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

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.

Existing evidence for modifiable risk factors for dementia is inconsistent. This is perhaps unsurprising given the , such as the potential for reverse causation and selection bias. The overall aim of the proposed work is to improve understanding of the causal determinants of, and mechanistic pathways to, dementia and cognitive decline, using novel analytical approaches and cross-cohort comparisons. I will improve causal inference in Mendelian randomisation studies of dementia by using simulation analyses to investigate and apply methods for dealing with selection bias. I will assess whether people at increased genetic risk of Alzheimer's (based on a polygenic risk score) have different life course trajectories of cognitive capability than people not at increased genetic risk. I will use novel statistical methods (such as Mendelian randomisation, offspring instrumental variable analysis and bivariate multilevel modelling) to identify causal risk factors for dementia and cognitive decline across the life course and use novel mediation methods (such as network Mendelian randomisation, counterfactual, decomposition and G computation) to assess possible mediation by circulating metabolites. The triangulation of research findings across different analytical methods and across cohorts in different settings is novel and will increase confidence in my findings. I will use data from cohorts within Dementias Platform UK, the Avon Longitudinal Study of Parents And Children (UK), EPIPorto (Portugal) and The HUNT Study. This work has the potential to inform preventive strategies, which is important given the rising economic burden of the ageing population and because current treatments are unable to delay the onset of, or cure, dementia.

Academia
The primary benefit to academia will be in the provision of new, in-depth understanding of modifiable life course risk factors for dementia and cognitive decline. The outputs of my research will have a wide and diverse academic appeal, since they may be used to generate new hypotheses about the identified risk factors and to develop public health interventions. I will develop trajectories of repeated measures of risk factors within multiple cohorts and will make these available to other researchers wishing to examine them in relation to other exposures and outcomes. I will develop an advanced epidemiological skill set by learning novel analytical approaches and working with experts in both epidemiology and dementia. I will directly reinvest these new skills back into the UK and USA research base through dissemination in methodological journals, conferences, teaching, seminars and talks.

Health policy makers
Authorities involved in setting clinical guidance will benefit from this research by receiving new knowledge about modifiable causes of dementia and cognitive decline. Given that my research will investigate modifiable causes of dementia across the life course, it has the potential to shed light on early life prevention opportunities, which may be more effective than prevention efforts later in life.

Health service planners and health economists
This research could be included in statistical models to predict future burden of disease due to the risk factors studied in this fellowship and also be used to predict the future likely benefit of prevention by intervening on each of the risk factors identified.

Charities such as Alzheimer's Association UK
One of the key priorities of Alzheimer's Association UK is the promotion of brain health. Thus, through generating evidence for risk factors for dementia, my work is directly relevant to informing the research agendas and prevention work of these charities.

The wider public
Improvements in policy, services or guidance as a result of this research will have a direct impact on improving the cognitive health of the general public. Improving the effectiveness of public services and policy may also result in reduced direct and indirect healthcare costs and lower economic impacts of dementia, which will benefit society as a whole. This research will also help to reduce the burden that ageing populations place on health and care provision services.

Benefits of this research could be both within the lifetime of the fellowship, e.g. providing new aetiological insights, and beyond the lifetime of the project, e.g. changes to guidance and policy for prevention and the potential health care savings following this.

Details of the actions I will take to achieve these benefits are detailed in the 'Pathways to Impact' attachment.