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. 2018;62(2):561-570.
doi: 10.3233/JAD-171042.

Homocysteine and Dementia: An International Consensus Statement

Free PMC article

Homocysteine and Dementia: An International Consensus Statement

A David Smith et al. J Alzheimers Dis. .
Free PMC article


Identification of modifiable risk factors provides a crucial approach to the prevention of dementia. Nutritional or nutrient-dependent risk factors are especially important because dietary modifications or use of dietary supplements may lower the risk factor level. One such risk factor is a raised concentration of the biomarker plasma total homocysteine, which reflects the functional status of three B vitamins (folate, vitamins B12, B6). A group of experts reviewed literature evidence from the last 20 years. We here present a Consensus Statement, based on the Bradford Hill criteria, and conclude that elevated plasma total homocysteine is a modifiable risk factor for development of cognitive decline, dementia, and Alzheimer's disease in older persons. In a variety of clinical studies, the relative risk of dementia in elderly people for moderately raised homocysteine (within the normal range) ranges from 1.15 to 2.5, and the Population Attributable risk ranges from 4.3 to 31%. Intervention trials in elderly with cognitive impairment show that homocysteine-lowering treatment with B vitamins markedly slows the rate of whole and regional brain atrophy and also slows cognitive decline. The findings are consistent with moderately raised plasma total homocysteine (>11 μmol/L), which is common in the elderly, being one of the causes of age-related cognitive decline and dementia. Thus, the public health significance of raised tHcy in the elderly should not be underestimated, since it is easy, inexpensive, and safe to treat with B vitamins. Further trials are needed to see whether B vitamin treatment will slow, or prevent, conversion to dementia in people at risk of cognitive decline or dementia.

Keywords: Alzheimer’s disease; Homocysteine; brain atrophy; causation; cobalamin; cognitive impairment; dementia; folate; risk-factor; vitamin B12; vitamin B6.


Hypothetical ‘sufficient causes’ for dementia that involve raised plasma total homocysteine (tHcy) as one of the single component causes. For example, B might be age, C hypercholesterolemia, D hypertension, E smoking, F ApoE4, G low physical activity, H low education. Based on Rothman & Greenland [14].
Parallel pathways for causation of cognitive impairment involving homocysteine. Raised tHcy may directly cause cognitive impairment (blue arrow). Many modifiable factors determine tHcy [3, 11]. Some of these factors may directly cause cognitive impairment (red arrows) as well as causing cognitive impairment indirectly by raising tHcy (grey arrows). Reverse causality (dashed line) could also explain the association of Hcy with cognitive impairment.

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    1. McCaddon A, Davies G, Hudson P, Tandy S, Cattell H (1998) Total serum homocysteine in senile dementia of Alzheimer type. Int J Geriatr Psychiatry 13, 235–239. - PubMed
    1. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM (1998) Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 55, 1449–1455. - PubMed
    1. Refsum H, Smith AD, Ueland PM, Nexo E, Clarke R, McPartlin J, Johnston C, Engbaek F, Schneede J, McPartlin C, Scott JM (2004) Facts and recommendations about total homocysteine determinations: An expert opinion. Clin Chem 50, 3–32. - PubMed
    1. Diaz-Arrastia R (1998) Hyperhomocysteinemia: A new risk factor for Alzheimer disease? Arch Neurol 55, 1407–1408. - PubMed
    1. McCaddon A (2006) Homocysteine and cognition–a historical perspective. J Alzheimers Dis 9, 361–380. - PubMed

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