University of Bristol - Dr Evie Stergiakouli Using genetics to identify dementia risk factors See glossary at bottom of page for definition of underlined words. Summary This study seeks to provide consistent evidence for the non-genetic risk factors which lead to dementia. A genetic study will take place using information provided by the Avon Longitudinal Study of Parents and Children (ALSPAC). This will allow analysis of many traits including early life lipid levels, blood glucose levels, behaviour and level of cognition to see their effects on Alzheimer’s disease. Understanding early life risk factors involved in dementia will help inform preventative methods – something which is of paramount importance as there is no current cure for the dementia. What do we already know? Most of the evidence on the role of non-genetic risk factors for Alzheimer’s disease (AD) has been from observational studies in adults. These studies have suggested that cardiovascular, anthropometric and cognitive factors may be involved in the development of late-life AD, but the findings are conflicting. Confounding factors, such as cardiovascular disease or socioeconomic factors, may result in biased estimates of associations between risk factors and AD. In addition to potential confounders, bias due to reverse causation may also occur in epidemiological studies of AD risk factors, making it difficult to establish the direction of effects (for example whether the hypothesised risk factor causes AD, or is a consequence of the disease). Consequently, there is currently no consistent evidence for environmental risk factors which can be modified to decrease the risk of AD. Genetic variants, identified from large genetic studies, are a useful tool for researching the causes of AD if they are used as proxies for potential risk factors. This is because genetic variants are randomly assigned at conception for each individual and they cannot be influences by the disease or confounding factors. What is this project trying to find out? We will investigate 1) whether there is a shared genetic component between AD and early life lipid levels, glycaemic, anthropometric, behavioral and cognitive traits, and 2) whether any of these environmental risk factors are causally related to AD. How will they do this? The Avon Longitudinal Study of Parents and Children (ALSPAC) is a large cohort study of mothers and their children, for whom longitudinal information on behavioural, cognitive and psychiatric outcomes has been collected at multiple time points. Blood samples have also been collected to measure levels of blood markers such as lipids and glycaemic traits. Genetic data are available on more than 9,000 mothers and their children. Using these genetic data we will calculate genetic predictors for each individual in the ALSPAC study (mothers and their children) and investigate the genetic overlap between AD and plasma lipid levels, anthropometric and cognitive traits for both children and their mothers. To infer causality for environmental risk factors of AD, we will use Mendelian randomisation; genetic variants will be used as proxies for modifiable exposures and the causal association between these and AD will be estimated. Why is it important? Understanding early life risk factors will provide insight into potentially effective screening and preventative methods. As no cure exists for Alzheimer’s disease and pathological changes can occur more than two decades before the onset of symptoms, the identification of early life modifiable risk factors is of immense public health importance. Glossary Non-genetic risk factors – Behaviours that may increase your chances of getting a disease that are not effected by the genetic makeup of the individual (eg. Exercise, diet etc.).Cardiovascular – Of or relating to the heart and blood vessels.Anthropometric – The physical differences between humans. Cognition –The mental process of knowing, including aspects such as awareness, perception, reasoning, and judgement.Confounding factor – A confounding factor is something that cannot be controlled for but may effect the overall result of a study. Reverse causation – This can occur when people change their diet or other lifestyle factor after developing a disease. It is best explained using an example: When lifelong smokers develop lung cancer, they may quit smoking – this change may make it seem as if ex-smokers are more likely to die of lung cancer than non-smokers. This is clearly not true and is an example of reverse causation.Epidemiological studies – A study which seeks to understand the factors that determine the presence or absence of diseases.Lipid – Any chemical compound that is not soluble in water but soluble in organic solvents. Such compounds include fats, oils and sterols. Glycaemic (Glycemic) – A reduction of the levels of glucose in the blood.Longitudinal information – A type of study which involves repeated observations of one thing over short or long periods of time.Mendelian randomisation – A method for measuring variation of genes and their effects on disease onset that control for reverse causation and confounding factors. Modifiable exposures – Risk factors (or exposures) of a disease which can be modified (eg. diet, level of exercise). Further information Please click here for more information on the work of Dr Evie Stergiakouli. Please click here for more information on the work of Dr Emma Anderson. Please click here for more information on the work of Dr Laura Howe. Please click here for more information on the work of Prof George Davey Smith.