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Background: Parkinson's disease (PD) is a neurodegenerative disorder for which environmental factors influence disease risk and may act via an epigenetic mechanism. The microtubule-associated protein tau (MAPT) is a susceptibility gene for idiopathic PD. Methods: Methylation levels were determined by pyrosequencing of bisulfite treated DNA in a leukocyte cohort (358 PD and 1084 controls) and two brain cohorts (Brain1 comprising 69 cerebellum controls, Brain2 comprising 3 brain regions from 28 PD and 12 controls). In vitro assays involved the transfection of methylated promoter-luciferase constructs or treatment with an exogenous micronutrient. Results: In normal leukocytes, MAPT H1/H2 diplotype and gender were predictors of MAPT methylation. Haplotype-specific pyrosequencing confirmed H1 haplotype to have higher methylation than H2 in normal leukocyte and brain tissues. MAPT methylation was negatively associated with MAPT expression in Brain1 cohort and transfected cells. Methylation levels differed between three normal brain regions (Brain2, putamen > cerebellum > anterior cingulate cortex). In PD samples, age at onset was positively associated with MAPT methylation in leukocytes. Moreover, there was hypermethylation in the cerebellum and hypomethylation in the putamen of PD patients compared with controls (Brain2 cohort). Finally, leukocyte methylation status was positively associated with blood Vitamin E levels, the effect being more significant in H2 haplotype carriers; this result was confirmed in cells exposed to 100 μM Vitamin E. Conclusions: The significant effects of gender, diplotype and brain region suggest that hypermethylation of the MAPT is neuroprotective by reducing MAPT expression. Vitamin E effect on MAPT represents a possible gene-environment interaction.