Effects of Molecular Hydrogen Assessed by an Animal Model and a Randomized Clinical Study on Mild Cognitive Impairment

Curr Alzheimer Res. 2018 Mar 14;15(5):482-492. doi: 10.2174/1567205014666171106145017.


Background: Oxidative stress is one of the causative factors in the pathogenesis of neurodegenerative diseases including mild cognitive impairment (MCI) and dementia. We previously reported that molecular hydrogen (H2) acts as a therapeutic and preventive antioxidant.

Objective: We assess the effects of drinking H2-water (water infused with H2) on oxidative stress model mice and subjects with MCI.

Methods: Transgenic mice expressing a dominant-negative form of aldehyde dehydrogenase 2 were used as a dementia model. The mice with enhanced oxidative stress were allowed to drink H2-water. For a randomized double-blind placebo-controlled clinical study, 73 subjects with MCI drank ~300 mL of H2-water (H2-group) or placebo water (control group) per day, and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) scores were determined after 1 year.

Results: In mice, drinking H2-water decreased oxidative stress markers and suppressed the decline of memory impairment and neurodegeneration. Moreover, the mean lifespan in the H2-water group was longer than that of the control group. In MCI subjects, although there was no significant difference between the H2- and control groups in ADAS-cog score after 1 year, carriers of the apolipoprotein E4 (APOE4) genotype in the H2-group were improved significantly on total ADAS-cog score and word recall task score (one of the sub-scores in the ADAS-cog score).

Conclusion: H2-water may have a potential for suppressing dementia in an oxidative stress model and in the APOE4 carriers with MCI.

Keywords: ADAS-cog score; ApoE4; aldehyde dehydrogenase 2; hydrogen; hydrogen water; mild cognitive impairment; oxidative stress; randomized clinical study.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Aged
  • Aldehyde Dehydrogenase, Mitochondrial / genetics
  • Aldehyde Dehydrogenase, Mitochondrial / metabolism
  • Animals
  • Antioxidants / administration & dosage*
  • Apolipoproteins E / genetics
  • CA1 Region, Hippocampal / drug effects
  • CA1 Region, Hippocampal / pathology
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / genetics
  • Cognitive Dysfunction / pathology
  • Disease Models, Animal
  • Double-Blind Method
  • Drinking Water
  • Female
  • Humans
  • Hydrogen / administration & dosage*
  • Male
  • Mental Processes / drug effects
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurodegenerative Diseases / drug therapy
  • Neurodegenerative Diseases / pathology
  • Neurodegenerative Diseases / psychology
  • Neuroprotective Agents / administration & dosage
  • Oxidative Stress
  • Treatment Outcome


  • Antioxidants
  • Apolipoproteins E
  • Drinking Water
  • Neuroprotective Agents
  • Hydrogen
  • Aldehyde Dehydrogenase, Mitochondrial