Objectives To examine the association between cognitively stimulating work and subsequent risk of dementia and to identify protein pathways for this association. Design Multicohort study with three sets of analyses. Setting United Kingdom, Europe, and the United States. Participants Three associations were examined: cognitive stimulation and dementia risk in 107 896 participants from seven population based prospective cohort studies from the IPD-Work consortium (individual participant data meta-analysis in working populations); cognitive stimulation and proteins in a random sample of 2261 participants from one cohort study; and proteins and dementia risk in 13 656 participants from two cohort studies. Main outcome measures Cognitive stimulation was measured at baseline using standard questionnaire instruments on active versus passive jobs and at baseline and over time using a job exposure matrix indicator. 4953 proteins in plasma samples were scanned. Follow-up of incident dementia varied between 13.7 to 30.1 years depending on the cohort. People with dementia were identified through linked electronic health records and repeated clinical examinations. Results During 1.8 million person years at risk, 1143 people with dementia were recorded. The risk of dementia was found to be lower for participants with high compared with low cognitive stimulation at work (crude incidence of dementia per 10 000 person years 4.8 in the high stimulation group and 7.3 in the low stimulation group, age and sex adjusted hazard ratio 0.77, 95% confidence interval 0.65 to 0.92, heterogeneity in cohort specific estimates I2=0%, P=0.99). This association was robust to additional adjustment for education, risk factors for dementia in adulthood (smoking, heavy alcohol consumption, physical inactivity, job strain, obesity, hypertension, and prevalent diabetes at baseline), and cardiometabolic diseases (diabetes, coronary heart disease, stroke) before dementia diagnosis (fully adjusted hazard ratio 0.82, 95% confidence interval 0.68 to 0.98). The risk of dementia was also observed during the first 10 years of follow-up (hazard ratio 0.60, 95% confidence interval 0.37 to 0.95) and from year 10 onwards (0.79, 0.66 to 0.95) and replicated using a repeated job exposure matrix indicator of cognitive stimulation (hazard ratio per 1 standard deviation increase 0.77, 95% confidence interval 0.69 to 0.86). In analysis controlling for multiple testing, higher cognitive stimulation at work was associated with lower levels of proteins that inhibit central nervous system axonogenesis and synaptogenesis: slit homologue 2 (SLIT2, fully adjusted β −0.34, P<0.001), carbohydrate sulfotransferase 12 (CHSTC, fully adjusted β −0.33, P<0.001), and peptidyl-glycine α-amidating monooxygenase (AMD, fully adjusted β −0.32, P<0.001). These proteins were associated with increased dementia risk, with the fully adjusted hazard ratio per 1 SD being 1.16 (95% confidence interval 1.05 to 1.28) for SLIT2, 1.13 (1.00 to 1.27) for CHSTC, and 1.04 (0.97 to 1.13) for AMD. Conclusions The risk of dementia in old age was found to be lower in people with cognitively stimulating jobs than in those with non-stimulating jobs. The findings that cognitive stimulation is associated with lower levels of plasma proteins that potentially inhibit axonogenesis and synaptogenesis and increase the risk of dementia might provide clues to underlying biological mechanisms. Pre-existing access policies for individual level data for each of the participating cohort studies specify that research data requests can be submitted to each steering committee; these will be promptly reviewed for confidentiality, data protection issues, or intellectual property restrictions and will not unreasonably be refused. Code for the statistical analyses of this paper is provided in the supplementary file (pp 26-33).

中文翻译：

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工作场所的认知刺激、血浆蛋白和痴呆风险：人群队列研究的三项分析

目的 研究认知刺激工作与随后的痴呆风险之间的关联，并确定这种关联的蛋白质途径。设计具有三组分析的多队列研究。设置英国、欧洲和美国。参与者检查了三个关联：来自 IPD-Work 联盟的 7 个基于人群的前瞻性队列研究（工作人群中的个体参与者数据荟萃分析）的 107 896 名参与者的认知刺激和痴呆风险；来自一项队列研究的 2261 名参与者的随机样本中的认知刺激和蛋白质；来自两项队列研究的 13 656 名参与者的蛋白质和痴呆风险。主要结果测量 认知刺激在基线时使用标准问卷工具测量主动与被动工作，并在基线和随着时间的推移使用工作暴露矩阵指标进行测量。扫描了血浆样品中的 4953 种蛋白质。根据队列的不同，痴呆事件的随访时间在 13.7 至 30.1 年之间。通过关联的电子健康记录和重复的临床检查来识别痴呆症患者。结果在 180 万人年的风险中，记录了 1143 名痴呆症患者。与工作中认知刺激低的参与者相比，高认知刺激的参与者患痴呆症的风险较低（高刺激组每 10 000 人年痴呆的粗发病率 4.8 和低刺激组 7.3，年龄和性别调整风险比0.77，95% 置信区间 0。65 至 0.92，队列特定估计的异质性 I2=0%，P=0.99）。这种关联对教育、成年期痴呆的危险因素（吸烟、大量饮酒、缺乏身体活动、工作压力、肥胖、高血压和基线糖尿病）和心脏代谢疾病（糖尿病、冠心病、卒中）在痴呆诊断之前（完全调整的风险比为 0.82，95% 置信区间为 0.68 至 0.98）。在随访的前 10 年（风险比 0.60，95% 置信区间 0.37 至 0.95）和第 10 年（0.79，0.66 至 0.95）也观察到痴呆风险，并使用重复的工作暴露矩阵指标进行复制认知刺激（每增加 1 个标准差的风险比增加 0.77，95% 置信区间 0.69 至 0.86）。在控制多项测试的分析中，工作中较高的认知刺激与抑制中枢神经系统轴突形成和突触形成的蛋白质水平较低相关：狭缝同源物 2（SLIT2，完全调整的 β -0.34，P<0.001），碳水化合物磺基转移酶 12（CHSTC ，完全调整的 β -0.33，P<0.001）和肽基甘氨酸 α-酰胺化单加氧酶（AMD，完全调整的 β -0.32，P<0.001）。这些蛋白质与痴呆风险增加相关，SLIT2 的每 1 SD 的完全调整风险比为 1.16（95% 置信区间 1.05 至 1.28），CHSTC 为 1.13（1.00 至 1.27），AMD 为 1.04（0.97 至 1.13） . 结论 与从事非刺激性工作的人相比，从事认知刺激工作的人老年痴呆症的风险较低。认知刺激与潜在抑制轴突形成和突触形成并增加痴呆风险的较低水平的血浆蛋白相关的发现可能为潜在的生物学机制提供线索。每个参与的队列研究的个体水平数据的预先存在的访问政策规定，研究数据请求可以提交给每个指导委员会；将及时审查这些内容的机密性、数据保护问题或知识产权限制，并且不会被无理拒绝。本文的统计分析代码在补充文件（第 26-33 页）中提供。每个参与的队列研究的个体水平数据的预先存在的访问政策规定，研究数据请求可以提交给每个指导委员会；将及时审查这些内容的机密性、数据保护问题或知识产权限制，并且不会被无理拒绝。本文的统计分析代码在补充文件（第 26-33 页）中提供。每个参与的队列研究的个体水平数据的预先存在的访问政策规定，研究数据请求可以提交给每个指导委员会；将及时审查这些内容的机密性、数据保护问题或知识产权限制，并且不会被无理拒绝。本文的统计分析代码在补充文件（第 26-33 页）中提供。