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

Article type: Research Article

Authors: Stoccoro, Andrea^{a; b} | Tannorella, Pierpaola^a | Salluzzo, Maria Grazia^c | Ferri, Raffaele^c | Romano, Corrado^c | Nacmias, Benedetta^d | Siciliano, Gabriele^e | Migliore, Lucia^{a; f} | Coppedè, Fabio^{a; f; *}

Affiliations: [a] Department of Translational Research and New Technologies in Medicine and Surgery, Section of Medical Genetics, University of Pisa, Pisa, Italy | [b] Doctoral School in Genetics Oncology and Clinical Medicine, University of Siena, Siena, Italy | [c] IRCCS, Oasi Maria SS Institute for Research on Mental Retardation and Brain Aging, Troina, Italy | [d] Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy | [e] Department of Clinical and Experimental Medicine, University of Pisa, Neurological Clinic, Pisa, Italy | [f] Interdepartmental Research Center Nutrafood Nutraceuticals and Food for Health, University of Pisa, Pisa, Italy

Correspondence: [*] Correspondence to: Prof. Fabio Coppedè, PhD, Department of Translational Research and New Technologies in Medicine and Surgery, Medical Genetics Lab, University of Pisa, Medical School, Via Roma 55, 56126 Pisa, Italy. Tel.: +39 050 2218544; E-mail: fabio.coppede@med.unipi.it.

Abstract: 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) ɛ4 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 (CT+TT versus CC: OR = 1.34; 95% CI = 1.03–1.73) resulted in increased LOAD risk. Similarly, in APOE ɛ4 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 ɛ4 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 ɛ4 or in non-APOE ɛ4 carriers.

Keywords: Alzheimer’s disease, APOE, folate, homocysteine, methylenetetrahydrofolate reductase, MTHFR C677T

DOI: 10.3233/JAD-161081

Journal: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1451-1457, 2017