S-Adenosylmethionine Is Decreased in the Cerebrospinal Fluid of Patients with Alzheimer’s Disease (original) (raw)
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S-Adenosylmethionine Is Decreased in the Cerebrospinal Fluid of Patients with Alzheimer’s Disease
Neurodegenerative Diseases, 2010
significantly lower CSF levels of the methyl group donor SAM (193 8 31 vs. 207 8 37 nmol/l; p = 0.032). Accordingly, the SAM/SAH ratio, which represents the methylation capacity, was significantly lower in the CSF of the AD patients (7.6 8 2.4 vs. 9.1 8 2.8; p = 0.003). Further, explorative analysis of all subjects showed that CSF SAM levels were lower in carriers of the APOE4 allele compared with noncarriers (189 8 30 vs. 207 8 36 nmol/l; p = 0.010). Of the individuals with CSF SAM levels in the lowest quartile, 63% carried the APOE4 allele compared with 17% of the individuals with CSF SAM levels in the highest quartile (Pearson: 2 = 9.9; p = 0.002; odds ratio 0.126, 95% confidence interval 0.32-0.49). Conclusion: These data suggest that AD is associated with lower CSF SAM levels and that this is at least partly due to an association of the APOE4 allele with reduced SAM levels in the CSF.
2014
Background Alzheimer's disease (AD), the commonest form of dementia, affects people in both industrialised and developing countries. Risk factors for the development of AD include age, the presence of the Apolipoprotein ε4 allele, low vitamin B 12 and folate levels, and elevated plasma homocysteine concentrations. Most research involving the associations between these risk factors and AD have been conducted in Europe and North America. We know little about AD and its risk factors in a low to middle income country like South Africa, where nutrition is poor and the background population ApoE ε4 allelic frequency is high. Objective In this prospective observational study, I wished to determine the relationships between plasma homocysteine, vitamin B 12 , folate, ApoE ε4 status and cognition in a sample of older persons from the greater Cape Town metropolitan area of the Western Cape region of South Africa. Methods Cognitively healthy controls and AD participants, diagnosed using NINCDS-ADRDA criteria, were recruited from the community. The study had both cross-sectional and longitudinal components. Cross-sectionally, I related non-fasting plasma homocysteine concentrations, vitamin B 12 levels, folate concentrations and the ApoE ε4 genotype to scores from a battery of cognitive tests including the Mini Mental State Examination (MMSE), the Cambridge Cognitive Examination (CAMCOG) and the Learning Subscale score of the CAMCOG. In the longitudinal analysis, I tested whether baseline plasma homocysteine concentrations related to cognitive decline one year after the initial assessment. Results One hundred and thirteen participants were recruited: 60 controls and 53 AD participants. Plasma homocysteine levels increased with age (r s = 0.418, p<0.001) and were inversely related to cognitive scores in all participants. Homocysteine concentrations were inversely related to vitamin B 12 and folate in all study participants (vitamin B 12 r s =-0.47, p<0.001, folate r s =-0.33, p=0.001). Homocysteine was inversely related to cognition but, in a regression model, this relation was confounded by the effects of age and years of education. Another regression model showed that vitamin B 12 and age independently predicted cognitive scores. There were more ApoE ε4 carriers in the AD group compared with controls and ε4 carrier status was significantly associated with AD. The ApoE ε4 allele modified the relationship between homocysteine and cognition. The association between homocysteine and cognition was strong in ApoE ε4 carriers (e.g. MMSE, r s =0.33, p=0.003), but absent in ε4 non-carriers. High baseline homocysteine concentrations did not predict cognitive decline 1 year later. Conclusions These findings, the first from an African low to middle income country, are consistent with those from studies in industrialised countries. Plasma homocysteine levels increased with age and were inversely related to vitamin B 12 and folate. The ApoE ε4 allele strengthened the association between homocysteine and cognition, probably through mechanisms that increase neuronal susceptibility to homocysteine toxicity. My study supports the idea that homocysteine-lowering therapy can reduce the risk of developing AD or slow the progression of the disease.
