 allele status. Methods: A total of 289 participants ≥70 years (56.4% female, mean age 78.1 years, SD=4.7) of the randomized, double-blind, multicenter, placebo-controlled Nolan trial had their plasma p-tau181 assessed, and daily took either a nutritional blend (composed of thiamin, riboflavin, niacin, pantothenic acid, pyridoxine, biotin, folic acid, cobalamin, vitamin E, vitamin C, vitamin D, choline, selenium, citrulline, eicosapentaenoic acid - EPA, and docosahexaenoic acid - DHA) or placebo for 1 year. Results: After 1-year, both groups presented a significant increase in plasma p-tau181 and GFAP values, with no effect of the intervention (p-tau181 between-group difference: 0.27pg/mL, 95%CI: -0.95, 1.48; p=0.665; GFAP between-group difference: -3.28 pg/mL, 95%CI: -17.25, 10.69; p=0.644). P-tau-and APOE ε4-stratified analyses provided similar findings. Conclusions: In community-dwelling older adults, we observed an increase in plasma p-tau181 and GFAP levels that was not different between the supplementation groups after one year.
... An RCT in healthy adults providing omega-3 and multivitamins both individually and in combination found that long-chain omega-3 index only improved in those receiving fish oil and multivitamins in combination, suggesting that the multinutrient aided the incorporation of polyunsaturated fatty acids into red blood cells [65]. Similarly, supplementation with a B vitamin formula slowed cognitive decline and brain atrophy only if participants had high omega-3 status at baseline [66,67]. Most recently, a longitudinal study in Australia (n = 69,990) explored the combined effect of diet quality and dietary supplements on obesity and cardiovascular disease [68]. ...
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Citation: Young, L.M.; Gauci, S.; Arnoldy, L.; Martin, L.; Perry, N.; White, D.J.; Meyer, D.; Lassemillante, A.-C.; Ogden, E.; Silber, B.; et al.
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. Over the years, significant progress has been made in understanding the underlying pathophysiology of AD, leading to the development of various therapeutic strategies. This chapter aims to explore recent innovations in the diagnosis, treatment, and prevention of AD. We will discuss emerging diagnostic techniques, novel therapeutic targets, and promising interventions that hold potential for managing AD and improving patients' quality of life.
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Context: Nutritional interventions may benefit cognition in people with mild cognitive impairment (MCI). However, evidence is yet to be synthesized in a way that can inform recommendations for clinical and public health settings. Objective: To systematically review evidence on the effect of dietary patterns, foods, and nutritional supplements on cognitive decline in individuals with MCI. Data sources: Guided by the Preferred Reporting items for Systematic Review and Meta-Analysis Protocols 2015 statement, the Medline, EMBASE, and CINAHL databases, the JBI Database of Systematic Reviews and Implementation Reports, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects were searched (publication years 2005 to 2020). Included studies were English-language systematic reviews and meta-analyses of randomized controlled trials and cohort studies reporting on the effectiveness of nutritional interventions on cognition of individuals with MCI. Data extraction: Two reviewers independently selected studies and extracted data on cognitive outcomes and adverse events. Review quality was assessed using AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews-2). Primary study overlap was managed following Cochrane Handbook guidelines. Data analysis: Of the 6677 records retrieved, 20 reviews were included, which, in turn, reported on 43 randomized controlled trials and 1 cohort study that, together, addressed 18 nutritional interventions. Most reviews were limited by quality and the small number of primary studies with small sample sizes. Reviews were mostly positive for B vitamins, omega-3 fatty acids, and probiotics (including 12, 11 and 4 primary studies, respectively). Souvenaid and the Mediterranean diet reduced cognitive decline or Alzheimer's disease progression in single trials with <500 participants. Findings from studies with a small number of participants suggest vitamin D, a low-carbohydrate diet, medium-chain triglycerides, blueberries, grape juice, cocoa flavanols, and Brazil nuts may improve individual cognitive subdomains, but more studies are needed. Conclusions: Few nutritional interventions were found to convincingly improve cognition of individuals with MCI. More high-quality research in MCI populations is required to determine if nutritional treatments improve cognition and/or reduce progression to dementia. Systematic review registration: Open Science Framework protocol identifier DOI:10.17605/OSF.IO/BEP2S.
