Gene-environment and gene-gene interaction in the determination of plasma homocysteine levels in healthy middle-aged men

Healthy middle-aged men (n = 1,470) from eight general practices across Britain were examined for plasma total homocysteine levels and genotyped for the A222V polymorphism in the methylene-tetrahydrofolate (MTHFR) gene, the 68 bp insertion polymorphism in exon 8 of the cystathionine b synthase (CBS) gene and the D919G polymorphism in the methionine synthase (MS) gene. The median value for plasma homocysteine was 11.90 micromol/l (25-75% Interquartile range 10.10-14.20) for the whole sample. Smokers had significantly higher homocysteine levels than non-smokers (12.90 vs 11.70 micromol/l and p < 0.00005) and levels significantly differed according to folate (p-value < 0.00005), with men in the lowest quartile of folate having the highest median homocysteine levels. Genotype at all three loci was associated with differences in plasma homocysteine level. Individuals homozygous for the MTHFR V222 allele had 1.6 micromol/l higher median homocysteine levels when compared to the other two genotypes (p < 0.00005), while for the CBS and MS genes, individuals carrying one or more of the rare alleles had lower median homocysteine than individuals homozygous for the common allele (0.80 micromol/l, p < 0.03, and 0.70 micromol/l, p < 0.04 respectively). The raising effect associated with homozygosity for the V222 allele was greater in men in the lowest quartile of folate (interaction between folate and genotype p = 0.02), but none of the genotype effects was significantly modulated by B12 levels. While the raising effects of V222 and MS D919 homozygosity on homocysteine level were essentially additive, the homocysteine lowering effect associated with the CBS 68bp allele was seen most strongly in men homozygous for the V222 allele (MTHFR-CBS genotype interaction p = 0.03) and the D919 allele (MS-CBS interaction p = 0.09). Age, folate, B12 and smoking explained 13.48% of the variance while the three genotypes combined and with interaction terms explained only an additional 2.63%. This interaction between CBS genotype and MTHFR and MS genotype points to a key role of the CBS transulphuration pathway in the metabolism of homocysteine that may be particularly important as a compensatory mechanism in subjects with low dietary folate.     

Homocysteine and related genetic polymorphisms in Down's syndrome IQ

OBJECTIVE: Down's syndrome (DS) is the most frequent genetic cause of Alzheimer-type dementia. Its metabolic phenotype involves an increased trans-sulphuration of homocysteine. The aim of the present study was to investigate the influence of homocysteinaemia (t-Hcys), folate, vitamin B(12), and related polymorphisms on intelligence quotient (IQ) in DS. METHODS: The IQ of 131 patients with trisomy 21 from a specialist centre in Sicily was determined and classified according to DMS-IV. The effects of age, folate, vitamin B(12), t-Hcys, and genetic polymorphisms on IQ were evaluated separately and in combination using regression analyses. RESULTS: IQ was significantly lower in DS patients with t-Hcys >7.5 micromol/l (median) and in those who were carriers of methylenetetrahydrofolate reductase (MTHFR) 677 T allele and of methylenetetrahydrofolate reductase 677 T and transcobalamin 776 G combined alleles (p = 0.0013, p = 0.0165, and p = 0.0074, respectively). The IQ correlated significantly with t-Hcys and folate in single and multiple regression analyses, independently of age. In addition, t-Hcys >9.6 micromol/l (upper quartile) was found to be associated with low IQ (<40, median of study group) with an odds ratio of 2.61 (p = 0.0203). The odds ratio was increased by threefold in carriers of MTHFR 677T allele. The MTHFR 677T allele/transcobalamin 776 G allele combination was associated with the risk of DS patients to have an IQ less that the median with an odds ratio of 2.68 (95% CI 1.26 to 5.70, p = 0.0104). CONCLUSION: This study found evidence of an association between t-Hcys and MTHFR 677 T and transcobalamin 776 G alleles with IQ in patients with DS. The association may be related to a defective remethylation of homocysteine, affecting IQ.     