Homocysteine and methylenetetrahydrofolate reductase polymorphism in Alzheimer??s disease
NeuroReport, 2004
Homocysteine metabolism is influenced by genetic polymorphisms of the methylenetetrahydrofolate reductase (MTHFR 677 C--&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;T and 1298 A--&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;C) and transcobalamin genes (TCN1 776 C--&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;G ). We evaluated the association of homocysteine with Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD) and the influence of related polymorphisms and APOE, in 180 cases and 181 controls from southern Italy. Homocysteine (upper tercile) was associated with AD risk, with an odds ratio of 2.8 (95% confidence interval (CI) 1.54-5.22, p=0.0008), which was increased 2.2- and 2.0-fold by MTHFR 677T (odds ratio 6.28, 95% CI 2.88-16.20, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) and APOE epsilon4 (odds ratio: 5.60, 95% CI 1.12-28.05, p=0.0361), respectively. In conclusion, association of homocysteine with AD was aggravated by MTHFR 677T and APOE epsilon4 alleles.
Clinical Biochemistry, 2009
Objectives: To study the interplay between serum concentrations of homocysteine, steroid hormones and vitamins B and mutations in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, in association to Alzheimer's type dementia (ATD). Design and methods: Case-control study including 19 individuals diagnosed with ATD and 36 healthy controls. Serum concentrations of the analytes were determined and MTHFR 1298A → C mutation was screened by PCR-RFLP. Results: Multivariable logistic regression analysis identified homocysteine (OR = 1.92, P b 0.01), cholesterol (OR = 1.14, P b 0.001), estradiol (OR = 0.728, P b 0.001), uric acid (OR = 2.42, P b 0.02), vitamin B 12 (OR = 0.984, P b 0.004) and MTHFR 1298A → C mutation (OR = 6.01, P b 0.04) as independent predictors of ATD. Positive interaction between homocysteine and uric acid, creatinine, urea or cortisol (P b 0.02) and negative interaction between homocysteine and vitamin B 12 or MTHFR 1298A → C mutation (P b 0.03) were observed. Conclusions: High serum concentrations of homocysteine, cholesterol and uric acid, and low concentrations of estradiol and vitamin B 12 , as well as the MTHFR 1298A → C mutation are simultaneously associated to ATD.
Homocysteine metabolism and CSF markers for Alzheimer's disease
Alzheimer's & Dementia, 2009
Dislurbed homocysteinc metabolism is a risk factor for Alzheimer's disease (AD) and may conlribute to lhe disease palhophysiology by increasing both amyloid-ß (Ai3) production and phosphorylnled tau (P-tau) accumulation. Hen:, we evalualed the relntionship belween lhe cerebrospinal fluid (CSF) concentralions of homocysteine (Hcys), S-adenosylrneLhionine (SAM), S-adenosylhomocysleine (SAH). und 5.methyltelrahydrofolate (5-MTHF), and the markers for AD palhology, Aßl-4.2 and P lau 18 J , in 98 cognitively healthy subjects aged 16-81 years and 54 AD palienls. In multivariale regression tests including age, gender. creatinine. und presence 01' the apolipoprotein E e-4 allele, P-tau 181 was associnted with SAH (f3 = 0.490; p < 0.001), 5.MTHF (ß = -0.273; P = 0.010) levels. and SAM/SAH ratio (ß =-O.319;p =0.013) in controls, und with SAH (ß """ 0.529; p = 0.001) in AD patienls. The levels of Aßl-42 were not associated with the CSF concenlrations 01' Hcys. SAM. SAH. or 5-MTHF neither in the AD nOT in lhe contral group. The results suggest thal alteration of the hornocysteine rnelabolism is relalcd to increased accumulation of phosphoryJated lau and may conlribute 10 the neurofibril.lary pathology in normal aging and in AD.
