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Brain atrophy in cognitively impaired elderly: the importance of long-chain omega-3 fatty acids and B vitamin status in a randomized controlled trial.

Jernerén F, Elshorbagy AK, Oulhaj A, Smith SM, Refsum H, Smith AD (2015) Am J Clin Nutr.  102(1) 215-21. doi: 10.3945/ajcn.114.103283. Epub 2015 Apr 15. 

Web URL: View this and related abstracts via PubMed here.



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 fattyacid 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 (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. 


The pioneering clinical trial 'VITACOG', led by researchers at Oxford University, found that age-related cognitive decline and brain shrinkage in older adults with mild cognitive impairment was significantly slowed by supplementation with B vitamins (B6, B12 and folate). For the initial trial report, see:

In this further analysis of the trial data, the researchers found that the B vitamin treatment reduced cognitive decline and brain shrinkage only in participants who had higher blood levels of the long-chain Omega-3 fatty acids 
EPA and DHA (found in fish and seafood). 

No improvements were seen in particpants whose initial omega-3 status was low.  However, the beneficial effect of the B vitamins in those with higher blood omega-3 was so pronounced that this led to a significant treatment effect for the study sample as a whole, as initially reported.

This important finding highlights that nutrients work synergistically - not in isolation - and that adequate supplies of both B vitamins and long-chain omega-3 are needed to prevent age-related cognitive decline and dementia, and the physical brain shrinkage associated with these conditions. 

It also offers a possible explanation for the failure of some previous trials of B vitamin supplementation for brain health and cognition, and illustrates the importance of considering subgroups in the design and analysis of clinical trials, as well as overall nutritional status. 

Please find related news items here:

For more information about the VITACOG trial and the larger research programme of which it formed a part, see:  

See also: