A haplotype of the methylenetetrahydrofolate reductase gene is protective against late-onset Alzheimer's disease

Neurobiol Aging. 2004 Mar;25(3):291-4. doi: 10.1016/S0197-4580(03)00082-4.


Epidemiological studies have shown that elevated plasma homocysteine (Hcy) levels play an important role in the pathogenesis of Alzheimer's disease (AD). In spite of the evidence that a C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene elevates plasma Hcy levels, the impact of the C677T polymorphism on the development of AD is controversial. Here, we performed a genetic case-control study in a Japanese population to investigate whether three polymorphisms of the MTHFR gene, C677T (Ala222Val), A1298C (Glu429Ala), and A1793G (Arg594Gln), are associated with the development of late-onset AD (LOAD). In our study, the MTHFR gene had four major regional haplotypes: Haplotype A (677C-1298A-1793G), Haplotype B (677T-1298A-1793G), Haplotype C (677C-1298C-1793G), and Haplotype D (677C-1298C-1793A). The frequency of Haplotype C in LOAD was significantly lower than that in control group. Furthermore, the benefit conferred by the presence of at least one Haplotype C was stronger in LOAD patients who lacked the ApoE 4 allele (OR=0.293; 95% CI=0.115-0.744; P=0.010). The results indicate that Haplotype C of the MTHFR gene is protective against the development of LOAD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / enzymology*
  • Alzheimer Disease / epidemiology
  • Alzheimer Disease / genetics*
  • Apolipoprotein E4
  • Apolipoproteins E / blood
  • Brain / enzymology*
  • Case-Control Studies
  • DNA Mutational Analysis
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease / genetics
  • Genetic Testing
  • Haplotypes / genetics*
  • Homocysteine / biosynthesis
  • Homocysteine / blood
  • Humans
  • Immunity, Innate / genetics*
  • Japan / epidemiology
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
  • Methylenetetrahydrofolate Reductase (NADPH2) / metabolism
  • Polymorphism, Genetic / genetics


  • Apolipoprotein E4
  • Apolipoproteins E
  • Homocysteine
  • Methylenetetrahydrofolate Reductase (NADPH2)