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Background: Mild cognitive impairment (MCI) is the prodromal stage of dementia. In this stage, reasonable intervention measures can help to delay the decline of cognitive function. Supplementation of n-3 polyunsaturated fatty acids (n-3PUFAs) may be beneficial to delay the decline of cognitive function in the elderly. Objective: To investigate the effectiveness of docosapentaenoic acid (DHA) or/and eicosapentaenoic acid (EPA) supplements in the elderly with MCI. Methods: Eight electronic databases, PubMed, Cochrane Library, Embase, VIP, SinoMed, Web of Science, CNKI, and WANFANG DATA, were searched for related articles from inception until January 2022. Subgroup analyses and sensitivity analyses were performed to detect confounding variables. Standardized mean differences (SMD) with 95% confidence intervals (CI) were determined. Heterogeneity was evaluated by I2 statistics. Publication bias was detected using funnel plots. Stata12.0 was used for Begg's and Egger's test to quantify whether publication bias. Linear relationship between global cognition and covariates was examined in meta-regression analysis. Results: Twelve studies (n = 1,124) were included. The methodological quality of research is mostly medium. Compared with placebo, n-3PUFAs supplements have benefits on global cognition [SMD = 0.51, 95% CI(0.12, 0.91), p = 0.01]. No significant differences were observed between intervention group and placebo on language fluency, executive functions, and depression. Conclusion: Our findings indicated DHA and/or EPA supplements have benefits on global cognition, and it may also reduce the level of blood amyloid-β (Aβ)-related biomarkers (e.g., Aβ 40, Aβ 42) and inflammatory factors (e.g., 1L-6, 1L-10). Since there are only two relative articles, more research is needed in the future to clarify the relationship.
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Long chain polyunsaturated omega-3 fatty acids (n-3 FA), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are known to be important components in a healthy diet and contribute to healthy functioning of the heart and the brain, among other organs. Although there are epidemiological studies on the strong relationship between fish or n-3 FA consumption and lower risk of cognitive decline, results from randomized controlled trials (RCTs) are less consistent. Here, we performed a scoping review on RCTs with n-3 FA supplementation where cognition was evaluated. Seventy-eight RCTs published before April 2022 were included in this review. Among these RCTs, 43.6% reported a positive cognitive outcome after the consumption of n-3 FA compared to the placebo. However, there was a large diversity of populations studied (age ranges and health status), wide range of doses of EPA + DHA supplemented (79 mg/day – 5,200 mg/day) and a multitude of tests evaluating cognition, mainly diagnostic tests, that were used to assess cognitive scores and overall cognitive status. RCTs were thereafter categorized into non-cognitively impaired middle-aged adults (n = 24), non-cognitively impaired older adults (n = 24), adults with subjective memory complaints (n = 14), adults with mild cognitive impairments (MCI, n = 9) and people with diagnosed dementia or other cognitive changes (n = 7). Among these categories, 66.7% of RCTs conducted with MCI adults reported a positive cognitive outcome when supplemented with n-3 FA vs. the placebo. Therefore, this scoping review provides rationale and questions to a) strengthen the design of future RCTs with n-3 FA for cognitive outcomes, and b) generate more informative data to support clinicians in their practice in assessing cognition before and after a nutritional intervention.
