The Impact of MTHFR Gene Polymorphisms on Cerebral Small and Large Vessel Disease, Vascular Cognitive Impairment and Cerebral Volumetric Reduction

Objective: The study aims to evaluate the association of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with cerebral small vessel disease (CSVD), cerebral large vessel disease (CLVD), vascular cognitive impairment (VCI) and global and regional brain volumes. Methods: Clinical, laboratory, neuroimaging, volumetric, cognitive and MTHFR genotyping data were retrospectively collected from 62 patients with CSVD (n = 40) or CLVD (n = 22), all carriers of at least one MTHFR variant. Brain volumes were compared between patients with VCI carrying C677T (n = 30) and patients without VCI (n = 32). Analyses were repeated in the open-source platform jamovi and p-values were corrected for multiple comparisons with the Holm procedure. Results: The cohort comprised 41 women and 21 men (mean age 56.9 years). The CT and TT genotypes of C677T, the AC and CC genotypes of A1298C, blood pressure, total cholesterol and triglycerides differed between CSVD and CLVD at the unadjusted level (p < 0.05), but none of these differences remained significant after Holm correction. VCI carriers of C677T showed lower white matter (332.9 ± 25.5 vs. 437.9 ± 35.7 cm3) and gray matter volumes (626.0 ± 45.7 vs. 699.7 ± 51.5 cm3), higher cerebrospinal fluid volume (238.3 ± 42.2 vs. 197.1 ± 24.8 cm3) and reduced hippocampal, amygdalar, thalamic, superior frontal, middle temporal, entorhinal, parahippocampal and middle occipital volumes (all Holm-adjusted p < 0.05). Conclusions: Differences in MTHFR genotype distribution between CSVD and CLVD were not robust to correction for multiple testing, whereas VCI carriers of C677T showed global and selective regional volume loss that withstood correction. MTHFR variants are susceptibility markers rather than direct causes of vascular injury; these associations, which could not be adjusted for comorbid vascular risk factors or for concomitant neurodegenerative pathology, require confirmation in prospective, controlled studies with homocysteine measurements.