The C677T variant in MTHFR modulates associations between brain integrity, mood, and cognitive functioning in old age

Abstract

Introduction: The C677T functional variant in the methylene-tetrahydrofolate reductase (MTHFR) gene leads to reduced enzymatic activity and elevated blood levels of homocysteine. Hyperhomocysteinemia has been linked with higher rates of cardiovascular diseases, cognitive decline, and late-life depression.

Methods and materials: Here, 3D magnetic resonance imaging data was analyzed from 738 individuals (age: 75.5 ± 6.8 years; 438 men/300 women) including 173 Alzheimer's patients, 359 subjects with mild cognitive impairment, and 206 healthy older adults, scanned as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI).

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 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.

Conclusion: This study sheds light on important relationships between vascular risk factors, age-related cognitive decline, and late-life depression, and represents a significant advance in our understanding of clinically relevant associations relating to MTHFR genotype.

Keywords: MRI; MTHFR; age-related cognitive decline; brain atrophy; homocysteine; late-life depression.

Figure 1

Simplified illustration of the one-carbon cycle

Figure 2. Effects of the C677T variant on regional brain volumes (N=738)

Negative beta values (warm colors) show regions where each risk T allele was associated with a 2-4 % volume deficit, as shown on the color bar. Tests for associations are adjusted for age, sex, and diagnosis; maps are corrected for multiple comparisons with the searchlight false discovery rate method at q=0.05. Images are in radiological convention (left side of the brain shown on the right).

Figure 3. Mediation of the association between genotype and medial orbitofrontal volumes by plasma homocysteine levels (N=634)

Path coefficients for simple mediation analysis using the PROCESS Procedure for SPSS. The a-path represents the association between genotype and plasma homocysteine levels. The b-path denotes the relationship between plasma homocysteine levels and medial orbitofrontal volumes, while also controlling for genotype. The c’-path and the c-path represent the associations between genotype and medial orbitofrontal volumes with and without plasma homocysteine levels included as a mediator, respectively. *p<0.05, **p<0.01, ***p<0.001.

Figure 4. Mediation of the association between MMSE performance and GDS-15 scores by medial orbitofrontal volumes (N=640)

Path coefficients for simple mediation analysis using the PROCESS Procedure for SPSS. The a-path represents the association between MMSE scores and medial orbitofrontal volumes. The b-path denotes the relationship between medial orbitofrontal volumes and GDS scores, while also controlling for MMSE performance. The c’-path and the c-path represent the associations between MMSE and GDS scores with and without medial orbital cortical volumes included as a mediator, respectively. *p<0.05, **p<0.01, ***p<0.001.