MTHFR C677T and Brain MRI Patterns Across Cognitive and Vascular Disorders: A Systematic Review

Background: Elevated plasma homocysteine, arising from impaired one-carbon metabolism, has been implicated in cerebral microvascular injury and in neurodegeneration. The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is the commonest genetic determinant of homocysteine concentration, but whether it leaves a measurable structural footprint on the brain remains unresolved. We synthesised genotype-stratified structural MRI findings in Alzheimer’s disease, mild cognitive impairment, and vascular cognitive disorders. Methods: Four sources (PubMed, Europe PMC, OpenAlex, Semantic Scholar) were searched up to 20 September 2026. Eligible reports gave C677T-stratified structural MRI outcomes in adults with clinically defined cognitive disorders. Quality was appraised with an adapted Newcastle–Ottawa Scale, and exploratory random-effects meta-analyses supplemented a narrative synthesis. Results: Thirteen studies (3880 participants across partly overlapping cohorts) were included. Moderate-to-severe white matter lesions were modestly more frequent in TT homozygotes, consistently across contributing studies, with no consistent excess in heterozygotes. Regional volume findings were inconsistent and largely confined to one cohort, whereas whole-brain atrophy rate, hippocampal and medial temporal measures, lacunes, microbleeds, and diffusion metrics showed no genotype-only association. Homocysteine was higher in T-allele carriers wherever measured. Conclusions: The evidence is more compatible with a modest association with vascular white matter injury than with a reproducible neurodegenerative imaging phenotype and does not support genotype-guided clinical decision-making. Longitudinal, biomarker-characterised cohorts with harmonised imaging, adequately powered genotype groups, and measured nutritional status are the main priorities.