Genetic influence of plasma homocysteine on Alzheimer's disease

Neurobiol Aging. 2018 Feb:62:243.e7-243.e14. doi: 10.1016/j.neurobiolaging.2017.09.033. Epub 2017 Oct 13.


Observational studies have consistently reported elevated plasma homocysteine as a risk factor for Alzheimer's disease (AD). However, results from clinical trials of homocysteine-lowering treatments are inconsistent. This discrepancy may be explained by a lack of causal association between homocysteine and AD. Mendelian randomization studies have the potential to provide insight into the causality of this association through studying the effect of genetic predisposition to high homocysteine on AD. Our analyses using summarized (n = 54,162) and individual participant (n = 6987) data from Caucasian participants did not show an effect of plasma homocysteine genetic risk on susceptibility to AD. Although with smaller sample sizes, further subanalyses also did not support an effect of genetically determined plasma homocysteine on cognitive impairment and decline, beta-amyloid and tau pathology and gray matter atrophy in AD. However, we found associations with tau tangle burden (n = 251) and gray matter atrophy (n = 605) in cognitively normal elderly. Our results do not support a causal association between elevated homocysteine and risk, severity, and progression of AD. However, the relationship between genetically determined homocysteine and brain pathology in cognitively normal elderly requires further exploration.

Keywords: Aging; Alzheimer's disease; Causal association; Mendelian randomization; Plasma homocysteine; Polygenic score.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics*
  • Amyloid beta-Peptides
  • Atrophy
  • Cognitive Dysfunction / genetics
  • Female
  • Genetic Association Studies*
  • Genetic Predisposition to Disease / genetics*
  • Gray Matter / pathology
  • Homocysteine / blood*
  • Homocysteine / genetics*
  • Humans
  • Male
  • Multifactorial Inheritance
  • Risk Factors
  • White People / genetics
  • tau Proteins


  • Amyloid beta-Peptides
  • tau Proteins
  • Homocysteine