Plasma homocysteine, MTHFR C677T, CBS 844ins68bp, and MTHFD1 G1958A polymorphisms in spontaneous cervical artery dissections

Abstract. Mild hyperhomocysteinemia is a probable risk factor for atherosclerotic diseases and stroke. Recently, associations of elevated plasma homocysteine concentrations in the acute phase and of MTHFR 677 TT genotype with spontaneous cervical artery dissections (sCAD) have been reported. The purpose of this study was to test this hypothesis in the currently largest sample of patients with sCAD, taking into account known factors influencing plasma homocysteine levels. Ninety-five patients with past sCAD were compared with 95 age- and sex-matched healthy individuals. Homocysteine, vitamin B6, B12, folate, and polymorphisms of methylenetetrahydrofolate reductase (MTHFR C677T), cystathionine -synthase (CBS 844ins68bp) and methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase (MTHFD1 G1958A) were assessed and any associations were analysed using multivariate statistics. The occurrence of sCAD was associated with elevated homocysteine levels with an odds ratio of 1.327 per 20 % percentile. Homocysteine levels were influenced by gender, smoking status, occurrence of hypertension, vitamin B12 and folate levels, and by the MTHFR TT genotype. MTHFR, CBS 844ins68bp, and MTHFD1 G1958A genotype were not independently associated with the occurrence of sCAD. These data suggest that elevated homocysteine is associated with the occurrence of sCAD. The MTHFR C677T polymorphism is associated with the homocysteine level.     

Serum homocysteine and folate levels in korean schizophrenic patients

Objective

This study was conducted to confirm the results of the authors'' previous research on schizophrenia manifesting high serum homocysteine and low folate levels. This study is anchored on a theory that a high serum homocysteine concentration affects schizophrenia by virtue of a neurotoxic mechanism, and on a report that some schizophrenia patients with high homocysteine levels benefited from high folate ingestion.

Methods

The serum homocysteine, folate, and vitamin B₁₂ levels of 236 normal-control-group subjects and 234 schizophrenia subjects who met the diagnostic criteria based on DSM-IV-TR were compared. The homocysteine levels were measured via fluorescence polarization immunoassay, and the folate and vitamin B₁₂ levels were determined via radioimmunoassay.

Results

The homocysteine levels of the patient group were significantly higher than those of the normal control group. The homocysteine level was more negatively correlated with the folate level in the schizophrenia group than in the control group. The percentages of female and male schizophrenia subjects manifesting high homocysteine levels were 33.8 and 51.5%, respectively. The percentage of schizophrenia subjects with low folate levels was 66.2%. In the low- and normal-folate-level groups, the patient group showed significantly higher homocysteine levels than the normal control group. The low-folate-level patient group particularly showed significantly higher homocysteine levels than the low-folate-level normal control group.

Conclusion

Some schizophrenia patients with high serum homocysteine levels may have the genetic defect of having low folate serum levels. In such cases, folate ingestion may be a good management modality for clinical improvement.     

Cystathionine beta synthase as a risk factor for Alzheimer disease

One of the known risk factors for developing Alzheimer disease (AD) is hyperhomocysteinemia. The latter may result from mutations of the genes coding for three key enzymes involved in homocysteine metabolism (methylenetetrahydrofolate reductase [MTHFR], methionine synthase [MS], and cystathionine beta-synthase [CBS]). Although MTHFR and MS polymorphisms have been shown to be positively associated with AD in some populations, the relationship of the CBS gene with AD remains undefined. In order to evaluate whether AD is associated with CBS gene changes leading to decreased CBS activity and homocysteine accumulation, we genotyped the CBS 844ins68 mutation and VNTR polymorphisms of the CBS gene in 206 AD patients and 186 age-matched controls. A slight increase in both 844ins68 mutation and VNTR allele 19 frequencies was detected in the whole AD patient group, compared with controls. The division of AD patients and controls into three age-at-onset/age dependent subgroups (<65 years, 65-74 years, > 75 years) revealed that the 844ins68 mutation and VNTR allele 19 are independent risk factors for AD development in subjects aged 75 years or more.     

Homocysteine, folate, lipid profile and MTHFR genotype and disability in children with myelomeningocele

Study design We performed a cross-sectional study in myelomeningocele children.Objective To investigate plasma total homocysteine, folate, lipid profile, 5,10- metylenetetrahydrofolate reductase genotype (MTHFR) and disability.Materials and methods Sixty patients aged between 2 and 14 years with myelomeningocele (18 ambulatory and 42 non-ambulatory) and 150 healthy children of same age, are investigated for lipid profile, homocysteine concentration and for the determination of MTHFR genotype.Results Plasma homocysteine concentrations were significantly higher in myelomeningocele children than in the control group. In myelomeningocele female group, there were higher levels of total cholesterol and very-low-density lipoprotein cholesterol with respect to the control group. Myelomeningocele children walking with tutorial aid showed triglyceride levels significantly lower than those observed in myelomeningocele non-walking children.Conclusion Disability, insulin uptake, lipid, homocysteine, hormones plasma levels, and genetic factors such as allelic variants of MTHFR are possible for cardiovascular disease in myelomeningocele children. This study highlights the importance of a continuous surveillance of any changes in the lipid profile that should be corrected as soon as possible. Constant physical activity necessary to increase HDL levels should be planned in all susceptible children. Nonetheless, further investigations are necessary to identify new homocysteine susceptible genes for prevention of early atherosclerosis and consequent cardiovascular disease.     

