B vitamins are essential for many aspects of brain function. They are essential for healthy methylation, which is needed to build brain cell membranes and neurotransmitters that pass messages between brain cells. Hence B vitamins, especially B6, B12 and folate, are essential for the brain’s structure, ‘talking’ and ‘listening’. When in short supply, blood levels of homocysteine go up, indicating faulty methylation.
Both high homocysteine (Hcy) and low folate and B12 levels increase risk for Alzheimer’s disease (AD).1, 2 The higher the Hcy and the lower the folate and B12 the greater is the rate of cognitive decline.3
An International Consensus Statement in 2018 concluded that moderately raised plasma total Hcy (> 11µmol/L), found in half of those over age 704, is one of the main causes of age-related cognitive decline and dementia.5 Two major meta-analyses of hundreds of studies conclude that raised homocysteine is one of the best evidenced risk factors for AD and accounts for around a fifth of all risk6, 7.
Homocysteine-lowering B vitamin treatment
Raised Hcy can readily be lowered by supplementation with B vitamins8 and several trials have investigated the effect of lowering homocysteine on cognitive decline. Randomised Controlled Trials that fulfil the criteria of the International Consensus Statement show:
• In those over 50 with raised Hcy (>13µmol/L), but not diagnosed with cognitive impairment, supplementing folic acid (0.8mg/d) for three years resulted in a significant improvement in cognition compared to placebo (the FACIT trial).9
• The VITACOG trial on people with Mild Cognitive Impairment by Professor David Smith and his group of the OPTIMA Study at the University of Oxford, showed that Hcy above 11 µmol/L, correlated with accelerated brain shrinkage and cognitive decline. Those given daily folic acid (0.8mg/d), vitamin B12 (0.5 mg/d) and B6 (20mg/d) had a significant 30% reduction in the rate of brain shrinkage versus placebo4 and almost a nine-fold reduction in shrinkage of the medial temporal lobe, which is a key area of the brain that shrinks in AD.10 In addition, the B vitamins slowed cognitive and clinical decline.11
Figure 4: Those with raised baseline homocysteine given B vitamins vs placebo showed almost a nine-fold reduction in shrinkage in Alzheimer’s related areas of the brain in a year (used with permission from Douaud10 Yellow denotes area of significant atrophy in 2 years)
Treatment with B vitamins later in the disease process, in those diagnosed with AD, has shown modest benefit in those in the mild stage but not in those with moderately severe AD.12
B vitamins and Omega-3 are synergistic
Dr Jerneren at Oxford University analysed the data from the previous VITACOG study giving B vitamins versus placebo, but divided the participants into those with a high, medium and low blood level of omega-3 fatty acids at the start of the trial. Those with low omega-3 status showed no beneficial effect from the B vitamin treatment while those with high omega-3 showed a 73% decrease in rate of brain shrinkage, bring their level of brain shrinkage down to that seen in healthy elderly who do not develop dementia.13 Furthermore, those with a high omega-3 status showed the largest cognitive benefits to B vitamin treatment.14
Two trials in China on people with mild cognitive impairment have shown slowing of cognitive decline in those given folic acid and B1215 or with a combination of folic acid and the omega-3 fatty acid DHA.16
These studies suggest that Hcy-lowering B vitamins can, at least, slow cognitive decline in people with a raised Hcy level over age 50 and those over 70 with Mild Cognitive Impairment and may also slow cognitive decline in those with mild AD, but not in moderate to severe AD.
Homocysteine is both a marker and a cause of brain damage
An article in Nature Reviews/Neurology confirms the growing evidence supporting raised Hcy levels as a likely primary predictor and potential cause of the brain damage that identifies AD.17. Further reviews elucidate the various hypotheses and evidence for Hcy being a factor in the causation of AD-related brain damage.3, 8 Hcy and its derivatives are neurotoxins. Hcy is also an indicator of disrupted methylation, which leads to raised levels of amyloid and tau proteins and associated plaques and neurofibrilliary tangles found in the Alzheimer’s brain. Raised Hcy leads to increased oxidative stress and damage to the blood-brain barrier. It also impairs circulation by increasing cerebrovascular damage.
1. Van Dam F, Van Gool WA. Hyperhomocysteinemia and Alzheimer’s disease: A systematic review. Arch Gerontol Geriatr. 2009; 48: 425-30.
2. Zhang X, Bao G, Liu D, Yang Y, Li X, Cai G, et al. The association between folate and Alzheimer’s Disease: a systematic review and meta-analysis. Front Neurosci. 2021; 15: 661198.
3. Smith AD, Refsum H. Homocysteine, B vitamins, and cognitive impairment. Annu Rev Nutr. 2016; 36: 211-39.
4. Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G, et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment. A randomized controlled trial. PLoS ONE. 2010; 5: e12244.
5. Smith AD, Refsum H, Bottiglieri T, Fenech M, Hooshmand B, McCaddon A, et al. Homocysteine and dementia: An international consensus statement. J Alzheimers Dis. 2018; 62: 561-70.
6. Beydoun MA, Beydoun HA, Gamaldo AA, Teel A, Zonderman AB, Wang Y. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health. 2014; 14: 643.
7. Yu JT, Xu W, Tan CC, Andrieu S, Suckling J, Evangelou E, et al. Evidence-based prevention of Alzheimer’s disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. J Neurol Neurosurg Psychiatry. 2020; 91: 1201-9.
8. Smith AD, Refsum H. Homocysteine – from disease biomarker to disease prevention. J Intern Med. 2021.
9. Durga J, van Boxtel MP, Schouten EG, Kok FJ, Jolles J, Katan MB, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. 2007; 369: 208-16.
10. Douaud G, Refsum H, de Jager CA, Jacoby R, Nichols TE, Smith SM, et al. Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A. 2013; 110: 9523-8.
11. 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: 592-600.
12. Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, et al. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008; 300: 1774-83.
13. Jernerén F, Elshorbagy AK, Oulhaj A, Smith SM, Refsum H, Smith AD. Brain atrophy in cognitively impaired elderly: the importance of long-chain omega-3 fatty acids and B vitamin status in a randomized controlled trial. Am J Clin Nutr. 2015; 102: 215-21.
14. 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: 547-57.
15. Ma F, Zhou X, Li Q, Zhao J, Song A, An P, et al. Effects of folic acid and vitamin B12 , alone and in combination on cognitive function and inflammatory factors in the elderly with Mild Cognitive Impairment: a single-blind experimental design. Curr Alzheimer Res. 2019; 16: 622-32.
16. Li M, Li W, Gao Y, Chen Y, Bai D, Weng J, et al. Effect of folic acid combined with docosahexaenoic acid intervention on mild cognitive impairment in elderly: a randomized double-blind, placebo-controlled trial. Eur J Nutr. 2020.
17. Sachdev PS. Alzheimer disease: Homocysteine and Alzheimer disease: an intervention study. Nat Rev Neurol. 2011; 7: 9-10.