From the Aging Research Center (G.G., B.H., D.L.V., L.F., J.W., D.R.), Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Stockholm University, Sweden; Department of Clinical Geriatrics (B.H.), Klinikum Ingolstadt, Germany; Stockholm Gerontology Research Centre (D.L.V., L.F., D.R.), Sweden; OPTIMA (D.S., H.R.), Department of Pharmacology, University of Oxford, United Kingdom; Department of Nutrition (H.R.), Institute of Basic Medical Sciences University of Oslo, Norway; Institute of Environmental Medicine (IMM) (P.L., T.B.), Karolinska Institutet; Department of Cardiology (P.L.), Danderyd Hospital, Stockholm, Sweden; Department of Environmental Health (A.B.), Harvard T.H. Chan School of Public Health, Boston, MA; and Environment and Health Administration (K.E.), City of Stockholm, Sweden.
Neurology. 2023 Sep 19;101(12):e1231-e1240. doi: 10.1212/WNL.0000000000207656. Epub 2023 Jul 13.
Growing evidence links air pollution with dementia risk, but the biological mechanisms are largely unknown. We investigated the role played by homocysteine (tHcy) and methionine in this association and explored whether this could be explained by cardiovascular diseases (CVDs).
Data were extracted from the ongoing Swedish National study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study. At baseline, 2,512 dementia-free participants were examined up to 2013 (mean follow-up: 5.18 ± 2.96 years). Two air pollutants (particulate matter ≤2.5 μm [PM] and nitrogen oxides [NO]) were assessed yearly from 1990 until 2013 using dispersion models at residential addresses. The hazard ratio of dementia over air pollution levels was estimated using Cox models adjusted for age, sex, education, smoking, socioeconomic status, physical activity, retirement age, creatinine, year of assessment, and the use of supplements. The total effect of air pollutants on dementia was decomposed into 4 pathways involving tHcy/methionine: (1) direct effect; (2) indirect effect (mediation); (3) effect due to interaction; and (4) effect due to both mediation and interaction. To test whether the association was independent from CVDs (ischemic heart disease, atrial fibrillation, heart failure, and stroke), we repeated the analyses excluding those individuals who developed CVDs.
The mean age of the study participants was 73.4 years (SD: 10.4), and 62.1% were female individuals. During an average period of 5 years (mean: 5.18; SD: 2.96 years), 376 cases with incident dementia were identified. There was a 70% increased hazard of dementia per unit increase of PM during the 5 years before baseline (hazard ratio [HR]: 1.71; 95% CI 1.33-2.09). Overall, 50% (51.6%; 95% CI 9.0-94.1) of the total effect of PM on dementia was due to mediation of tHcy (6.6%; 95% CI 1.6-11.6) and/or interaction (47.8%; 95% CI 4.9-91.7) with tHcy and 48.4% ( = 0.03) to the direct effect of PM on dementia. High levels of methionine reduced the dementia hazard linked to PM by 31% (HR: 0.69; 95% CI 0.56-0.85) with 24.8% attributable to the interaction with methionine and 25.9% ( = 0.001) to the direct effect of PM. No mediation effect was found through methionine. Attenuated results were obtained for NO. Findings for tHcy were attenuated after excluding those who developed CVDs, while remained similar for methionine.
High levels of homocysteine enhanced the dementia risk attributed to air pollution, while high methionine concentrations reduced this risk. The impact of homocysteine on cardiovascular conditions partly explains this association. Alternative pathways other than cardiovascular mechanisms may be at play between methionine and dementia.
越来越多的证据表明空气污染与痴呆风险之间存在关联，但其中的生物学机制在很大程度上尚不清楚。我们研究了同型半胱氨酸（tHcy）和蛋氨酸在这种关联中所起的作用，并探讨了这种关联是否可以通过心血管疾病（CVD）来解释。
本研究的数据来自正在进行的瑞典 Kungsholmen 老龄化和护理研究（SNAC-K），这是一项基于人群的纵向研究。在基线时，有 2512 名无痴呆症的参与者接受了检查，随访时间最长为 2013 年（平均随访时间：5.18±2.96 年）。使用分散模型，在参与者的居住地址，每年评估两种空气污染物（≤2.5μm 的颗粒物[PM]和氮氧化物[NO]）。使用 Cox 模型，根据年龄、性别、教育、吸烟、社会经济地位、体力活动、退休年龄、肌酐、评估年份以及补充剂的使用情况，对痴呆症与空气污染水平之间的风险比进行了调整。通过 4 种涉及 tHcy/蛋氨酸的途径，对空气污染物对痴呆症的总影响进行了分解：（1）直接影响；（2）间接影响（中介作用）；（3）交互作用的影响；（4）中介作用和交互作用的共同影响。为了检验这种关联是否独立于 CVD（缺血性心脏病、心房颤动、心力衰竭和中风），我们排除了那些发生 CVD 的个体，对分析结果进行了重复。
研究参与者的平均年龄为 73.4 岁（标准差：10.4），62.1%为女性。在平均 5 年（平均：5.18；标准差：2.96 年）的时间内，有 376 例新发痴呆症病例。在基线前的 5 年中，PM 每增加一个单位，痴呆症的发病风险增加 70%（风险比[HR]：1.71；95%CI 1.33-2.09）。总体而言，PM 对痴呆症的总影响有 50%（51.6%；95%CI 9.0-94.1）归因于 tHcy 的中介作用（6.6%；95%CI 1.6-11.6）和/或与 tHcy 的交互作用（47.8%；95%CI 4.9-91.7），而 PM 对痴呆症的直接影响占 48.4%（ = 0.03）。高蛋氨酸水平使 PM 相关的痴呆症发病风险降低了 31%（HR：0.69；95%CI 0.56-0.85），其中 24.8%归因于与蛋氨酸的交互作用，25.9%（ = 0.001）归因于 PM 的直接作用。未发现蛋氨酸通过中介作用产生影响。对于 NO 则没有发现这种影响。在排除了发生 CVD 的个体后，tHcy 的结果有所减弱，而蛋氨酸的结果则保持相似。
高水平的同型半胱氨酸增强了空气污染引起的痴呆症风险，而高蛋氨酸浓度降低了这种风险。同型半胱氨酸对心血管状况的影响部分解释了这种关联。蛋氨酸和痴呆症之间可能存在除心血管机制以外的其他途径。
