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B Vitamins, Homocysteine, and Cognitive Decline: Setting the Record Straight

By Christopher Clark
December 22, 2016
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A common fear among people approaching old age is the fear of being diagnosed with Alzheimer’s disease (AD) or another form of dementia. This fear creates considerable stress, anxiety, and even despair. According to a UK government poll, for example, 62% of respondents would consider a dementia diagnosis as the effective end of their life.1 It’s difficult to estimate the prevalence of all forms of dementia, but the most common form, Alzheimer’s disease, afflicts 11% of those over 65 years of age and nearly one-third of those over 85.2

Perhaps one reason why people view dementia so catastrophically is because it’s seen as being unpreventable. We can partly attribute this misconception to poorly designed nutrition studies, some of which have downplayed the role of B vitamins in preventing or mitigating dementia. To understand these studies and the true role of B vitamins, we must first examine homocysteine and its relationship to dementia.

What is Homocysteine?

Homocysteine is a breakdown product of protein metabolism. It’s always present in the blood, but at low concentrations (<10 mmol/L).3 When concentrations exceed a certain threshold (~10-11 mmol/L), there are many consequences.4 Increased plasma total homocysteine (hereafter referred to as tHcy) is associated with increased risks for each of the following conditions.5

  • Cardiovascular disease
  • Stroke
  • Cognitive impairment
  • Brain atrophy
  • Vascular dementia
  • Alzheimer’s disease

This brings us to a key question. Does elevated tHcy cause the above conditions, or is it simply a marker for other causative factors, such as low B vitamin status, poor lifestyle, or impaired renal function?

Three large meta-analyses have investigated this question and has each has concluded that by decreasing tHcy, one does not prevent or mitigate cognitive decline or dementia6,7,8., , It’s well accepted that low B vitamin status – particularly folate, B6, and B12 – is associated with high tHcy.9,10, Scientists have therefore postulated that by increasing dietary and/or supplemental B vitamins, tHcy will decrease, thereby reducing cognitive decline and dementia risks. The aforementioned meta-analyses, however, cast doubt on this postulation. Clarke et al., for example, concluded, “Homocysteine lowering by using B vitamins had no significant effect on individual cognitive domains or global cognition or on cognitive aging.”11

This raises a second key question. Can we trust the conclusions of these meta-analyses?

Methodological Errors

A new study, published by Smith et al. in Annual Review of Nutrition, examines the methodology used in the meta-analyses mentioned above.12 In discussing the shortcomings of the trials included within those meta-analyses, Smith et al. highlights a “cardinal principal in nutrition.” This principal states that relationships between nutrient status and given outcomes adhere to a sigmoidal curve, as shown below. This means that when nutrient status is low, additional intake is beneficial; when too high, additional intake is detrimental; and when nutrient status is between these low and high bands, there exists a plateau for which additional intake has no effect.

screen-shot-2016-12-22-at-9-24-57-am

This is important because many of the trials comprising the three meta-analyses include B vitamin interventions in cases where participants already had adequate B vitamin status (the plateau zone). As Smith et al. explains, “One cannot expect a trial to succeed if all the participants have a more than adequate B vitamin status or are unlikely to respond.”

Other methodological problems identified by Smith et al. include trials that are too short to observe cognitive decline and trials for which subjects are too young for cognitive decline to reasonably be expected. Also, regarding the Clarke et al. meta-analysis, cognitive decline could not even be assessed for 76% of the 20,431 total subjects because baseline cognitive measures were not available for those subjects. As Smith et al. point out, it’s impossible to determine whether or not cognition has declined when you don’t even know the starting point.

For two of the trials (consisting of 2,825 total subjects) within the Clarke et al. study, however, baseline cognitive measures were indeed available. Both of those trials showed significant cognitive improvements when B vitamins were administered to patients with elevated tHcy.13,14, Clark et al. dismissed these results as “due to chance,” but according to Smith et al., “We think this attitude verges on bad science: Instead of dismissing results as ‘due to chance,’ one should ask, ‘Why are the results different in these trials?’”15,16,

To conclude on this point, the notion that cognitive decline cannot be prevented or mitigated through improvements to one’s B vitamin status has been advanced, in part, by several less-than-rigorous studies. Be that as it may, do other studies suggest the opposite? Do other studies suggest that cognitive decline can be prevented through improvements to one’s B vitamin status?

The VITACOG Trial

Published in 2010, the Oxford University VITACOG trial was designed to determine whether brain atrophy in patients with mild cognitive impairment (MCI) could be slowed via B vitamin supplementation and subsequent lowering of tHcy.17 Volunteers were randomized to placebo or a daily dose of a combination of folic acid (0.8 mg), vitamin B12 (0.5 mg), and vitamin B6 (20 mg) for 2 years.

The B vitamin group experienced a highly significant 30% decrease in the rate of global brain atrophy. The decrease was even greater for those with higher baseline tHcy levels. From this study, the following causal chain of events was proposed:

Improved B vitamin status → decreased tHcy → slowed atrophy rate → slowed cognitive decline

The authors concluded, “The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins.” Further trials are needed to determine whether ‘slowed conversion to dementia’ can be added to the above chain of events after ‘slowed cognitive decline.’