Severe methylenetetrahydrofolate reductase (MTHFR) deficiency: a case report of nonclassical homocystinuria

Severe methylenetetrahydrofolate reductase deficiency is an autosomal recessive metabolic disorder of folate metabolism causing elevated plasma homocysteine levels and homocystinuria (MIM 236250). A developmentally delayed 10-year-old girl presented with symptoms of progressive ataxia, dysarthria, tremor, mental status changes, and white-matter changes on magnetic resonance imaging. These changes occurred during a 3- to 4-month time period, with an acceleration of symptoms during 2 to 3 weeks. The patient was found to have extremely high serum homocysteine and low-normal serum methionine. She received treatment with vitamin B12, folate, betaine, multivitamins, and aspirin, with subsequent improvement of her symptoms and reduction in her serum homocysteine level. This case emphasizes the need to include homocystinuria in the differential diagnosis of children with acute/subacute neurological changes, particularly in the context of developmental delay.     

Homocysteine, folate, methylation, and monoamine metabolism in depression

OBJECTIVES: Previous studies suggest that folate deficiency may occur in up to one third of patients with severe depression, and that treatment with the vitamin may enhance recovery of the mental state. There are, however, difficulties in interpreting serum and red cell folate assays in some patients, and it has been suggested that total plasma homocysteine is a more sensitive measure of functional folate (and vitamin B12) deficiency. Other studies suggest a link between folate deficiency and impaired metabolism of serotonin, dopamine, and noradrenaline (norepinephrine), which have been implicated in mood disorders. A study of homocysteine, folate, and monoamine metabolism has, therefore, been undertaken in patients with severe depression. METHODS: In 46 inpatients with severe DSM III depression, blood counts, serum and red cell folate, serum vitamin B12, total plasma homocysteine, and, in 28 patients, CSF folate, S-adenosylmethionine, and the monoamine neurotransmitter metabolites 5HIAA, HVA, and MHPG were examined. Two control groups comprised 18 healthy volunteers and 20 patients with neurological disorders, the second group undergoing CSF examination for diagnostic purposes. RESULTS: Twenty four depressed patients (52%) had raised total plasma homocysteine. Depressed patients with raised total plasma homocysteine had significant lowering of serum, red cell, and CSF folate, CSF S-adenosylmethionine and all three CSF monoamine metabolites. Total plasma homocysteine was significantly negatively correlated with red cell folate in depressed patients, but not controls. CONCLUSIONS: Utilising total plasma homocysteine as a sensitive measure of functional folate deficiency, a biological subgroup of depression with folate deficiency, impaired methylation, and monoamine neurotransmitter metabolism has been identified. Detection of this subgroup, which will not be achieved by routine blood counts, is important in view of the potential benefit of vitamin replacement.     

Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders

Folate is a cofactor in one-carbon metabolism, during which it promotes the remethylation of homocysteine -- a cytotoxic sulfur-containing amino acid that can induce DNA strand breakage, oxidative stress and apoptosis. Dietary folate is required for normal development of the nervous system, playing important roles regulating neurogenesis and programmed cell death. Recent epidemiological and experimental studies have linked folate deficiency and resultant increased homocysteine levels with several neurodegenerative conditions, including stroke, Alzheimer's disease and Parkinson's disease. Moreover, genetic and clinical data suggest roles for folate and homocysteine in the pathogenesis of psychiatric disorders. A better understanding of the roles of folate and homocysteine in neuronal homeostasis throughout life is revealing novel approaches for preventing and treating neurological disorders.     

