The C677T Variant in MTHFR Modulates Associations Between Brain Integrity, Mood, and Cognitive Functioning in Old Age

Background The C677T functional variant in the methylenetetrahydrofolate reductase (MTHFR) gene leads to reduced enzymatic activity and elevated blood homocysteine levels. Hyperhomocysteinemia has been linked with higher rates of cardiovascular diseases, cognitive decline, and late-life depression. Methods Three-dimensional magnetic resonance imaging data were analyzed from 738 individuals (aged 75.5 ± 6.8 years; 438 men, 300 women), including 173 patients with Alzheimer's disease, 359 subjects with mild cognitive impairment, and 206 healthy older adults, scanned as part of the Alzheimer's Disease Neuroimaging Initiative. Results We found that this variant associates with localized brain atrophy, after controlling for age, sex, and dementia status, in brain regions implicated in both intellectual and emotional functioning, notably the medial orbitofrontal cortices. The medial orbitofrontal cortex is involved in the cognitive modulation of emotional processes, and localized atrophy in this region was previously linked with both cognitive impairment and depressive symptoms. Here, we report that increased plasma homocysteine level mediates the association between MTHFR genotype and lower medial orbitofrontal volumes and that these volumes mediate the association between cognitive decline and depressed mood in this elderly cohort. We additionally show that vitamin B₁₂ deficiency interacts with the C677T variant in the etiology of hyperhomocysteinemia. Conclusions This study sheds light on important relationships between vascular risk factors, age-related cognitive decline, and late-life depression, and it represents a significant advance in our understanding of clinically relevant associations relating to MTHFR genotype.