Single‐cell transcriptomic analysis reveals APOE genotype‐dependent sex differences in Alzheimer's disease

INTRODUCTION Alzheimer's disease (AD) is the most common form of dementia, with approximately two‐thirds of AD patients being female. Basic and clinical research studies provide strong evidence that sex‐specific differences contribute to AD complexity. Additionally, sex‐specific interactions between apolipoprotein E ( APOE ) 𝜀4, the primary genetic risk factor of AD, and AD‐associated neurodegenerative processes are well documented. However, there has been no comprehensive investigation into the interplay between sex and APOE genotypes at the single‐cell level. METHODS In this study, we systematically explore sex‐ and APOE ‐associated differences in single‐cell transcriptomics in AD. RESULTS Our work provides a high‐resolution landscape of sex and APOE genotype‐specific transcriptomic changes across 54 high‐resolution cell types in AD and highlights genes and brain cell populations that show significant sex‐ and APOE ‐specific differences in AD. DISCUSSION This study lays the groundwork for understanding the complex molecular mechanisms of AD and informs the development of targeted sex‐ and APOE ‐stratified interventions for AD.