Serum homocysteine, folate level and methylenetetrahydrofolate reductase 677, 1298 gene polymorphism in Korean schizophrenic patients

High homocysteine serum level has been regarded as one of the important factors that influence the development of schizophrenia. Genetic variations of methylenetetrahydrofolate reductase, which is a main enzyme reducing homocysteine level, are reported in schizophrenic patients. We measured the serum level of homocysteine/folate and methylenetetrahydrofolate reductase C677T/A1298C gene polymorphism in 235 patients with schizophrenia. Plasma homocysteine levels were higher and folate levels were lower in patients than in comparison subjects. Variations of C677T were more frequent in patients than in comparison subjects. Patients with the 677TT genotype showed higher homocysteine levels than patients with the CC and CT genotypes. These findings suggest that folate supplement may be beneficial to some schizophrenic patients with homocysteinemia due to the genetic defect of methylenetetrahydrofolate reductase.     

Folate Augmentation of Treatment – Evaluation for Depression (FolATED): protocol of a randomised controlled trial

Background

Clinical depression is common, debilitating and treatable; one in four people experience it during their lives. The majority of sufferers are treated in primary care and only half respond well to active treatment. Evidence suggests that folate may be a useful adjunct to antidepressant treatment: 1) patients with depression often have a functional folate deficiency; 2) the severity of such deficiency, indicated by elevated homocysteine, correlates with depression severity, 3) low folate is associated with poor antidepressant response, and 4) folate is required for the synthesis of neurotransmitters implicated in the pathogenesis and treatment of depression.

Methods/Design

The primary objective of this trial is to estimate the effect of folate augmentation in new or continuing treatment of depressive disorder in primary and secondary care. Secondary objectives are to evaluate the cost-effectiveness of folate augmentation of antidepressant treatment, investigate how the response to antidepressant treatment depends on genetic polymorphisms relevant to folate metabolism and antidepressant response, and explore whether baseline folate status can predict response to antidepressant treatment. Seven hundred and thirty patients will be recruited from North East Wales, North West Wales and Swansea. Patients with moderate to severe depression will be referred to the trial by their GP or Psychiatrist. If patients consent they will be assessed for eligibility and baseline measures will be undertaken. Blood samples will be taken to exclude patients with folate and B12 deficiency. Some of the blood taken will be used to measure homocysteine levels and for genetic analysis (with additional consent). Eligible participants will be randomised to receive 5 mg of folic acid or placebo. Patients with B12 deficiency or folate deficiency will be given appropriate treatment and will be monitored in the 'comprehensive cohort study'. Assessments will be at screening, randomisation and 3 subsequent follow-ups.

Discussion

If folic acid is shown to improve the efficacy of antidepressants, then it will provide a safe, simple and cheap way of improving the treatment of depression in primary and secondary care.

Trial registration

Current controlled trials ISRCTN37558856     

Folic acid and mental symptoms in children with epilepsy.

312 children resident at a hospital school received a neuropsychiatric examination and information was provided on their IQ status. Children with a fall in their IQ were identified. Serum and red cell folate values were estimated and the relationship between neuropsychiatric disturbances and folate disturbances explored. Patients with a fall in IQ, neurotic disturbance and depression all had significantly lower serum folic acid levels than the rest of the population, and the children with neurotic disturbances and depression had significantly lower red cell folate values. The relationship between folic acid metabolism and the neuropsychiatric disturbances is discussed in the light of these findings.     

Serum folate and homocysteine levels in patients with obsessive-compulsive disorder

Previous studies have shown that folate deficiency, increased homocysteine, impaired metylation have been identified in depressive disorder. Recently, growing research has resulted in the biological association between obsessive-compulsive disorder (OCD) and affective disorders. Therefore, in the present study it was evaluated whether or not folate and homocysteine levels changed. Serum folate and homocysteine concentrations were measured in 23 patients with OCD and in same number of controls. In addition, all patients were assessed by Yale-Brown Obsession Compulsion Scale (Y-BOCS). Serum folate values were significantly lower in OCD patients than in controls, while homocysteine concentrations were higher in patients compared with controls. Serum folate values were significantly and negatively related to Y-BOCS scores. Total serum homocysteine concentrations were positively correlated to Y-BOCS scores and the duration of illness. There was a trend toward a negative correlation between the concentrations of serum folate and homocysteine. In conclusion, we identified that a group of patients with OCD might have folate deficiency, higher homocysteine levels and probable impaired metylation and monoamine metabolism.     

Improvement of cognitive functions after cobalamin/folate supplementation in elderly patients with dementia and elevated plasma homocysteine.

