The Clinical Correlation Of Gene Polymorphism Of Methylenetetrahydrofolate Reductase With Alzheimer's Disease

BackgroundAlzheimer's disease(AD)is the most common type of dementia in the elderly,and its clinical manifestations are mainly progressive cognitive impairment,diminished living ability,and abnormal mental conduct.AD has become a significant financial burden for families and society as the population continues to age.However,there is currently no effective treatment for AD,making early detection and intervention critical.Amnestic mild cognitive impairment(aMCI)is a transitional state between AD and normal aging,characterized by episodic memory impairment and acting as a precursor to AD.The study of the risk factors and pathogenesis of AD and aMCI has substantial clinical implications for early intervention.In recent years,the methylenetetrahydrofolate reductase(MTHFR)gene has emerged as a risk gene in AD research,C677T(rs1801133)is the most common single nucleotide polymorphism with wild-type CC,heterozygous mutant CT,and homozygous mutant TT genotypes.The enzymatic activities of the TT genotype and CT genotype populations were 30 percent and 65 percent of that of the CC genotype population,respectively.Since MTHFR is involved in the remethylation of homocysteine(Hcy),the decrease of MTHFR enzyme activity might result in aberrant metabolism of Hcy and elevated serum Hcy levels,thereby promoting the onset and progression of AD.However,However,findings from research on therapies for AD or aMCI patients with increased Hcy levels have been varied,and genetic background may play a role.it is still controversial whether the MTHFR C677T polymorphism is related to the risk of AD or aMCI and is affected by gender and APOE gene,and the particular neurological mechanisms of MTHFR C677T and the MTHFR-APOE gene interaction are yet unknown.Studies of gene imaging have become increasingly useful in uncovering disease mechanisms in recent years.The application of structural magnetic resonance makes it more convenient and objective to detect the changes of gray matter structure,which is helpful to explore the influence of MTHFR C677T polymorphism and MTHFR-APOE gene interaction on the brain gray matter volume of AD or aMCI patients,and provide an important basis for the early diagnosis,intervention,and progression monitoring of the disease.Objective(1)To investigate the effects of serum Hcy,folate,and vitamin B₁₂ levels on cognitive function and their correlations with AD and aMCI,as well as the effects of the MTHFR C677T genotypes on serum Hcy,folate,and vitamin B₁₂ levels,and to find whether the association between MTHFR C677T polymorphism and the risk of AD and aMCI is affected by APOE gene.(2)In order to gain a better understanding of the role of the MTHFR C677T polymorphism in aMCI pathogenesis,using structural magnetic resonance analysis to investigate the effects of MTHFR C677T polymorphism and interaction effects of MTHFR-APOE genotypes on gray matter atrophy in patients with aMCI.Methods(1)We performed a cross-sectional case-control study to compare the differences in serum Hcy,folate,and vitamin B₁₂ levels among AD,aMCI and HC groups.The association among serum Hcy,folate,vitamin B₁₂,and different cognitive function scores were assessed using the partial correlation.Logistic regression analysis was applied to obtain the odds ratios(OR)and P for the trend in models.The differences in serum Hcy,folic acid and vitamin B12 levels corresponding to different genotypes of MTHFR C677T were compared.According to APOE?4 and gender variables,stratified analysis was conducted to compare the distribution of MTHFR C677T polymorphism between different groups,and to explore the relationship between MTHFR C677T polymorphism and the risk of AD and aMCI in different APOE?4 subgroups.At the clinical level,the association of MTHFR C677T polymorphism and serum Hcy level with AD and aMCI was investigated.