Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID)

Atticus H. Hainsworth, Natalie E. Yeo, Erica M. Weekman, Donna M. Wilcock

Research output: Contribution to journalArticlepeer-review

98 Scopus citations


Homocysteine is produced physiologically in all cells, and is present in plasma of healthy individuals (plasma [HCy]: 3-10 μM). While rare genetic mutations (CBS, MTHFR) cause severe hyperhomocysteinemia ([HCy]: 100-200 μM), mild-moderate hyperhomocysteinemia ([HCy]: 10-100 μM) is common in older people, and is an independent risk factor for stroke and cognitive impairment. As B-vitamin supplementation (B6, B12 and folate) has well-validated homocysteine-lowering efficacy, this may be a readily-modifiable risk factor in vascular contributions to cognitive impairment and dementia (VCID).Here we review the biochemical and cellular actions of HCy related to VCID. Neuronal actions of HCy were at concentrations above the clinically-relevant range. Effects of HCy <100 μM were primarily vascular, including myocyte proliferation, vessel wall fibrosis, impaired nitric oxide signalling, superoxide generation and pro-coagulant actions. HCy-lowering clinical trials relevant to VCID are discussed. Extensive clinical and preclinical data support HCy as a mediator for VCID. In our view further trials of combined B-vitamin supplementation are called for, incorporating lessons from previous trials and from recent experimental work. To maximise likelihood of treatment effect, a future trial should: supply a high-dose, combination supplement (B6, B12 and folate); target the at-risk age range and target cohorts with low baseline B-vitamin status. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

Original languageEnglish
Pages (from-to)1008-1017
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Issue number5
StatePublished - May 1 2016

Bibliographical note

Publisher Copyright:
© 2015 Elsevier B.V.


  • Brain
  • Dementia
  • Homocysteine
  • Hyperhomocysteinemia
  • Vascular cognitive impairment

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology


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