MTHFR gene A1298C (rs1801131) polymorphism and its correlations with cerebrospinal fluid biomarkers, cognitive level, and brain structure changes in patients with Alzheimer’s disease

Objective To investigate the relationship of A1298C (rs1801131) polymorphism in the MTHFR gene encoding methylenetetrahydrofolate reductase with the cerebrospinal fluid β-amyloid 1-42 subtype (Aβ1-42) level, cognitive level, and brain structure changes in patients with Alzheimer’s disease (AD). Methods A total of 1 271 subjects who met the inclusion criteria in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database were selected. A multivariable linear regression model was used to analyze the relationship of MTHFR gene A1298C (rs1801131) polymorphism with cerebrospinal fluid Aβ1-42 level, cognitive level, and brain structure changes in AD patients. A mediation model was used to analyze the role of cerebrospinal fluid Aβ1-42 level in mediating the relationship between MTHFR gene A1298C (rs1801131) polymorphism and cognitive level. Results Multivariable linear regression model analysis showed that A1298C-C allele was negatively correlated with the level of Aβ1-42 in cerebrospinal fluid, hippocampal volume, and cognitive level (β=-0.121--0.084,t=-3.308--1.953,P<0.05), and positively correlated with cognitive status and ventricular volume (β=0.108,0.126,t=3.749,3.653,P<0.05). The mediation model showed that the level of Aβ1-42 in cerebrospinal fluid mediated 26.0% of the relationship between A1298C-C allele and memory function (ADNI_Memory score), and 19.9% of the relationship between A1298C-C allele and Mini-Mental State Examination score. Conclusion MTHFR gene A1298C (rs1801131) polymorphism affects cerebrospinal fluid biomarkers, cognitive level, hippocampal volume, and ventricular volume in AD patients. A1298C-C allele may promote the development and progression of AD by reducing the level of Aβ1-42 in cerebrospinal fluid. Targeted modification of the MTHFR gene may represent an important intervention stra-tegy for populations with a high genetic risk of AD in the future.