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

痴呆症描述了一系列症状，包括记忆力丧失和思维、解决问题或语言困难。“痴呆症”一词包括几种不同类型的疾病，其中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亡原因，因此，找到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医疗保健系统造成巨大负担，而且对患有这种疾病的人的家人和朋友也是如此。此外，目前可用的治疗方法无法延迟痴呆症的发作或治愈痴呆症。因此，我们必须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），以便我们能够首先进行干预并预防它的发生。现有的研究试图确定痴呆症的危险因素，但结果相互矛盾。到目前为止，我们唯一有良好、一致证据的风险因素是年龄较大、女性、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，饮酒和体育活动的证据不太清楚，因为他们报告了积极的（即增加风险），消极的（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，可以开始长达20年前，人们开始表现出明显的症状开始。这使得很难评估正在研究的风险因素是痴呆症的原因还是后果。例如，目前还不清楚成年期的抑郁是否是痴呆症的危险因素，或者痴呆症中发生的早期大脑变化是否会导致抑郁症状。此外，仍然积极参与研究的痴呆症患者通常比那些因疾病或死亡而离开研究的人更“健康”，这可能会使研究结果产生偏差（即给我们错误的答案）。我的项目旨在研究痴呆症遗传风险增加的人在整个生命过程中认知能力的差异。例如，痴呆症遗传风险增加的人在学校的成绩较低，在早期生活中达到较低的认知高峰吗？他们的认知能力是否在更早的年龄开始下降，或者比那些没有痴呆症遗传风险增加的人下降得更快？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的见解，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关于痴呆症风险因素的一些相互冲突的文献，这反过来将有助于将干预措施转化为公共卫生政策，其首要目标是预防痴呆症。

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.