Brain Atrophy in Cognitively Impaired Elderly:
The Importance of Long-chain ω-3 Fatty Acids
and B Vitamin Status in a Randomized Controlled Trial

This section is compiled by Frank M. Painter, D.C.
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FROM:   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. [1] (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. [2] (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. [3]

In a 2013 study, Douaud et al. [4] 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.


  1. 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

  2. Nutrient Biomarker Patterns, Cognitive Function, and MRI Measures of Brain Aging
    Neurology. 2012 (Jan 24); 78 (4): 241–249 ~ FULL TEXT

  3. 4 Vitamins That Strengthen Older Brains
    The New York Times ~ January 2, 2012 ~ FULL TEXT

  4. 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 as ISRCTN94410159.

KEYWORDS:   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 the manuscript.

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