Life course aetiology of dementia and cognitive decline: improving causal inference

痴呆症描述了一系列症状，包括记忆丧失、思考困难、解决问题或语言障碍。“痴呆症”一词包括几种不同类型的疾病，阿尔茨海默氏症是最常见的。痴呆症现在是英格兰和威尔士的第二大死因，因此，寻找预防痴呆症的方法是公共卫生的优先事项。痴呆症不仅对我们的经济和卫生保健系统造成了巨大负担，而且对患有这种疾病的人的家人和朋友也造成了沉重负担。此外，目前可用的治疗方法无法延缓或治愈痴呆症的发病。因此，我们有必要确定增加一个人患痴呆症风险的因素，特别是我们能够改变的因素（如吸烟或饮食），这样我们就可以干预并预防它的发生。现有的研究试图确定痴呆症的风险因素，结果却相互矛盾。到目前为止，我们有充分、一致证据的唯一风险因素是年龄较大、女性、受教育程度低、头部创伤和一些心血管风险因素，如糖尿病。其他风险因素，如吸烟、饮酒和体育活动，证据不太清楚，因为它们报告了积极（即增加风险）、消极（即降低风险）和对痴呆症风险没有影响。一个关键问题是，在研究痴呆症的原因时有许多并发症。这是一种复杂的疾病，有许多可能的原因，可能在人们开始出现明显症状之前长达20年。这使得很难评估所研究的风险因素是痴呆症的原因还是后果。例如，目前尚不清楚成年期的抑郁是否是痴呆的一个危险因素，或者痴呆患者早期发生的大脑变化是否会导致抑郁症状。此外，那些仍然积极参与研究的痴呆症患者往往比那些因疾病或死亡而退出研究的人更“健康”，这可能会使研究结果产生偏差（即给我们错误的答案）。我的项目旨在描述痴呆症遗传风险增加的人在整个生命过程中是否以及如何在认知能力方面有所不同。例如，患痴呆症遗传风险较高的人在学校的成绩是否较低，在早期生活中是否达到较低的认知峰值？他们的认知能力是在更早的年龄开始下降，还是比那些没有患痴呆症遗传风险的人下降得更快？我的项目还旨在通过采用最先进的分析方法和研究许多不同的人群（队列）来确定痴呆症的因果风险因素。在多个人群中一致的研究结果不仅会为我的研究结果提供信心，并对痴呆症的真实因果风险因素产生重要见解，而且还将有助于为痴呆症预防策略提供信息。总之，拟议的研究将有助于澄清有关痴呆症风险因素的一些相互矛盾的文献，这反过来将有助于将其转化为干预措施的公共卫生政策，以预防痴呆症为首要目标。

Dementia describes a set of symptoms including memory loss and difficulties with thinking, problem-solving or language. The term 'dementia' encompasses several different types of disease, with Alzheimer's being the most common. Dementia is now the second leading cause of death in England and Wales, thus, finding ways to prevent it is a public health priority. Dementia is not only a great burden on our economy and health care system, but also on the families and friends of those suffering with the disease. Furthermore, treatments that are currently available are unable to delay the onset of, or cure, dementia. Therefore, it is essential that we identify factors that increase a person's risk of dementia, especially things that we are able to change (such as smoking or diet), so that we can intervene and prevent it occurring in the first place. Findings from existing studies that have tried to identify risk factors for dementia are conflicting. The only risk factors for which we have good, consistent evidence so far are older age, being female, low education, head trauma and some cardiovascular risk factors such as diabetes. Evidence for other risk factors such as smoking, alcohol consumption and physical activity, is less clear, in that they have reported positive (i.e. increasing risk), negative (i.e. decreasing risk) and no effects on dementia risk. One key problem is that there are many complications when studying causes of dementia. It is a complex disease that has many possible causes and can begin up to 20 years before people start showing noticeable symptoms. This makes it difficult to assess whether the risk factors being studied are a cause or a consequence of dementia. For example, it is still unclear whether depression in adulthood is a risk factor for dementia, or whether the early brain changes that occur in dementia result in depressive symptoms. Moreover, people with dementia who are still actively participating in studies are often more 'healthy' than those who leave studies due to illness or death, which can bias study results (i.e. give us the wrong answer). My project aims to characterise if and how people at increased genetic risk of dementia differ in terms of their cognitive capability across the whole life course. For example, do people with increased genetic risk of dementia achieve lower grades at school and achieve a lower cognitive peak in early life? Do they start to decline cognitively at an earlier age, or at a faster rate than people who are not at increased genetic risk of dementia? My project also aims to identify causal risk factors for dementia by employing state of the art analytical approaches and by studying many different groups of people (cohorts). Consistent research findings across multiple cohorts of people will not only provide confidence in my findings and yield important insights into true, causal risk factors for dementia, but it will also help to inform dementia prevention strategies. In summary, the proposed research will help to bring clarity to some of the conflicting literature on dementia risk factors, which in turn will improve translation into public health policies for interventions, with the overriding aim of preventing dementia.