Homocysteine And Alzheimer's Disease:Evidence For A Causal Link From Mendelian Randomization

Background/Objective: The relationship between plasma homocysteine(Hcy)levels and Alzheimer's disease(AD)has been studied for many years,but remains controversial.While a recent meta-analysis of epidemiological studies,which included observational studies,indicated that homocysteine may be a risk factor for Alzheimer's disease,there remains a need to further demonstrate this link due to the large degree of heterogeneity between studies.Epidemiological studies have certain limitations,as their results can be affected by confounding factors and reverse causation.In this study,we evaluated the relationship between plasma homocysteine and Alzheimer's disease by using a Mendelian randomization method to avoid problems of confounding bias and reverse causality.Methods: We searched the Pub Med and Embase databases for reports regarding the MTHFR C677 T polymorphism(rs1801133)from the time of their inception to Dec.2016.These reports were combined with related observational studies,and used to evaluate the effect of MTHFR C677T(rs1801133)on the risk for AD.A recent meta-analysis of Genome-Wide Association Studies(GWAS)had previously suggested a relationship between homocysteine and MTHFR C677T(rs 1801133).Results: We identified a total of 145 studies and 34 studies with 9397 subjects included in our met-analysis based on the included and excluded standard.The pooled odds ratios(ORs)with their 95% confidence intervals(95% CIs)were calculated to evaluate the strength of any association between the MTHFR C677T(rs1801133)polymorphism and AD risk based on different genetic models: allele model(T versus C),homozygous model(TT versus CC),heterozygous model(CT versus CC),dominant model(TT + CT versus CC),and recessive model(TT versus CT + CC).Cochran's Q statistic and the I2 test were used to evaluate statistical heterogeneity among the eligible studies.A p-value< 0.1 and I2 value >50% indicated substantial heterogeneity across studies.When this occurred,a random-effects model was selected to perform the meta-analysis;otherwise,the fixed-effects model was selected.and demonstrated a significant relationship between plasma total homocysteine levels and the risk for Alzheimer's disease [(OR = 3.37;95% CI = 1.90–5.95;P =2.9 × 10-5).Conclusion: Our meta-analysis demonstrated a causal link between plasma total homocysteine and the risk for Alzheimer's disease,and demonstrated that a one SD increase in the natural log-transformed plasma Hcy level was associated with a 3.37-fold increase in the risk for developing AD and provides a new insight into the etiology and prevention of Alzheimer's disease.