Hyperhomocysteinemia and risk of incident cognitive outcomes: An updated dose-response meta-analysis of prospective cohort studies

Ageing Res Rev. 2019 May:51:55-66. doi: 10.1016/j.arr.2019.02.006. Epub 2019 Feb 28.


Objective: This study aimed to comprehensively assess the dose-response relationship between blood homocysteine levels and risk of all cause, Alzheimer and vascular dementia, as well as cognitive impairment without dementia (CIND).

Method: We searched for all related prospective cohort studies reporting homocysteine as an exposure from patients with cognitive disorders as a result in the PubMed and EMBASE databases up to June 18, 2018. Pooled relative risks (RRs) and corresponding 95% confidence intervals (CIs) were extracted. The dose-response meta-analyses were conducted to assess potential linear and non-linear dose-response relations. Summary RRs and 95% CIs were calculated using a random- or fixed-effects model.

Results: Twenty-eight prospective cohort studies were eligible in this meta-analysis. During average follow-up periods ranging from 2.7 to 35 years there were 2557 cases (1035 all-cause dementia, 530 Alzheimer's disease, 92 vascular dementia and > 900 CIND) among 28,257 participants. There was a clear linear dose-response relationship between blood homocysteine concentration and risk of Alzheimer-type dementia (P > 0.05 for non-linearity). The pooled RR of Alzheimer-type dementia was 1.15 (95% CI: 1.04 to 1.26; I2 = 56.6%, n = 5) for every 5 μmol/L increase in blood homocysteine. Sensitivity analysis showed similar results, and there was no clear evidence of publication bias with Begg's and Egger's tests for Alzheimer dementia (P = 0.806, 0.084, respectively), strengthening the linear relationship between blood homocysteine levels and risk of Alzheimer dementia. Due to the presence of publication bias and low statistical power, elevated levels of blood homocysteine were not appreciably associated with risk of all-cause, vascular dementia and CIND.

Conclusions: Every 5 μmol/L increase in blood homocysteine is linearly associated with a 15% increase in relative risk of Alzheimer-type dementia. This meta-analysis provides further evidence that a higher concentration of blood homocysteine is associated with a higher risk of Alzheimer-type dementia.

Keywords: Alzheimer’s disease; Cognitive impairment; Dementia; Dose-response; Homocysteine.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / blood
  • Alzheimer Disease / epidemiology
  • Cognition / physiology
  • Cognitive Dysfunction / blood*
  • Cognitive Dysfunction / epidemiology*
  • Cohort Studies
  • Dementia, Vascular / blood
  • Dementia, Vascular / epidemiology
  • Homocysteine / blood*
  • Humans
  • Hyperhomocysteinemia / blood*
  • Hyperhomocysteinemia / epidemiology*
  • Prospective Studies
  • Risk Factors


  • Homocysteine