The Methylenetetrahydrofolate Reductase C677T Polymorphism and Risk for Late-Onset Alzheimer's disease: Further Evidence in an Italian Multicenter Study

Background: A functional polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, namely C677T (rs1801133), results in increased Hcy levels and has been associated with risk of late-onset Alzheimer's disease (LOAD). Many investigators reported association between rs1801133 and LOAD risk in Asian populations and in carriers of the apolipoprotein E (APOE) ϵ4 allele, but recent meta-analyses suggest a contribution also in other populations, including Caucasians and/or northern Africans. Objective: To further address this issue, we performed a relatively large case-control study, including 581 LOAD patients and 468 matched controls of Italian origin. APOE data were available for a subgroup of almost 600 subjects. Methods: Genotyping for rs1801133 was performed with PCR-RFLP techniques. Results: In the total population, the MTHFR 677T allele (OR=1.20; 95 CI=1.01-1.43) and carriers of the MTHFR 677T allele (CTTT versus CC: OR=1.34; 95 CI=1.03-1.73) resulted in increased LOAD risk. Similarly, in APOE ϵ4 carriers, we observed an increased frequency of MTHFR 677CT carriers (CT versus CC: OR=2.82; 95 CI=1.25-6.32). Very interestingly, also in non-APOE ϵ4 carriers, both MTHFR 677T allele (OR=1.38; 95 CI=1.03-1.85) and MTHFR 677TT genotype (OR=2.08; 95 CI=1.11-3.90) were associated with LOAD. All these associations survived after corrections for age, gender, and multiple testing. Conclusions: The present results suggest that the MTHFR C677T polymorphism is likely a LOAD risk factor in our cohort, either in APOE ϵ4 or in non-APOE ϵ4 carriers.