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Hyperhomocysteinemia is a recognized risk factor for cognitive decline and incident dementia in older adults. Two recent reports addressed the cumulative epidemiological evidence for this association but expressed conflicting opinions. Here, the evidence is reviewed in relation to Sir Austin Bradford Hill's criteria for assessing "causality," and the latest meta-analysis of the effects of homocysteine-lowering on cognitive function is critically examined. The meta-analysis included 11 trials, collectively assessing 22 000 individuals, that examined the effects of B vitamin supplements (folic acid, vitamin B12, vitamin B6) on global or domain-specific cognitive decline. It concluded that homocysteine-lowering with B vitamin supplements has no significant effect on cognitive function. However, careful examination of the trials in the meta-analysis indicates that no conclusion can be made regarding the effects of homocysteine-lowering on cognitive decline, since the trials typically did not include individuals who were experiencing such decline. Further definitive trials in older adults experiencing cognitive decline are still urgently needed. © The Author(s) 2015. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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Increased brain atrophy rates are common in older people with cognitive impairment, particularly in those who eventually convert to Alzheimer disease. Plasma concentrations of omega-3 (ω-3) fatty acids and homocysteine are associated with the development of brain atrophy and dementia. We investigated whether plasma ω-3 fatty acid concentrations (eicosapentaenoic acid and docosahexaenoic acid) modify the treatment effect of homocysteine-lowering B vitamins on brain atrophy rates in a placebo-controlled trial (VITACOG). This retrospective analysis included 168 elderly people (≥70 y) with mild cognitive impairment, randomly assigned either to placebo (n = 83) or to daily high-dose B vitamin supplementation (folic acid, 0.8 mg; vitamin B-6, 20 mg; vitamin B-12, 0.5 mg) (n = 85). The subjects underwent cranial magnetic resonance imaging scans at baseline and 2 y later. The effect of the intervention was analyzed according to tertiles of baseline ω-3 fatty acid concentrations. There was a significant interaction (P = 0.024) between B vitamin treatment and plasma combined ω-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) on brain atrophy rates. In subjects with high baseline ω-3 fatty acids (>590 μmol/L), B vitamin treatment slowed the mean atrophy rate by 40.0% compared with placebo (P = 0.023). B vitamin treatment had no significant effect on the rate of atrophy among subjects with low baseline ω-3 fatty acids (<390 μmol/L). High baseline ω-3 fatty acids were associated with a slower rate of brain atrophy in the B vitamin group but not in the placebo group. The beneficial effect of B vitamin treatment on brain atrophy was observed only in subjects with high plasma ω-3 fatty acids. It is also suggested that the beneficial effect of ω-3 fatty acids on brain atrophy may be confined to subjects with good B vitamin status. The results highlight the importance of identifying subgroups likely to benefit in clinical trials. This trial was registered at www.controlled-trials.com as ISRCTN94410159. © 2015 American Society for Nutrition.
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Subjective memory complaints are common with aging. Docosahexaenoic acid (DHA; 22:6 n-3) is a long-chain polyunsaturated fatty acid (LCPUFA) and an integral part of neural membrane phospholipids that impacts brain structure and function. Past research demonstrates a positive association between DHA plasma status/dietary intake and cognitive function. The current meta-analysis was designed to determine the effect of DHA intake, alone or combined with eicosapentaenoic acid (EPA; 20:5 n-3), on specific memory domains: episodic, working, and semantic in healthy adults aged 18 years and older. A secondary objective was to systematically review/summarize the related observational epidemiologic literature. A systematic literature search of clinical trials and observational studies that examined the relationship between n-3 LCPUFA on memory outcomes in healthy adults was conducted in Ovid MEDLINE and EMBASE databases. Studies of subjects free of neurologic disease at baseline, with or without mild memory complaints (MMC), were included. Random effects meta-analyses were conducted to generate weighted group mean differences, standardized weighted group mean differences (Hedge's g), z-scores, and p-values for heterogeneity comparing DHA/EPA to a placebo. A priori sub-group analyses were conducted to evaluate the effect of age at enrollment, dose level, and memory type tested. Episodic memory outcomes of adults with MMC were significantly (P<.004) improved with DHA/EPA supplementation. Regardless of cognitive status at baseline, > 1 g/day DHA/EPA improved episodic memory (P<.04). Semantic and working memory changes from baseline were significant with DHA but no between group differences were detected. Observational studies support a beneficial association between intake/blood levels of DHA/EPA and memory function in older adults. DHA, alone or combined with EPA, contributes to improved memory function in older adults with mild memory complaints.
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Background: Elevated plasma homocysteine is a risk factor for Alzheimer disease, but the relevance of homocysteine lowering to slow the rate of cognitive aging is uncertain. Objective: The aim was to assess the effects of treatment with B vitamins compared with placebo, when administered for several years, on composite domains of cognitive function, global cognitive function, and cognitive aging. Design: A meta-analysis was conducted by using data combined from 11 large trials in 22,000 participants. Domain-based z scores (for memory, speed, and executive function and a domain-composite score for global cognitive function) were available before and after treatment (mean duration: 2.3 y) in the 4 cognitive-domain trials (1340 individuals); Mini-Mental State Examination (MMSE)–type tests were available at the end of treatment (mean duration: 5 y) in the 7 global cognition trials (20,431 individuals). Results: The domain-composite and MMSE-type global cognitive function z scores both decreased with age (mean ± SE: −0.054 ± 0.004 and −0.036 ± 0.001/y, respectively). Allocation to B vitamins lowered homocysteine concentrations by 28% in the cognitive-domain trials but had no significant effects on the z score differences from baseline for individual domains or for global cognitive function (z score difference: 0.00; 95% CI: −0.05, 0.06). Likewise, allocation to B vitamins lowered homocysteine by 26% in the global cognition trials but also had no significant effect on end-treatment MMSE-type global cognitive function (z score difference: −0.01; 95% CI: −0.03, 0.02). Overall, the effect of a 25% reduction in homocysteine equated to 0.02 y (95% CI: −0.10, 0.13 y) of cognitive aging per year and excluded reductions of >1 mo per year of treatment. Conclusion: Homocysteine lowering by using B vitamins had no significant effect on individual cognitive domains or global cognitive function or on cognitive aging.
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Background Cognitive impairment, including dementia, is a major health concern with the increasing aging population. Preventive measures to delay cognitive decline are of utmost importance. Alzheimer’s disease (AD) is the most frequent cause of dementia, increasing in prevalence from <1% below the age of 60 years to >40% above 85 years of age. Methods We systematically reviewed selected modifiable factors such as education, smoking, alcohol, physical activity, caffeine, antioxidants, homocysteine (Hcy), n-3 fatty acids that were studied in relation to various cognitive health outcomes, including incident AD. We searched MEDLINE for published literature (January 1990 through October 2012), including cross-sectional and cohort studies (sample sizes > 300). Analyses compared study finding consistency across factors, study designs and study-level characteristics. Selecting studies of incident AD, our meta-analysis estimated pooled risk ratios (RR), population attributable risk percent (PAR%) and assessed publication bias. Results In total, 247 studies were retrieved for systematic review. Consistency analysis for each risk factor suggested positive findings ranging from ~38.9% for caffeine to ~89% for physical activity. Education also had a significantly higher propensity for “a positive finding” compared to caffeine, smoking and antioxidant-related studies. Meta-analysis of 31 studies with incident AD yielded pooled RR for low education (RR = 1.99; 95% CI: 1.30-3.04), high Hcy (RR = 1.93; 95% CI: 1.50-2.49), and current/ever smoking status (RR = 1.37; 95% CI: 1.23-1.52) while indicating protective effects of higher physical activity and n-3 fatty acids. Estimated PAR% were particularly high for physical activity (PAR% = 31.9; 95% CI: 22.7-41.2) and smoking (PAR%=31.09%; 95% CI: 17.9-44.3). Overall, no significant publication bias was found. Conclusions Higher Hcy levels, lower educational attainment, and decreased physical activity were particularly strong predictors of incident AD. Further studies are needed to support other potential modifiable protective factors, such as caffeine.
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Few B-vitamin trials to lower homocysteine (Hcy) have reported evidence of beneficial effects on cognition in older adults with cognitive impairment or Alzheimer's disease. This article reviews the role of Hcy in cognitive decline. It also considers some reasons why meta-analyses have failed to find effects of B-vitamin treatment. Findings from the successful VITACOG trial are examined from a new perspective of critical levels of Hcy and brain atrophy that may impact on the efficacy of B-vitamin treatment. It appears that there is a critical level of brain shrinkage, possibly mediated by elevated Hcy, which when reached, results in cognitive decline, especially in episodic memory performance. Supplements, food sources, and effects of folic acid fortification are discussed in relation to B12 deficiency.