Homocysteine and folate as risk factors for dementia and Alzheimer disease
The American Journal of Clinical Nutrition
Background: In cross-sectional studies, elevated plasma total homocysteine (tHcy) concentrations have been associated with cognitive impairment and dementia. Incidence studies of this issue are few and have produced conflicting results. Objective: We investigated the relation between high plasma tHcy concentrations and risk of dementia and Alzheimer disease (AD) in an elderly population. Design: A dementia-free cohort of 816 subjects (434 women and 382 men; mean age: 74 y) from an Italian population-based study constituted our study sample. The relation of baseline plasma tHcy to the risk of newly diagnosed dementia and AD on follow-up was examined. A proportional hazards regression model was used to adjust for age, sex, education, apolipoprotein E genotype, vascular risk factors, and serum concentrations of folate and vitamin B-12. Results: Over an average follow-up of 4 y, dementia developed in 112 subjects, including 70 who received a diagnosis of AD. In the subjects with hyperhomocysteinemia (plasma tHcy 15 mol/L), the hazard ratio for dementia was 2.08 (95% CI: 1.31, 3.30; P ҃ 0.002). The corresponding hazard ratio for AD was 2.11 (95% CI: 1.19, 3.76; P ҃ 0.011). Independently of hyperhomocysteinemia and other confounders, low folate concentrations (ͨ11.8 nmol/L) were also associated with an increased risk of both dementia (1.87; 95% CI: 1.21, 2.89; P ҃ 0.005) and AD (1.98; 95% CI: 1.15, 3.40; P ҃ 0.014), whereas the association was not significant for vitamin B-12. Conclusions: Elevated plasma tHcy concentrations and low serum folate concentrations are independent predictors of the development of dementia and AD.
Journal of Alzheimer's Disease, 2008
Dysregulation of iron homeostasis is implicated in Alzheimer's disease (AD). In this pilot study, common variants of the apolipoprotein E (APOE) and HFE genes resulting in the iron overload disorder of hereditary hemochromatosis (C282Y, H63D and S65C) were evaluated as factors in sporadic AD in an Ontario sample in which folic acid fortification has been mandatory since 1998. Laboratory studies also were done to search for genetic effects on blood markers of iron status, red cell folates and serum B12. Participants included 58 healthy volunteers (25 males, 33 females) and 54 patients with probable AD (20 males, 34 females). Statistical analyses were interpreted at the 95% confidence level. Contingency table and odds ratio analyses supported the hypothesis that in females of the given age range, E4 significantly predisposed to AD in the presence but not absence of H63D. In males, E4 significantly predisposed to AD in the absence of H63D, and H63D in the absence of E4 appeared protective against AD. Among E4+ AD patients, H63D was associated with significant lowering of red cell folate concentration, possibly as the result of excessive oxidative stress. However, folate levels in the lowest population quartile did not affect the risk of AD. A model is presented to explain the experimental findings.
Current Alzheimer Research, 2009
We obtained brain MRIs, plasma homocysteine levels and apolipoprotein E genotyping for 11 American Indian Alzheimer disease (AD) subjects and 10 Indian controls. We calculated white matter hyperintensity volume (WMHV), whole brain volume (WBV), and ratio of white matter hyperintensity volume to whole brain volume (WMHV/WBV). There were no significant differences between AD subjects and controls in gender, history of hypertension, diabetes, or history of high cholesterol, but hypertension and diabetes were more common among AD subjects. There was no difference between AD and control groups in age (range for all subjects was 61-89 years), % Indian heritage, waist size or body mass index. Median Indian heritage was 50% or greater in both groups. Range of education was 5-13 years in the AD group and 12-16 years in controls. Median plasma homocysteine concentration was higher in AD subjects (11 μmol/L vs. 9.8 μmol/L), but did not achieve statistical significance. Significantly more AD subjects had apolipoprotein Eε4 alleles than did controls (63% vs.10%). Neuroimaging findings were not significantly different between the 2 groups, but AD subjects had greater WMHV (median 15.64 vs. 5.52 cc) and greater WMHV/WBV ratio (median 1.63 vs. 0.65 %) and a far greater range of WMHV. In combined AD subjects and controls, WBV correlated with BMI and age. WMHV and WMHV/WBV correlated inversely with MMSE scores (p = 0.001, 0.002, respectively). In addition, WMHV correlated positively with % Indian heritage (p = 0.047).