In 2010 Smith and Refsum  published their first data from the VITACOG Trial (Oxford University/ UK). The idea was to see if the administration of higher doses of 3 B vitamins (B6, B12, and Folic Acid) slowed down the atrophy (shrinking) of the whole brain in subjects with Mild Cognitive Impairment (MCI).
Figure 1: How dificiencies in B-Vitamins may lead to brain atrophy (shrinking) and cognitive impairment
Study design: A total of 223 subjects (average age 76.2 years) were randomly divided into a treatment group (110) and a placebo group (113). The treatment group received one tablet containing 0.8 mg folic acid, 0.5 mg cyanocobalamin, and 20 mg pyridoxine HCl for two years. The placebo group received the same tablet without B-vitamins.
The result was spectacular: a 30% slowing of brain atrophy was observed in the treatment group. When the researchers divided the treatment group into three subgroups following observation was made:
Figure 2 : Initial results from VITACOG Trial 
From Figure 2 can be seen that there was an essential difference in the rate of brain atrophy between the three subgroups. In general, the higher the plasma homocysteine (tHcy) levels were, the faster the observed brain shrinkage rate and the more effective was the B-vitamin treatment. Note: A couple of years later, the plasma homocysteine (tHcy) concentration in the blood was established as a dementia risk factor .
An increased Homocysteine level is closely related to vitamin B6, -B12, and folic acid deficiency. Such deficiency in B-vitamins will result in an increased homocysteine concentration and thus increased risk of whole-brain atrophy and dementia. Several pathways leading to such brain atrophy are shown in Fig 3 published by Smith et.al. .
At first sight, the VITACOG Trial showed no significant decline in semantic memory, episodic memory, or Mini-Mental State Exam (MMSE). Almost consequently, a meta-analysis classified the results of the VITACOG Trial to be negative , but those authors did not consider the subgroups. After looking more closely at the subgroup with tHcy-level above the median, a significant decline of slowing atrophy was observed in the B-vitamin treatment group . Additionally, a substantial improvement in the Clinical Dementia Rating (CDR) and Informant Questionnaire on Cognitive Decline (IQCODE) scores were observed in the treatment group whose baseline tHcy was in the upper quartile. However, this effect was not seen in the other treatment groups. These findings demonstrate the importance of outcomes related to subgroups of a clinical trial. While the overall result may appear insignificant, a closer look at the subgroups often discloses the true potential of treatment. Reason for this is simple: people with low tHcy levels have already sufficient B-vitamins for the detoxification. Thus an additional supplementation will not show a significant improvement. Supplements can only work where there is a deficiency that can be corrected.
The VITACOG Trial is not the only study showing the benefit of B-vitamins supplementation on decelerating whole brain atrophy. Other studies also showed remarkable results. For example, the treatment with B-vitamins helped slow Alzheimer´s disease-related gray matter atrophy by 90%. But only in patients with a tHcy well above the median.
The causal link between B-vitamins treatment and these observations was published in 2017  and concluded: vitamin B treatment (especially B12) lowers tHcy. This, in turn, slows down brain atrophy, which improves CDR scores. An improved CDR score slows down the decline in MMSE scores. Thus, in subjects with Mild Cognitive Impairment (MCI) and high tHcy serum levels, supplementation with vitamin B12, -B6, and folic acid slows down the disease process and prolongs the quality of life for the individual.
Figure 3: Possible pathways how homocysteine may lead to cognitive impairment.
A combination of B-vitamins and Omega-3 Supplementation enhances the prevention of cognitive decline in subjects diagnosed with Mild Cognitive Impairment and elevated tHcy levels.
As very often with nutrition-based therapies, the supplementation of one single deficient nutrient may not be sufficient. In many cases the combination of different bioactive compounds can generate synergetic health benefits. This was observed by the same authors of the initial VITACOG Trial in 2010. They published in 2016 a second significant subgroup effect observed in this Trial related to the total omega-3 fatty acid concentration in the plasma of the subjects. In particular, low omega-3 levels (<390 µmol/l) showed no beneficial response from B-vitamin treatment. However, omega-3 levels above 590 µmol/l showed a reduction in atrophy rate of 40%. The placebo group showed no omega-3 related reduction in brain atrophy. Also, only the study participants with high omega-3 status showed a significant cognitive benefit from B-vitamin supplementation .
These findings correlate well with the other omega-3 trials where EPA and DHA supplementation alone were linked to larger total brain and hippocampal volumes  and reduced atrophy of the medial temporal lobe .
 Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G, Oulhaj A, 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. doi: 10.1371/journal.pone.0012244.
 Smith AD, Refsum H. Homocysteine, B vitamins, and cognitive impairment. Annu Rev Nutr 2016;36:211-39. doi: 10.1146/annurev-nutr-071715-050947.
 Cooper C, Li R, Lyketsos C, Livingston G. Treatment for mild cognitive impairment: systematic review. Br J Psychiatry 2013;203:255-64. doi: 10.1192/bjp.bp.113.127811
 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 2012;27(6):592-600. doi: 10.1002/gps.2758.
 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;110(23):9523-8. doi: 10.1073/pnas.1301816110.
 Smith AD, Refsum H. Dementia prevention by disease-modification through nutrition. J Prev Alz Dis 2017;in press. doi: http://dx.doi.org/10.14283/jpad.2017.16
 Oulhaj A, Jernerén F, Refsum H, Smith AD, de Jager CA. Omega-3 fatty acid status enhances the prevention of cognitive decline by B vitamins in Mild Cognitive Impairment J Alzheimer’s Dis 2016;50(2):547-57. doi: 10.3233/JAD-150777
 Pottala JV, Yaffe K, Robinson JG, Espeland MA, Wallace R, Harris WS. Higher RBC EPA + DHA corresponds with larger total brain and hippocampal volumes: WHIMS-MRI study. Neurology 2014;82(5):435-42.
. Samieri C, Maillard P, Crivello F, Proust-Lima C, Peuchant E, Helmer C, Amieva H, Allard M, Dartigues JF, Cunnane SC, et al. Plasma long-chain omega-3 fatty acids and atrophy of the medial temporal lobe. Neurology 2012;79(7):642-50. doi: 10.1212/WNL.0b013e318264e394