Project Summary The relationship between education and Alzheimer’s Disease and related dementias (ADRD) is well- established; however, inequalities in access to education are a fundamental social disparity, resulting in differential cognitive outcomes in diverse contexts. Country, birth cohort, and gender disparities in access to education and occupation can be a source of natural experiments to reveal trends and mechanisms for the relationship between education and cognitive outcomes such as ADRD, including how genetic propensities both manifest and change across diverse historical and social settings. We propose to leverage the Interplay of Genes and Environment across Multiple Studies (IGEMS) consortium of longitudinal twin studies of development and aging to clarify the role of educational inequalities for ADRD. The IGEMS consortium is a collaboration involving 18 longitudinal twin studies of adult development and aging. Established in 2010, the consortium has developed standard processes for collaboration, data sharing, data harmonization, and data analyses. The current application proposes a new direction for the IGEMS consortium to support novel investigations of the education-ADRD association in the context of country, birth cohort, and gender disparities in access to educational opportunities, integrating multiple indicators of education. First, in addition to harmonized International Standard Classification of Education (ISCED) scores across countries and birth cohorts, IGEMS includes polygenic scores for education (PGSED). Second, parental education measures allow for a study of intergenerational mobility and clarifies potentially spurious relationships between education and ADRD that result from family background effects. Third, we will examine the impact of birth cohort and country, comparing access to educational and occupational opportunities using indexes of educational inequality (GINIED) as well as measures of social disparities. Dynamic gender disparities that vary over context and time will also help us to explain established gender differences in the relative protective effects of education and occupation for cognition including ADRD. The twin structure of our data permits use of established twin methods to test hypotheses on the nature of gene-environment (GE) interplay, while genotyping allows us to confirm and extend these twin analyses through analyses of PGSED and polygenic scores for dementia. Importantly, IGEMS is a multidimensionally diverse sample that spans multiple countries and historical periods, allowing us to determine whether models of GE interplay established at the micro-level (i.e., individual) might vary at the macro-level (i.e., country/historical period). We propose the following research aims. AIM 1: Investigate mechanisms of educational influences on cognitive functioning and ADRD risk at multiple levels: genetic (PGSED), individual (ISCED), inter-generational (parent ISCED), and environmental (GINIED)...