OBJECTIVE To examine the association between serum total homocysteine levels (tHcy) and dementia risk. METHODS A total of 1588 Japanese adults aged ≥60 years without dementia were prospectively followed from 2002 to 2012. Cox proportional hazards models and restricted cubic splines were used to estimate the HRs of tHcy levels on the risk of dementia. RESULTS During the follow-up, 372 subjects developed all-cause dementia; 247 had Alzheimer's disease (AD) and 98 had vascular dementia (VaD). Compared with the lowest tHcy quintile (≤6.4 µmol/L), the multivariable-adjusted HRs (95% CI) of the highest quintile (≥11.5 µmol/L) were 2.28 (1.51-3.43) for all-cause dementia, 1.96 (1.19-3.24) for AD and 2.51 (1.14-5.51) for VaD. In restricted cubic splines, the risk of all-cause dementia steadily increased between approximately 8-15 µmol/L and plateaued thereafter, with a similar non-linear shape observed for AD and VaD (all p for non-linearity ≤0.02). In stratified analyses by the most recognised genetic polymorphism affecting tHcy concentrations (methylenetetrahydrofolate reductase C677T), the positive association of tHcy with all-cause dementia persisted in both non-carriers and carriers of the risk allele, and even tended to be stronger in the former (p for heterogeneity=0.07). CONCLUSION High serum tHcy levels are associated with an elevated risk of dementia, AD and VaD in a non-linear manner, such that an exposure-response association is present only within a relatively high range of tHcy levels. Non-genetic factors affecting serum tHcy concentrations may play important roles in tHcy-dementia associations irrespective of the genetic susceptibility for raised tHcy.

中文翻译：

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在日本，血清高半胱氨酸和痴呆症的风险。

目的探讨血清总同型半胱氨酸水平（tHcy）与痴呆风险的关系。方法从2002年至2012年，对1588名≥60岁无痴呆症的日本成年人进行前瞻性随访。采用Cox比例风险模型和限制性三次样条曲线估计tHcy水平对痴呆症风险的HRs。结果在随访期间，有372名受试者发展为全因痴呆；其中372名受试者因全痴呆而患病。247例患有阿尔茨海默氏病（AD），98例患有血管性痴呆（VaD）。与最低的tHcy五分位数（≤6.4µmol / L）相比，全因痴呆的最高五分位数（≥11.5µmol / L）的多变量调整后HR（95％CI）为2.28（1.51-3.43），为1.96（ AD的尺寸为1.19-3.24），VaD的尺寸为2.51（1.14-5.51）。在受限三次样条中，全因痴呆的风险在大约8-15 µmol / L之间稳定增加，并随后趋于平稳，AD和VaD的非线性形状相似（非线性p≤0.02时均为p）。在最公认的影响tHcy浓度的遗传多态性（亚甲基四氢叶酸还原酶C677T）的分层分析中，tHcy与全因痴呆的正相关性在非携带者和高风险等位基因携带者中均存在，甚至在前者中更强（异质性的p = 0.07）。结论高血清tHcy水平以非线性方式与痴呆症，AD和VaD风险升高相关，因此仅在相对较高的tHcy水平范围内才存在暴露-反应关联。