Am J Clin Nutr. 2015 (Jul); 102 (1): 215–221 ~ FULL TEXT
Fredrik Jernerén, Amany K Elshorbagy, Abderrahim Oulhaj,
Stephen M Smith, Helga Refsum, and A David Smith
From the Oxford Project to Investigate Memory and Ageing (OPTIMA),
Department of Pharmacology,
University of Oxford, Oxford, United Kingdom;
This new study helps clarify earlier studies that found that B vitamins and/or Omega-3 fatty acids were able to slow the brain loss (shrinkage) found in Alzheimer’s disease.
In a 2010 study, Smith et al.  (in the Oxford Project to Investigate Memory and Ageing study) gave 271 individuals with mild cognitive impairment high-dose B vitamins for 2 years. Pre- and post-MRI studies were done, and they demonstrated that the B vitamin group experienced 30-percent slower rates of brain atrophy, on average, and in some cases patients experienced reductions as high as 53 percent.
In a 2012 study, Bowman et al.  (in the Oregon Brain Aging Study) reviewed blood nutrient levels in 104 dementia-free elders. They found two nutrient biomarker patterns (NBPs) that were associated with more favorable cognitive and MRI measures: one was high plasma levels of the vitamins B, C, D, and E, and the second NBP was high plasma marine omega-3 fatty acids. They also demonstrated that high trans fat blood levels were associated with less favorable cognitive function and less total cerebral brain volumes.
When this article was pre-released, the New York Times ran a banner headline titled:
4 Vitamins That Strengthen Older Brains. 
In a 2013 study, Douaud et al.  provided high-dose B-vitamin treatment to elderly subjects with increased dementia risk for 2 years. They found that B vitamins reduced brain shrinkage and reduced levels of plasma total homocysteine (tHcy). This is important because many cross-sectional and prospective studies have shown that high tHcy levels are associated with cognitive impairment, Alzheimer's disease (AD), and vascular dementia.
The current study also helps explain why some trials that focused solely on the B vitamins or Omega-3s had mixed results. Apparently having high blood levels of BOTH the B vitamins AND Omega-3 fatty acids provides better results in preventing the deterioration of brain tissue in Alzheimer's patients.
Homocysteine-lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial
PLoS One. 2010 (Sep 8); 5 (9): e12244 ~ FULL TEXT
Nutrient Biomarker Patterns, Cognitive Function, and MRI Measures of Brain Aging
Neurology. 2012 (Jan 24); 78 (4): 241–249 ~ FULL TEXT
4 Vitamins That Strengthen Older Brains
The New York Times ~ January 2, 2012 ~ FULL TEXT
Preventing Alzheimer's Disease-related Gray Matter Atrophy by B-vitamin Treatment
Proc Natl Acad Sci U S A. 2013 (Jun 4); 110 (23): 9523–9528 ~ FULL TEXT
BACKGROUND: 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.
OBJECTIVE: 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).
DESIGN: 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.
RESULTS: 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.
CONCLUSIONS: 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.
B vitamin; brain atrophy; homocysteine; mild cognitive impairment; ω-3
From the FULL TEXT Article:
Mild cognitive impairment (MCI)8 is a syndrome characterized
by a subtle decline in cognitive function and is considered
a transitory state between normal aging and clinical dementia
and Alzheimer disease (AD) (1, 2). A modest rate of brain atrophy
is observed in normal aging. However, in subjects with
MCI, dementia, or AD, the brain atrophy rates are markedly
faster (3–5). Furthermore, in MCI, the rate of atrophy is usually
higher in the subgroup that eventually converts to AD (6). There
are no available cures for AD, but an alternative approach is
strategies to delay disease progression at an early stage. Cranial
MRI is established as a method to monitor disease progression
(3, 4, 7, 8). Effective interventions may be detected by a slowing
of brain atrophy rate.
The role of ω-3 fatty acids in cognitive decline and dementia
is debated. Epidemiologic evidence is consistent with a protective
role of dietary intake of fish oils rich in ω-3 fatty acids
such as EPA and DHA (9, 10). Case-control studies have revealed
associations between DHA or EPA and brain volume
and lower degrees of white matter hyperintensities (11, 12). In
prospective studies, red blood cell DHA and EPA concentrations were positively correlated with higher total brain and hippocampal
volumes 8 y later (13), and higher relative concentrations of
plasma EPA were associated with a reduced brain atrophy rate in
the medial temporal lobe (14). However, results from randomized
clinical trials including ω-3 supplementation are not
equally convincing (9, 15). One reason for this discrepancy may
be a failure to identify the relevant subgroups that are likely to
benefit from supplementation (16).
