Homocysteine and Dementia

12 March 2018

In their excellent consensus statement regarding homocysteine and dementia, Smith et al. [1] made no mention of several important issues.

Metabolic B12 deficiency is very common, and usually missed, because most physicians think that a serum B12 level in the reference range (~ 160-600 pmol/L) excludes vitamin B12 deficiency. However, what is measured is total vitamin B12, and of that, only a small and variable proportion (~ 6-20%) is active. Many individuals with a serum B12 in the normal range are deficient in active B12; this is called metabolic B12 deficiency. To determine if a patient has adequate active B12 it is necessary to measure holotranscobalamin, or one of the metabolites that are elevated in B12 deficiency - methylmalonic acid (MMA) is specific, and total homocysteine (tHcy) can be a surrogate for tHcy in folate-replete patients. In the era of folate fortification, B12 is the main nutritional determinant of elevated tHcy [2, 3].

Stabler et al. [4] defined metabolic B12 deficiency as a serum B12 <258 pmol/L with a plasma tHcy > 14 µmol/L. Using that definition, among patients referred to a stroke prevention clinic, metabolic B12 deficiency or B12 deficiency with serum levels below the reference range was present in 30% of patients age 70 or higher [5]. In the same population, a tHcy > 14 was present in 40% of patients age 80 or higher [6], the very age group in which dementia is most common. (This has declined in recent years, at least in London, Ontario, with increasing awareness of the issues leading to more B12 supplementation.)

Renal function declines linearly with age; by age 80 the average estimated glomerular filtration rate is below 60 mL/min per 1.73 m2 [7]. Patients with renal failure have high levels of thiocyanate [8]; this may explain why in the early trials of B vitamins for homocysteine lowering in stroke prevention, toxicity of cyanocobalamin among participants with renal impairment obscured the benefit of B vitamins [9]. This means that instead of using cyanocobalamin, it is probably preferable to use methylcobalamin or hydroxocobalamin. In the WENBIT study [10], cyanocobalamin failed to lower levels of asymmetric dimethylarginine, an evil companion of homocysteine, whereas Koyama et al. [11] found that methylcobalamin lowered levels of both tHcy and ADMA.

Missed metabolic B12 deficiency represents an important opportunity to prevent both stroke and dementia [12].

J. David Spence M.D., FRCPC
Professor of Neurology and Clinical Pharmacology, Western University
Stroke Prevention & Atherosclerosis Research Centre
Robarts Research Institute
1400 Western Road
London, ON Canada N6G 2V4

[1] Smith AD, Refsum H, Bottiglieri T, Fenech M, Hooshmand B, McCaddon A, Miller JW, Rosenberg IH, Obeid R (2018) Homocysteine and Dementia: An International Consensus Statement. J Alzheimers Dis 62, 561-570.
[2] Quinlivan EP, McPartlin J, McNulty H, Ward M, Strain JJ, Weir DG, Scott JM (2002) Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease. Lancet 359, 227-228.
[3] Robertson J, Iemolo F, Stabler SP, Allen RH, Spence JD (2005) Vitamin B12, homocysteine and carotid plaque in the era of folic acid fortification of enriched cereal grain products. CMAJ 172, 1569-1573.
[4] Stabler SP, Lindenbaum J, Allen RH (1996) The use of homocysteine and other metabolites in the specific diagnosis of vitamin B-12 deficiency. J Nutr 126, 1266S-1272S.
[5] Spence JD (2006) Nutrition and stroke prevention. Stroke 37, 2430-2435.
[6] Spence D (2009) Mechanisms of thrombogenesis in atrial fibrillation. Lancet 373, 1006-1007.
[7] Spence JD, Urquhart BL, Bang H (2016) Effect of renal impairment on atherosclerosis: only partially mediated by homocysteine. Nephrol Dial Transplant 31, 937-944.
[8] Koyama K, Yoshida A, Takeda A, Morozumi K, Fujinami T, Tanaka N (1997) Abnormal cyanide metabolism in uraemic patients. Nephrol Dial Transplant 12, 1622-1628.
[9] Spence JD, Yi Q, Hankey GJ (2017) B vitamins in stroke prevention: time to reconsider. Lancet Neurol 16, 750-760.
[10] Loland KH, Bleie O, Borgeraas H, Strand E, Ueland PM, Svardal A, Nordrehaug JE, Nygard O (2013) The association between progression of atherosclerosis and the methylated amino acids asymmetric dimethylarginine and trimethyllysine. PLoS One 8, e64774.
[11] Koyama K, Ito A, Yamamoto J, Nishio T, Kajikuri J, Dohi Y, Ohte N, Sano A, Nakamura H, Kumagai H, Itoh T (2010) Randomized controlled trial of the effect of short-term coadministration of methylcobalamin and folate on serum ADMA concentration in patients receiving long-term hemodialysis. Am J Kidney Dis 55, 1069-1078.
[12] Spence JD (2016) Metabolic vitamin B12 deficiency: a missed opportunity to prevent dementia and stroke. Nutr Res 36, 109-116.


We agree that vitamin B12 is an important factor in relation to dementia. We have recently published two reviews that consider vitamin B12 in more detail [1, 2]. This Consensus Statement is about the relationship of elevated homocysteine, independent of its cause, to dementia.

A. David Smitha and Helga Refsuma,b

aOPTIMA, Department of Pharmacology, University of Oxford, Oxford, UK
bDepartment of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Norway

[1] Smith AD, Refsum H (2016) Homocysteine, B vitamins, and cognitive impairment. Annu Rev Nutr 36, 211-239.
[2] Smith AD, Warren MJ, Refsum H (2018) Vitamin B12. Adv Food Nutr Res 83, 215-279.