Results of a two-year clinical trial suggest that a mixture of B vitamins slows atrophy up to sevenfold in areas of the brain that are vulnerable to degeneration in Alzheimer’s disease. In the May 20 Proceedings of the National Academy of Sciences online, Gwenaëlle Douaud and colleagues at the University of Oxford, U.K., report that the benefit occurs only in people who have high plasma homocysteine. Senior author David Smith presented some of these data at the 12th International Stockholm/Springfield Symposium on Advances in Alzheimer Therapy last year (see ARF related news story).
This paper represents the latest installment of data from the VITACOG trial, which tested if a mixture of vitamins B6, B9 (folic acid), and B12 improves outcomes in people with mild cognitive impairment. Previously, Smith and colleagues reported that the vitamin mix halved total brain atrophy and slowed cognitive decline in participants who had baseline plasma homocysteine levels greater than 13 and 11.3 μmol/L, respectively (see ARF related news story on Smith et al., 2010; de Jager et al., 2011). B vitamins serve as cofactors for enzymes that convert homocysteine, a neurotoxin and suspected risk factor for Alzheimer’s disease, into methionine or cysteine. Now, Smith and colleagues detail a more sophisticated post-hoc brain analysis using voxel-based morphometry to look at local changes in brain matter.
Douaud and colleagues report that over the two years of treatment, 76 people in the placebo group lost on average 3.7 percent of gray matter in posterior regions, including the hippocampus, parahippocampal gyrus, retrosplenial precuneus, and lingual and fusimorm gyri. By contrast, the 80 volunteers in the treatment group lost about 0.5 percent of gray matter in those same regions, which are among those most vulnerable to neurodegeneration in AD, note the authors. Those areas of the brain are intimately involved in learning and memory, and shrink fastest as mild cognitive impairment progresses to dementia (see Desikan et al., 2008).
The vitamins most benefited the 42 people with high baseline homocysteine, reducing atrophy among local brain regions from an average of 5.2 percent to 0.6 percent. In that group, the protection also extended to anterior regions and the prefrontal cortex.
What does this mean for AD treatment? In previous clinical trials, B vitamin supplements failed to slow cognitive decline in people with mild to moderate AD (see ARF related news story) or in cognitively normal older adults (see Kang et al., 2008). The VITACOG study reported a slowing of cognitive decline, and Smith argues that the treatment might work best in those with mild cognitive impairment. In this imaging study the authors found that gray matter loss, particularly in the amygdalohippocampus complex and the entorhinal cortex, correlated with poorer performance in several cognitive measures, leading them to suggest that a fall in homocysteine protects against brain atrophy, which in turn prevents cognitive decline. "Larger and longer trials will be needed to determine the optimal plasma total homocysteine threshold warranting B vitamin supplementation and to monitor the treatment effect on the crucial outcome, the incidence of dementia," conclude the authors.—Tom Fagan
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- Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G, Oulhaj A, Bradley KM, Jacoby R, Refsum H. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One. 2010;5(9):e12244. PubMed.
- de Jager CA, Oulhaj A, Jacoby R, Refsum H, Smith AD. Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. Int J Geriatr Psychiatry. 2011 Jul 21; PubMed.
- Desikan RS, Fischl B, Cabral HJ, Kemper TL, Guttmann CR, Blacker D, Hyman BT, Albert MS, Killiany RJ. MRI measures of temporoparietal regions show differential rates of atrophy during prodromal AD. Neurology. 2008 Sep 9;71(11):819-25. PubMed.
- Kang JH, Cook N, Manson J, Buring JE, Albert CM, Grodstein F. A trial of B vitamins and cognitive function among women at high risk of cardiovascular disease. Am J Clin Nutr. 2008 Dec;88(6):1602-10. PubMed.
- Douaud G, Refsum H, de Jager CA, Jacoby R, Nichols TE, Smith SM, Smith AD. Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9523-8. PubMed.