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Poor folate status is associated with cognitive decline and dementia in older adults. Although impaired brain methylation activity and homocysteine toxicity are widely thought to account for this association, how folate deficiency impairs cognition is uncertain. To better define the role of folate deficiency in cognitive dysfunction, we fed rats folate-deficient diets (0 mg FA/kg diet) with or without supplemental L-methionine for 10 wk, followed by cognitive testing and tissue collection for hematological and biochemical analysis. Folate deficiency with normal methionine impaired spatial memory and learning; however, this impairment was prevented when the folate-deficient diet was supplemented with methionine. Under conditions of folate deficiency, brain membrane content of the methylated phospholipid phosphatidylcholine was significantly depleted, which was reversed with supplemental methionine. In contrast, neither elevated plasma homocysteine nor brain S-adenosylmethionine and S-adenosylhomocysteine concentrations predicted cognitive impairment and its prevention by methionine. The correspondence of cognitive outcomes to changes in brain membrane phosphatidylcholine content suggests that altered phosphatidylcholine and possibly choline metabolism might contribute to the manifestation of folate deficiency-related cognitive dysfunction.
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Observational data have suggested that high dietary intake of saturated fat and low intake of vegetables may be associated with increased risk of Alzheimer disease. To test the effects of oral supplementation with nutrients on cognitive function. In a double-masked randomized clinical trial (the Age-Related Eye Disease Study 2 [AREDS2]), retinal specialists in 82 US academic and community medical centers enrolled and observed participants who were at risk for developing late age-related macular degeneration (AMD) from October 2006 to December 2012. In addition to annual eye examinations, several validated cognitive function tests were administered via telephone by trained personnel at baseline and every 2 years during the 5-year study. Long-chain polyunsaturated fatty acids (LCPUFAs) (1 g) and/or lutein (10 mg)/zeaxanthin (2 mg) vs placebo were tested in a factorial design. All participants were also given varying combinations of vitamins C, E, beta carotene, and zinc. The main outcome was the yearly change in composite scores determined from a battery of cognitive function tests from baseline. The analyses, which were adjusted for baseline age, sex, race, history of hypertension, education, cognitive score, and depression score, evaluated the differences in the composite score between the treated vs untreated groups. The composite score provided an overall score for the battery, ranging from -22 to 17, with higher scores representing better function. A total of 89% (3741/4203) of AREDS2 participants consented to the ancillary cognitive function study and 93.6% (3501/3741) underwent cognitive function testing. The mean (SD) age of the participants was 72.7 (7.7) years and 57.5% were women. There were no statistically significant differences in change of scores for participants randomized to receive supplements vs those who were not. The yearly change in the composite cognitive function score was -0.19 (99% CI, -0.25 to -0.13) for participants randomized to receive LCPUFAs vs -0.18 (99% CI, -0.24 to -0.12) for those randomized to no LCPUFAs (difference in yearly change, -0.03 [99% CI, -0.20 to 0.13]; P = .63). Similarly, the yearly change in the composite cognitive function score was -0.18 (99% CI, -0.24 to -0.11) for participants randomized to receive lutein/zeaxanthin vs -0.19 (99% CI, -0.25 to -0.13) for those randomized to not receive lutein/zeaxanthin (difference in yearly change, 0.03 [99% CI, -0.14 to 0.19]; P = .66). Analyses were also conducted to assess for potential interactions between LCPUFAs and lutein/zeaxanthin and none were found to be significant. Among older persons with AMD, oral supplementation with LCPUFAs or lutein/zeaxanthin had no statistically significant effect on cognitive function. clinicaltrials.gov Identifier: NCT00345176.
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Epidemiological studies and basic research suggest a protective effect of long-chain omega-3 polyunsaturated fatty acids, antioxidants and B vitamins against brain aging. However, most randomized controlled trial (RCTs) with nutritional supplements have yielded disappointing effects on cognition so far. This paper suggests some original directions for future research to better support a role of nutrition in brain aging. The role of other nutrients such as docosapentaenoic acid and fat-soluble vitamins D and K should be investigated. A more holistic approach of nutrition is necessary, encompassing potential synergies between nutrients as found in a balanced diet. Potential beneficiaries of a nutritional supplementation should be better targeted, according to their dietary, cognitive and maybe genetic characteristics. Innovative RCTs should be implemented to assess the impact of nutrition for the prevention or treatment of cognitive decline in older persons, using intermediate biomarkers of disease progression and mechanisms of action of nutrients as outcomes.European Journal of Clinical Nutrition advance online publication, 27 August 2014; doi:10.1038/ejcn.2014.177.