OBJECTIVES: To investigate the effect of cobalamin/folate supplementation on cognitive function in elderly patients with dementia. METHOD: The cobalamin/folate status of the patients was evaluated by measuring plasma homocysteine, serum methylmalonic acid, serum cobalamin and blood folate. Thirty-three patients were studied and repeatedly assessed with the Mini-Mental State Examination (MMSE) and 'A short cognitive performance test for assessing memory and attention' (SKT) during vitamin substitution. RESULTS: Patients with mild-moderate dementia and elevated plasma homocysteine levels improved clinically with increased test scores after vitamin substitution, while severely demented patients and patients with normal plasma homocysteine levels did not improve clinically. CONCLUSIONS: Plasma homocysteine may be the best marker for detecting treatable cobalamin/folate deficiency in patients with dementia.     

Plasma homocysteine, folate and B12 in chronic schizophrenia

Elevated plasma levels of the amino acid homocysteine have been associated with schizophrenia, particularly in young male patients. Among other factors, low folate and vitamin B12 levels have been implicated in the increase in homocysteine. In order to investigate this association, we determined plasma homocysteine, folate and B12 levels in 97 (67 males and 30 females) inpatients with chronic schizophrenia and 103 (46 males and 57 females) controls. Patients and controls did not differ in folate or B12 levels, after adjusting for age. Patients with schizophrenia had higher plasma homocysteine than controls (mean=15.42 micromol/l in cases versus 11.54 micromol/l in controls: F(1,195)=17.978; p<0.001). This difference persisted after controlling for folate and B12 concentrations. Both male and female patients had increased plasma homocysteine compared to controls [(males: mean=16.61 micromol/l in cases versus mean=13.72 in controls: F(1,110)=5.54; p=0.020) (females: mean=12.78 micromol/l in cases versus mean=9.79 micromol/l in controls: F(1,84)=13.54; p<0.001)]. When dividing our sample into two age groups (age < and > or =50 years), both young and older females and younger males with schizophrenia had increased plasma homocysteine compared to controls. We therefore suggest that homocysteinemia is a general risk factor for schizophrenia. We further suggest that it is not limited to young male patients and is not necessarily associated with low folate or B12 levels.     

Folate and Alzheimer: when time matters

Folate is necessary for DNA and mtDNA integrity and via folate/B12-dependent methionine cycle for methylation of multiple substrates (epigenetic DNA and enzymes) and methylation of homocysteine. During embryogenesis, folate deficiency is a risk factor for neural tube defects and late in life for cognitive decline and Alzheimer’s dementia (AD). It induces several Alzheimer pathomechanisms like oxidative stress, Ca⁺⁺ influx, accumulation of hyperphosphorylated tau and β-amyloid. But impact of folic acid supplementation on prevention or delay of dementia is a matter of debate. Six out of seven randomized controlled trials (RCT) with B vitamin intervention periods between 2 and 5.4 years reported about cognitive benefits in the supplemented groups mainly for those subjects with high homocysteine or low folate levels at baseline. This review tries to demonstrate the connection between folate deficiency and AD, analyses selected epidemiologic studies and RCT on folate/B12/homocysteine with long-observation periods (≥2 years RCT; ≥4 years observational) and attempts to find explanations for the controversy in literature like short follow-up, heterogeneity of subjects concerning age, recruitment, baseline cognition, inclusion criteria and probably “misleading”(not representative for the past) folate/B12/homocysteine levels due to not reported short-term use of multivitamins or food-fortification. Population-based studies—epidemiologic and interventional—starting in the fourth decade would provide the best information about the impact of folate on later development of AD. Mandatory folate fortification areas will be important future field studies for—like neural tube defects—hopefully declining AD incidence and disproving safety concerns.     

Association of COMT and PRODH gene variants with intelligence quotient (IQ) and executive functions in 22q11.2DS subjects

The 22q11.2 deletion syndrome (22q11.2DS) carries the highest genetic risk factor for the development of schizophrenia. We investigated the association of genetic variants in two schizophrenia candidate genes with executive function (EF) and IQ in 22q11.2DS individuals.Ninety two individuals with 22q11.2 deletion were studied for the genetic association between COMT and PRODH variants and EF and IQ. Subjects were divided into children (under 12 years old), adolescents (between 12 and 18 years old) and adults (older than 18 years), and genotyped for the COMT Val158Met (rs4680) and PRODH Arg185Trp (rs4819756) polymorphisms. The participants underwent psychiatric evaluation and EF assessment. Our main finding is a significant influence of the COMT Val158Met polymorphism on both IQ and EF performance. Specifically, 22q11.2DS subjects with Met allele displayed higher IQ scores in all age groups compared to Val carriers, reaching significance in both adolescents and adults. The Met allele carriers performed better than Val carriers in EF tasks, being statistically significant in the adult group. PRODH Arg185Trp variant did not affect IQ or EF in our 22q11.2DS cohort. In conclusion, functional COMT variant, but not PRODH, affects IQ and EF in 22q11.2DS subjects during neurodevelopment with a maximal effect at adulthood. Future studies should monitor the cognitive performance of the same individuals from childhood to old age.     

