Project Summary/Abstract Gains in life expectancy and population aging are driving a sharp rise in Alzheimer's Disease and Related Dementias (ADRD). In this context, it is crucial to understand what factors can modify ADRD risk and cognitive decline in older ages. Education has been identified as one potential modifier, as higher education is robustly associated with lower ADRD risk. However, little is known about how much of this association reflects a causal effect from education to ADRD risk and how much is driven by common third factors, such as genetics, that may confound and moderate this relationship. In addition, the relevance of factors beyond the quantity of education – in particular the importance of education quality as a driver of ADRD risk, as well as a moderator in the relationship between education and ADRD – are not well understood. Filling these knowledge gaps is essential to the design of effective policies aimed at improving cognitive health and reducing disparities in ADRD risk. In this project, we propose to study how much of the association between education, cognition and ADRD risk in late-life is due to a causal effect running from education quantity and quality to cognition/ADRD risk. To deal with the fact that different people self-select into different types and quantities of schooling, we will use two natural experiments: one school reform that affected education quantity (years of compulsory schooling) and another that affected quality (academic curriculum). We will supplement existing datasets with the construction of polygenic indexes (PGIs) for educational attainment (EA) and for Alzheimer's Disease (AD), and by linking participants to local historic school quality measures such as pupil/teacher ratios and teacher pay. This will allow us to study the role of genetics and school quality in moderating the effects of both school reforms on ADRD. We will use data from three large international aging cohorts: the UK Biobank (UK), FinnGen (Finland) and Lifelines (the Netherlands). These cohorts allow us to study administrative-based measures of ADRD diagnosis, ADRD risk factors and survey-based measures of cognition. Moreover, the three cohorts were genotyped, allowing us to explore the role of genetics in driving ADRD risk as well as in moderating the relationship between education and ADRD risk. Establishing whether education has a causal effect on late-life cognition and ADRD risk is challenging but essential for identifying clinical and policy interventions. Without causal evidence, policy makers do not know whether education improves individuals' later-life cognitive health or whether the education-ADRD association reflects differences in the characteristics of individuals who self-select into education. Moreover, it is equally important to know what aspects of education causally affect ADRD risk. What is the relative benefit of increasing the quantity of education versus improving its quality? Are individuals who are predicted to get more education based on their genes protected against genetic risk of AD? The lack of such knowledge limits the design of policies aimed at reducing disparities in ADRD risk. Our project aims to start filling these knowledge gaps.

Project Narrative Gains in life expectancy and population aging are driving a sharp rise in Alzheimer's Disease and Related Dementias (ADRD), emphasizing the importance of identifying factors that can protect against ADRD risk and cognitive decline in older ages. We will study how education quantity and quality affect cognition and ADRD risk, and investigate the role of genetics in driving ADRD risk as well as in moderating the relationship between education and ADRD risk.