Abstract
INTRODUCTION: While higher socioeconomic factors (SEF) and cognitive performance (CP) have been associated with reduced Alzheimer's disease (AD) risk, recent evidence highlighted that these factors may have opposite effects on family history of AD (FHAD). METHODS: Leveraging data from the UK Biobank (N=448,100) and the All of Us Research Program (N=240,319), we applied generalized linear regression models, polygenic risk scoring (PRS), and one-sample Mendelian randomization (MR) to test the sex-specific SEF and CP associations with AD and FHAD. RESULTS: Observational and genetically informed analyses highlighted that higher SEF and CP were associated with reduced AD and sibling-FHAD, while these factors were associated with increased parent-FHAD. We also observed that population minorities may present different patterns with respect to sibling-FHAD vs. parent-FHAD. Sex differences in FHAD associations were identified in ancestry-specific and SEF PRS and MR results. DISCUSSION: This study contributes to understanding the sex-specific relationships linking SEF and CP to FHAD, highlighting the potential role of reporting, recall, and surviving-related dynamics.