Genetic influence of plasma homocysteine on Alzheimer's disease

Alzheimer’s Disease Neuroimaging Initiative

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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.

Original languageEnglish
Pages (from-to)243.e7-243.e14
JournalNeurobiology of Aging
StatePublished - Feb 2018


  • Aging
  • Alzheimer's disease
  • Causal association
  • Mendelian randomization
  • Plasma homocysteine
  • Polygenic score


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