Do maternal folate and homocysteine levels play a role in neurodevelopmental processes that increase risk for schizophrenia?

OBJECTIVE: Evidence from many different lines of research supports the hypothesis that schizophrenia is a disorder of development with etiological factors implicated as early as the second trimester in utero. We suggest that low maternal folate, acting to increase homocysteine levels, may provide a functional link between many of the identified prenatal risk factors and the hypothesized mechanisms whereby neurodevelopmental patterning deviates toward a schizophrenic potential. METHODS: PubMed was searched from the present back to 1963, when elevated homocysteine was identified as a pathogen in homocystinuria as first described by Carson and colleagues (Arch Dis Child 1963;38:425-36). All articles for homocystinuria, homocysteine, folate, and development with schizophrenia were evaluated. RESULTS: The findings from this review support the hypothesis that maternal low folate and high homocysteine levels may provide a potential teratogenic mechanism that increases the risk for developing schizophrenia. CONCLUSION: The potential role of maternal folate deficiency and hyperhomocystinemia in the genesis of schizophrenia would extend the range of their known teratogenic effects. Given the potential for preventive treatment offered by this hypothesis, we believe further investigation into this mechanism is warranted.     

C677T polymorphism of methylenetetrahydrofolate reductase gene affects plasma homocysteine level and is a genetic factor of late-onset Alzheimer's disease

Background: Elevated plasma homocysteine levels are known as a risk for atherosclerotic vascular disease and venous thrombosis and have been shown as a risk for late‐onset Alzheimer's disease (LOAD). Method: To examine the effect of genetic factors predisposing to elevated plasma homocysteine levels on the occurrence of LOAD, we determined the genotype of a C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene and a variable number tandem repeat (VNTR) spanning exon 13–intron 13 boundary of cystathionine β‐synthase (CBS) gene in patients with LOAD and community‐based control subjects. Results: Logistic regression indicated that the MTHFR‐T allele was a risk for LOAD (P < 0.05), independently from apolipoprotein E‐?4 (APOE‐?4) allele. Kaplan–Meier tests showed that in APOE‐?4 non‐carriers, individuals with the MTHFR‐TT genotype have occurences of LOAD earlier than those with the MTHFR‐CC genotype (P < 0.05). Multiple regression analysis indicates that MTHFR‐T allele increases plasma homocysteine levels (P = 0.0002), while the number of X chromosomes decreases (P = 0.01). Plasma homocysteine level was not correlated with age, plasma albumin reflecting nutritional condition, and the dose of APOE‐?4 allele. The CBS‐20 VNTR allele showed the same trend to increase plasma homocysteine level as the MTHFR‐T allele, but a risk effect for LOAD was not evident. Conclusion: A genetic propensity for elevated plasma homocysteine levels, explained by the MTHFR‐T allele encoding defective enzymatic function, is involved in the development of LOAD, particularly in APOE‐?4 non‐carriers, and that homocysteine metabolism could be a preventive target to LOAD in the elderly.     

Vitamin B12, folate,and homocysteine in depression: the Rotterdam Study

OBJECTIVE: The associations of vitamin B(12), folate, and homocysteine with depression were examined in a population-based study. METHOD: The authors screened 3,884 elderly people for depressive symptoms. Subjects with positive screening results had psychiatric workups. Folate, vitamin B(12), and homocysteine blood levels were compared in 278 persons with depressive symptoms, including 112 with depressive disorders, and 416 randomly selected reference subjects. Adjustments were made for age, gender, cardiovascular disease, and functional disability. RESULTS: Hyperhomocysteinemia, vitamin B(12) deficiency, and to a lesser extent, folate deficiency were all related to depressive disorders. For folate deficiency and hyperhomocysteinemia, the association with depressive disorders was substantially reduced after adjustment for functional disability and cardiovascular disease, but for vitamin B(12) this appeared independent. CONCLUSIONS: The association of vitamin B(12) and folate with depressive disorders may have different underlying mechanisms. Vitamin B(12) may be causally related to depression, whereas the relation with folate is due to physical comorbidity.