Prevention of dementia by targeting risk factors

对神经退行性疾病的驱动因素缺乏了解，以及由于痴呆症的长期潜伏期而对疾病的原因和后果造成的混淆，是导致大量痴呆症药物和生活方式试验失败的主要原因。《柳叶刀》2017年痴呆症预防委员会建议针对9个风险因素来预防痴呆症，但专家组承认，证据的局限性，如反向因果关系偏见，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，将评估可用于通过卫生政策干预预防痴呆症的风险因素，并将研究可用作早期痴呆症生物标志物和疾病修饰痴呆症治疗候选物的各种血浆代谢物。我们的多队列研究计划的目标是：（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由于反向因果关系而导致的偏倚，检查柳叶刀2017委员会风险因素与认知下降，临床验证的阿尔茨海默病和痴呆症的关联;（2）扩大分析范围，以研究慢性疾病在成年人生命过程中的轨迹如何影响痴呆症的风险;和（3）评估233种代谢物生物标志物，单独和组合，作为认知功能、阿尔茨海默病和痴呆的早期预测因子，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43项队列研究的IPD-Work联盟，Dementia Platform UK队列数据资源，UK Biobank，11项研究的美欧代谢组学-痴呆联盟，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（UCLEB）联盟，来自英国和其他地方的总计> 150万成年人。该计划是及时的，因为在有效的治疗干预措施取得进展之前必须产生强有力的证据。

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.