Prevention of dementia by targeting risk factors

由于缺乏对神经退行性变的驱动因素的了解，以及由于痴呆症的长期潜伏期而导致的疾病的原因和后果的混淆，是导致大量治疗痴呆症的药物和生活方式试验不成功的主要原因。2017年《柳叶刀》痴呆症预防委员会建议针对风险因素预防痴呆症，但专家组承认，证据的局限性，如反向因果偏倚，可能会影响这些结论。我们提出了一项雄心勃勃的工作计划，该计划将评估可用于通过卫生政策干预预防痴呆症的风险因素，并将检查广泛的血浆代谢物，这些代谢物可作为早期痴呆症生物标志物和用于改善疾病的痴呆症治疗的候选物。我们的多队列研究项目的目标是：(1)使用该领域最大的个人参与者数据集和一种新的分析策略来解释反向因果关系导致的偏倚，研究柳叶刀2017委员会风险因素与认知能力下降、临床验证的阿尔茨海默病和痴呆症的关联；(2)扩展分析，以研究成人生命过程中慢性疾病的轨迹如何影响痴呆症的风险；(3)评估233种代谢物生物标志物作为认知功能、阿尔茨海默病和痴呆症的早期预测指标，重点是在痴呆症诊断前至少10年评估的生物标志物。分析中使用的数据来源包括IPD-Work联盟的43项队列研究，痴呆症平台英国队列数据资源，英国生物银行，美国-欧洲代谢组学-痴呆症联盟的11项研究，以及伦敦大学学院-伦敦卫生和热带医学院-爱丁堡-布里斯托尔（UCLEB）联盟，来自英国和其他地方的总共150万成年人。这一规划是及时的，因为在有效的治疗干预措施取得进展之前，必须获得有力的证据。

Lack of understanding of the drivers of neurodegeneration and confusion of the causes and consequences of the disease due to the long latent phase of dementia have been major contributors to the large number of unsuccessful drug and lifestyle trials for dementia. The Lancet 2017 Commission on dementia prevention recommended targeting 9 risk factors to prevent dementia, but the expert group acknowledge that limitations in evidence, such as reverse causation bias, may affect these conclusions. We propose an ambitious programme of work which will evaluate risk factors that can be used to prevent dementia via health policy interventions, and will examine a wide range of plasma metabolites that can be used as early dementia biomarkers and candidates for disease-modifying dementia treatments. The objectives of our multi-cohort research programme are to: (1) examine associations of the Lancet 2017 Commission risk factors with cognitive decline, clinically-verified Alzheimer's disease and dementia using the largest individual-participant dataset in this field and a novel analytic strategy to account for bias due to reverse causation; (2) expand analyses to examine how trajectories of chronic diseases over the adult lifecourse shape risk of dementia; and (3) evaluate 233 metabolite biomarkers, singly and in combination, as early predictors of cognitive function, Alzheimer's disease and dementia, with a focus on biomarkers assessed at least 10 years before dementia diagnosis. The sources of data used in the analysis include the IPD-Work consortium of 43 cohort studies, the Dementia Platform UK cohort data resource, UK Biobank, the US-European metabolomics-dementia consortium of 11 studies, and the University College London-London School of Hygiene and Tropical Medicine-Edinburgh-Bristol (UCLEB) Consortium, in total of >1.5 million adults from the UK and elsewhere. This programme is timely because robust evidence must be generated before progress toward effective therapeutic interventions can be made.