Homocysteine is a nonessential, sulfur-containing amino acid
synthesized endogenously from methionine. Raised plasma total
homocysteine (tHcy) is a recognized modifiable risk factor for
cognitive impairment, dementia, and AD (10, 17, 18). The atrophy
rate of the brain is faster at low plasma vitamin B-12 concentrations
(19) and at high plasma tHcy concentrations (20, 21).
Results from Homocysteine and B Vitamins in Cognitive Impairment
(VITACOG), a randomized clinical trial with homocysteine-lowering
B vitamins in older people with MCI, showed
that treatment with high doses of B vitamins markedly reduced the
global brain atrophy rate, as well as atrophy rates in those gray
matter regions most commonly associated with AD (20, 21).
Multiple links between ω-3 fatty acids and homocysteine have
been suggested. There is an inverse correlation between tHcy
and plasma concentrations of ω-3 fatty acids (22, 23), and B
vitamins are important for the methylation and assembly of
phospholipids (24, 25). The purpose of this study was to determine
whether the plasma long-chain ω-3 fatty acid status
modifies the effect of high-dose B vitamin supplementation on
brain atrophy rates in elderly subjects with MCI.
In this retrospective exploratory analysis of data from a randomized,
placebo-controlled trial, we observed a significant
interaction effect between high-dose B vitamin treatment and ω-3
fatty acid concentrations on rate of atrophy of the whole brain.
The beneficial effect of high-dose B vitamin supplementation
was augmented by a high baseline status of ω-3 fatty acid. In
subjects with high plasma concentrations of ω-3 fatty acids
(EPA+DHA .590 mmol/L), B vitamin supplementation slowed
the mean brain atrophy rate by 40% compared with subjects in
the placebo group. In contrast, in subjects with low ω-3 fatty
acid concentrations (,390 mmol/L), there was no beneficial
effect of B vitamins on brain atrophy.
One major effect of the high-dose B vitamin treatment is to
lower plasma tHcy. We found that the effect of B vitamins in the
higher tertiles of ω-3 fatty acids is limited to patients with
baseline tHcy concentrations above the median ($11.3 mmol/L).
In this subgroup, the brain atrophy rate among patients in the
upper tertile of ω-3 fatty acid concentration (.590 mmol/L) was
reduced by ;70% by B vitamin treatment compared with placebo.
Although these results should be interpreted with some
caution due to the small group sizes, our results indicate that the
effect of B vitamins in subjects with moderate to high ω-3 fatty
acid concentrations is driven mainly by beneficial effects in
subjects with elevated baseline tHcy concentrations. We therefore
hypothesize that low tHcy concentrations, which are the
consequence of B vitamin treatment, facilitate the protective
effect of ω-3 fatty acids against brain atrophy (Table 2).
Long-chain ω-3 fatty acids have been associated with protective
roles in dementia and AD in epidemiologic studies (see
Introduction). Recently, Witte and coworkers (29) showed that
daily fish-oil supplementation (880 mg DHA and 1320 mg EPA)
in healthy elderly for 26 wk prevented the loss of total gray
matter volume. Only 2 studies investigating ω-3 fatty acids
along with B vitamins have been reported. One of these investigated
a nutritional supplement that also included ω-3 fatty
acids (EPA, 300 mg; DHA, 1200 mg) and B vitamins (folic acid,
0.4 mg; vitamin B-6, 1 mg; vitamin B-12, 0.003 mg) (30). The
supplement produced some beneficial effects in mild AD when
given for 24 wk, but this was not confirmed in a larger follow-up
study (31). The second study used a 2 3 2 factorial design, with
one arm including B vitamins (folate, 0.56 mg; vitamin B-6,
3 mg; vitamin B-12, 0.02 mg) and the other including ω-3 fatty
acids (EPA, 400 mg; DHA, 200 mg), and found that the combination
of both nutrient groups decreased the likelihood of
a lower score on a temporal orientation task in a subgroup with
prior stroke (32). Both studies were in populations with different
characteristics and used lower doses of B vitamins compared
with VITACOG, and none of these studies reported brain volume or brain atrophy data. The results of these studies are
therefore difficult to compare with ours.
