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.

Behavioral and Psychological Symptoms of Dementia (BPSD): Clinical Characterization and Genetic Correlates in an Italian Alzheimer’s Disease Cohort

“…Different studies supported the epistatic effect between MTHFR and APOE on cognitive performance in the elderly but also in AD [ 53 , 54 , 55 ]. Moreover, plasma homocysteine concentrations are associated with increased amyloid-β (Aβ) deposition in the brain [ 28 ]. Although this effect was supported, no studies are available to confirm this interaction also in the psychosis/hyperactivity dimension.…”

“…The T allele of the C677T polymorphism provokes the synthesis of an athermolabile variant of the enzyme leading to a reduced enzymatic activity, which in turn produce an increase in the blood Hcy levels [ 23 , 24 ]. Recent findings supported that this allele was associated with an increased risk of LOAD [ 25 , 26 ], and correlated with a significant increase of Hcy levels [ 27 , 28 ]. Concerning the A1298C, the C allele results in a reduced enzymatic activity, but does not influence its thermolability [ 29 , 30 ].…”

Serum Homocysteine as One of the Risk Factors of Cerebral Small Vessel Disease in Chinese Patients

“…Its diagnosis mainly depends on imaging changes. The common hazard factors for CSVD are old age, hypertension, diabetes, and hyperhomocysteinemia, among which hyperhomocysteinemia is currently considered to be one of the important independent risk factors for cognitive impairment [15,16]. Hcy levels are affected by age, nutritional status, heredity, and renal function.…”

MTHFR Gene Mutations Correlate with White Matter Disease Burden and Predict Cerebrovascular Disease and Dementia

“…It is well accepted that the orbitofrontal cortex is involved in cognitive function and emotional processing. In patients with hyperhomocysteinemia related to MTHFR mutations, there is a reported decrease in volume in the orbitofrontal cortex [24]. Reduced activity of MTHFR has also been noted to have an effect on the deregulation of the amyloid-β protein, which may provide another mechanism in the development of dementia [25].…”