Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
J Neurol Neurosurg Psychiatry. 2020 May;91(5):540-546. doi: 10.1136/jnnp-2019-322366. Epub 2020 Mar 31.
To examine the association between serum total homocysteine levels (tHcy) and dementia risk.
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.
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).
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.
探讨血清总同型半胱氨酸（tHcy）水平与痴呆风险的关系。
共纳入 1588 名年龄≥60 岁且无痴呆的日本成年人，从 2002 年至 2012 年进行前瞻性随访。采用 Cox 比例风险模型和限制三次样条来评估 tHcy 水平对痴呆风险的 HR。
随访期间，372 名受试者发生了全因痴呆；247 名患有阿尔茨海默病（AD），98 名患有血管性痴呆（VaD）。与 tHcy 最低五分位数（≤6.4 μmol/L）相比，最高五分位数（≥11.5 μmol/L）的多变量校正 HR（95%CI）分别为全因痴呆 2.28（1.51-3.43）、AD 1.96（1.19-3.24）和 VaD 2.51（1.14-5.51）。在限制三次样条中，全因痴呆的风险在大约 8-15 μmol/L 之间稳步上升，此后趋于平稳，AD 和 VaD 也呈现出类似的非线性形态（所有非线性 p 值均≤0.02）。在受影响 tHcy 浓度的最常见遗传多态性（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风险等位基因携带者中均持续存在，在前者中甚至更强（异质性 p 值=0.07）。
高血清 tHcy 水平与痴呆、AD 和 VaD 的风险呈非线性相关，只有在相对较高的 tHcy 水平范围内才存在暴露-反应关联。影响血清 tHcy 浓度的非遗传因素可能在 tHcy-痴呆关联中发挥重要作用，而与升高的 tHcy 遗传易感性无关。