Conclusions

The evidence strongly suggests that elevated tHcy promotes cognitive decline, dementia, and Alzheimer’s disease. Some trials support the use of B vitamins to reduce tHcy, thereby slowing cognitive decline. Other studies, particularly three well-known meta-analyses, don’t support the view that B vitamins can slow cognitive decline. These meta-analyses and their related trials, however, failed to adequately include subjects likely to respond to B vitamin treatment.

We can safely say that healthy B vitamin status, whether from proper diet, supplementation, or some combination thereof, supports cognitive health. Besides B vitamins, however, other factors are also involved, including omega-3 status and the consumption of aspirin. For example, in the VITACOG study, the protective effects of B vitamin treatments only occurred among those who had proper omega-3 status.18,19 Regarding aspirin, the protective B vitamin effects occurred only among those who didn’t consume aspirin. [20]

While more research must be done on this important subject, we recommend the Paleo diet as the ideal template for consuming ample amounts of B vitamins. This applies not only to elderly people or those at risk for cognitive decline, but to everyone. To learn more about specific foods that improve B vitamin status, check out Part 2 in our article series on B Vitamins.

References

[1] Alzheimer’s Society (UK). (May 13, 2016). Over half of people fear dementia diagnosis, 62 per cent think it means ‘life is over’. Retrieved from https://www.alzheimers.org.uk/site/scripts/news_article.php?newsID=2606

[2] Hebert LE, et al. (May 7, 2013). Alzheimer disease in the United States (2010-2050) estimated using the 2010 Census. Neurology, 80(19). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23390181

[3] Clarke R, et al. (Nov 1998). Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Archives of Neurology, 55(11). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/9823829

[4] Ravaglia G, et al. (Sep 2005). Homocysteine and folate as risk factors for dementia and Alzheimer disease. American Journal of Clinical Nutrition, 82(3). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16155278

[5] Smith AD, Refsum, H. (Jul 2016). Homocysteine, B Vitamins, and Cognitive Impairment. Annual Review of Nutrition, 36. Retrieved from //ajcn.nutrition.org/content/75/5/785.full

[6] Clarke R, et al. (Jun 2014). Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals. American Journal of Clinical Nutrition, 100(2). Retrieved from //ajcn.nutrition.org/content/100/2/657

[7] Ford AH, et al. (2012). Effect of homocysteine lowering treatment on cognitive function: a systematic review and meta-analysis of randomized controlled trials. Journal of Alzheimer’s Disease, 29(1). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/22232016

[8] Wald DS, et al. (Jun 2010). Effect of folic acid, with or without other B vitamins, on cognitive decline: meta-analysis of randomized trials. American Journal of Medicine, 123(6). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/20569758

[9] Wolters M, et al. (Oct 2003). B vitamin status and concentrations of homocysteine and methylmalonic acid in elderly German women. American Journal of Clinical Nutrition, 78(4). Retrieved from //ajcn.nutrition.org/content/78/4/765.full

[10] Morris M, et al. (Aug 2005). Relation between homocysteine and B-vitamin status indicators and bone mineral density in older Americans. Bone, 37(2). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/15950558

[11] Clarke R, et al. (Jun 2014). Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals. American Journal of Clinical Nutrition, 100(2). Retrieved from //ajcn.nutrition.org/content/100/2/657

[12] Smith AD, Refsum, H. (Jul 2016). Homocysteine, B Vitamins, and Cognitive Impairment. Annual Review of Nutrition, 36. Retrieved from //ajcn.nutrition.org/content/75/5/785.full

[13] Durga J, et al. (Jan 2007). Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. The Lancet, 369(9557). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/17240287

[14] Kang JH, et al. (Dec 2008). A trial of B vitamins and cognitive function among women at high risk of cardiovascular disease. American Journal of Clinical Nutrition, 88(6). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19064521

[15] Clarke R, et al. (Jun 2014). Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals. American Journal of Clinical Nutrition, 100(2). Retrieved from //ajcn.nutrition.org/content/100/2/657

[16] Smith AD, Refsum, H. (Jul 2016). Homocysteine, B Vitamins, and Cognitive Impairment. Annual Review of Nutrition, 36. Retrieved from //ajcn.nutrition.org/content/75/5/785.full

[17] Smith DA, et al. (Sep 2010). Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial. PLOS-One. Retrieved from //journals.plos.org/plosone/article?id=10.1371/journal.pone.0012244

[18] Oulhaj A, et al. (2015). Omega-3 fatty acid status enhances the prevention of cognitive decline by B vitamins in mild cognitive impairment. Journal of Alzheimer’s Disease, 50(2). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26757190

[19] Jernerén F, et al. (Apr 2015). Brain atrophy in cognitively impaired elderly: the importance of long-chain ω-3 fatty acids and B vitamin status in a randomized controlled trial. American Journal of Clinical Nutrition, 104(5). Retrieved from //ajcn.nutrition.org/content/early/2015/04/15/ajcn.114.103283

[20] Smith DA, et al. (Sep 2010). Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial. PLOS-One. Retrieved from //journals.plos.org/plosone/article?id=10.1371/journal.pone.0012244

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