Is high homocysteine level a risk factor for cognitive decline in elderly? A systematic review, meta-analysis, and meta-regression

Am J Geriatr Psychiatry. 2011 Jul;19(7):607-17. doi: 10.1097/JGP.0b013e3181f17eed.


Objective: [corrected] High homocysteine (Hct) has been causatively linked to Alzheimer disease (AD) and vascular dementia (VaD) in old age, but research methodologies and outcome measures are heterogeneous. It remains unclear whether the findings can be generalized across studies.

Methods: Random-effects meta-analyses were conducted on studies examining the relationship between Hct level and risk of developing dementia/cognitive decline between comparison groups. Meta-regression identified patient- and trial-related factors, which may contribute to heterogeneity.

Results: Seventeen relevant studies (6,122 participants; 13 cross-sectional and fourprospective studies) were included. Compared with controls, Hct was significantly elevated in AD (pooled standardized mean difference [SMD]: 0.59; 95% confidence interval [CI]: 0.38-0.80; significant heterogeneity: τ = 0.105) and VaD (pooled SMD: 1.30; 95% CI: 0.75-1.84; significant heterogeneity: τ = 0.378). Meta-regression identified mean age as significant moderator for AD versus controls and mean age and mean folate levels as significant moderators for VaD versus controls. Hct was significantly higher in VaD relative to AD (pooled SMD: 0.48; 95% CI: 0.23-0.73; moderately significant heterogeneity: τ = 0.076); proportion of men and mean folate levels were significant moderators. High-Hct level was not associated with risk of developing dementia in prospective studies (pooled odds ratio: 1.34; 95% CI: 0.94-1.91, nonsignificant heterogeneity: τ = 0.048).

Conclusion: Individuals with AD and VaD have higher Hct levels than controls; however, a causal relationship between high-Hct level and risk of developing dementia is not supported. More prospective studies and randomized controlled trials are required to test the therapeutic benefits of lowering Hct levels.

Publication types

  • Comparative Study
  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Aged
  • Alzheimer Disease / diagnosis*
  • Dementia / diagnosis*
  • Dementia, Vascular / diagnosis*
  • Dietary Supplements / adverse effects
  • Female
  • Folic Acid / blood
  • Folic Acid / therapeutic use
  • Homocysteine* / blood
  • Humans
  • Male
  • Middle Aged
  • Odds Ratio
  • Regression Analysis
  • Risk Factors
  • Vitamin B 12 / blood
  • Vitamin B 12 / therapeutic use


  • Homocysteine
  • Folic Acid
  • Vitamin B 12