(2)In order to understand the role of risk genes in the pathological mechanism of aMCI,we used 3D-T1 structural magnetic resonance technology,and performed voxel-based morphological analysis(VBM)and full factorial covariance analysis,which may help to find MTHFR C677T polymorphism,APOE gene,and the effect of MTHFR C677T-APOE genes interaction on the gray matter volume of aMCI patients.Results(1)A total of 74 AD patients,85 aMCI patients and 81 healthy controls(HC)were included,and there were no significant differences in gender,age and education levels among the three groups.Compared with HC group,the serum Hcy levels in AD group and aMCI group were significantly higher(P<0.001;P<0.001),while serum folate levels in aMCI group was significantly lower(P=0.015).The proportion of APOE?4carriers in AD group was significantly higher than that in aMCI group and HC group(P<0.001;P<0.001).The results of partial correlation analysis showed that serum Hcy concentration was negatively associated with Mini-Mental State Examination(MMSE)score(r=-0.156,P=0.016),Montreal Cognitive Assessment(Mo CA)score(r=-0.192,P=0.003),and Cambridge Cognitive Examination-Chinese Version(CAMCOG-C)total score(r=-0.140,P=0.032)and CAMCOG-C subitem memory score(r=-0.153,P=0.019),attention(r=-0.129,P=0.047)and perception score(r=-0.151,P=0.020),while serum folate concentration was inversely correlated with CAMCOG-C subitem abstraction score(r=0.133,P=0.040).The findings of regression analysis revealed the association between the quartiles of serum Hcy,folate and the prevalence of AD and aMCI.Serum folate levels were adversely linked with aMCI(Q4/Q1,OR=0.251,95%CI=0.097-0.653,P _trend=0.003),and serum Hcy concentrations showed positive association with the risk of aMCI and AD(Q4/Q1,OR=5.537,95%CI=2.073-14.788,P _trend=0.001;Q4/Q1,OR=3.684,95%CI=1.231-11.027,P _trend=0.010)after adjusting for age,sex,education levels and APOE?4.The MTHFR C677T polymorphism had a significant effect on serum Hcy and folate levels.Compared with CC and CT genotypes,serum folate levels were decreased in TT genotypes,while serum Hcy levels were significantly increased.Although the MTHFR 677T allele and the TT genotype were not found to be significantly associated with the risk of AD or aMCI in regression analysis,we did find there was an increasing trend between MTHFR TT genotype and the risk of aMCI in APOE?4 non-carriers(OR=3.670,95%CI=1.077-12.509,P=0.038).Moreover,The MTHFR T allele(OR=1.476,95%CI=0.796-2.738,P=0.741)as well as TT genotype(OR=3.166,95%CI=0.812-12.341,P=0.097)may have a tendency to increase the risk of AD in APOE?4 non-carriers,but there was no equivalent expression among APOE 4 carriers,notwithstanding the lack of significance.(2)A total of 60 aMCI patients and 30 healthy subjects were included,and gray matter structural changes were analyzed by voxel-based morphometry(VBM).Age,gender,years of education,and TIV were set as covariates.A full factorial analysis of covariance revealed that aMCI patients showed significant gray matter atrophy in the bilateral hippocampus,right parahippocampal gyrus and left superior temporal gyrus compared with the HC group.In aMCI patients,compared with APOE?4 non-carriers,APOE?4 carriers had significant right hippocampal atrophy(voxel=429,peak MNI:29,-36,-2).Although the main effect of MTHFR C677T polymorphism,and the interaction effect of MTHFR C677T-APOE gene on gray matter volume was not found,however,in APOE?4 non-carriers,we found that aMCI disease interacts with the MTHFR C677T polymorphism,and the region which effected by interaction effect is the right precuneus(voxel=81,peak MNI:17,-60,27),and subsequent simple effects analysis showed that in healthy subjects without APOE?4 risk allele,the gray matter volume of the right precuneus was smaller in MTHFR 677T allele carriers than in CC genotype carriers.In aMCI patients who did not carry the APOE?4 risk allele,MTHFR 677T allele carriers had greater gray matter volume in the right precuneus compared with those who carrying the CC genotype.Conclusion(1)Elevated serum Hcy levels are associated with cognitive functions such as memory,attention and perception.In addition,increased serum Hcy levels may increase the risk of AD and aMCI.MTHFR C677T polymorphism plays an important role in Hcy metabolism,which leads to increased serum Hcy levels and decreased folate levels.In APOE?4 non-carriers,the MTHFR 677T allele and TT genotype may have a tendency to increase the risk of AD and aMCI.(2)Both aMCI disease and APOE?4 allele have effects on gray matter atrophy,while the effect of MTHFR C677T polymorphism on gray matter volume is mainly in subjects who do not carry APOE?4 allele.The gray matter regions affected by the interaction between aMCI disease and the MTHFR C677T polymorphism is predominantly in the right precuneus.Further confirmation of this finding is required in a larger cohort of APOE?4 non-carriers.