Fatty acids are delivered to various target tissues as components
of phospholipids, of which phosphatidylcholine is the most
abundant in plasma. Experiments in rodents have shown that
phosphatidylcholine molecules enriched in DHA are distributed
selectively to certain tissues, including the brain (33). It is
therefore conceivable that a reduced phosphatidylcholine synthesis
will affect the transport of ω-3 fatty acids to the brain, with
possible implications for brain health. Indeed, low plasma concentrations
of phosphatidylcholine enriched in DHA and EPA have
been linked to the risk of dementia (34, 35). Phosphatidylcholine is
synthesized in the liver via the cytidine 5#-diphosphate–choline
dependent pathway or from phosphatidylethanolamine through
3 consecutive S-adenosylmethionine–dependent methylation reactions
catalyzed by phosphatidylethanolamine N-methyltransferase
(PEMT). DHA content in phosphatidylcholine has been proposed
as a marker of PEMT activity (36), and plasma DHA is
disproportionally reduced by disruption of PEMT in a mouse
model (37). As a consequence, PEMT activity is considered
vital for the delivery and incorporation of ω-3 fatty acids into the
brain (37, 38).
PEMT is inhibited by S-adenosylhomocysteine (SAH), the
precursor of homocysteine. At high tHcy concentrations, SAH
accumulates, which in turn may reduce PEMT activity. In patients
with AD, there is an inverse correlation between plasma
SAH and DHA concentrations in erythrocyte phosphatidylcholine,
possibly because of inhibition of PEMT by SAH (39). In
chick embryos, exposure to homocysteine altered brain lipid
composition, with reduced concentrations of phosphatidylcholine
and an increase of phosphatidylethanolamine while also
reducing the proportion of DHA in brain cell membranes (40).
In rats, a B vitamin–enriched diet increased plasma total DHA
concentration compared with a B vitamin–deficient diet (41).
These reports are consistent with the hypothesis that a good B
vitamin status and low tHcy concentrations are required for an
optimal utilization and distribution of ω-3 fatty acids.
Although a biochemical interaction at the level of phospholipid
metabolism seems likely, there are other potential explanations
for the observed interaction. For example, it is possible
that both ω-3 fatty acids and B vitamins protect against hyperphosphorylation
of tau, with potential consequences for tangle
formation (42, 43). Also, both B vitamins and ω-3 fatty acids
might attenuate inflammation associated with AD. A combination
of B vitamins and ω-3 fatty acids was recently shown to
reduce oxidative stress and inflammation in a rodent model of
hypertension (44). Whether any of these mechanism explain the
interaction reported herein is a focus for future studies.
There are some limitations of this study. In this study, we did
not measure phosphatidylcholine, which is probably the best
source of DHA for the brain (34, 38). In future studies, it would be
valuable to also investigate the distribution of ω-3 fatty acids
in the various plasma compartments and also examine the effect
of B vitamins on phosphatidylcholine. Finally, our study was
a randomized controlled trial with B vitamins, not ω-3 fatty
acids. In future trials, it would be useful to also include treatment
with ω-3 fatty acids.
In conclusion, we have shown that the effect of B vitamin
supplementation on brain atrophy rates depends on pre-existing
plasma ω-3 fatty acid concentrations; this finding could possibly
explain why some B vitamin trials on brain function have failed.
Conversely, our results suggest that tHcy status may also determine
the effects of ω-3 fatty acids in cognitive decline and
dementia and so could explain why some trials of ω-3 fatty acids
have failed. Altogether, our results emphasize the importance of
identifying subgroups in clinical trials. A randomized clinical
trial of B vitamin and ω-3 fatty acid supplementation using
a 2 3 2 factorial design is clearly warranted to shed light on the
roles of homocysteine and ω-3 fatty acids in brain atrophy, MCI,
dementia, and AD.
The authors’ responsibilities were as follows—FJ, AKE, HR, and ADS:
designed the research; FJ: conducted the lipid analyses and wrote the first
draft of the manuscript; FJ, AO, and SMS: analyzed data; and all authors:
critically reviewed the analyses and the manuscript. ADS is named as inventor
on 3 patents held by the University of Oxford on the use of B vitamins
to treat AD or MCI (US6008221, US6127370, and PCT/GB2010/051557);
HR is named as inventor on patent PCT/GB2010/051557. Under the University
of Oxford’s rules, they could benefit financially if the patents are
exploited. FJ, AKE, AO, and SMS reported no personal or financial conflicts
of interest. None of the funders or the sponsor (University of Oxford) played
any role in the design and conduct of the study; collection, management,
analysis, and interpretation of the data; or preparation, review, or approval of