Single‐cell transcriptomic analysis reveals <i>APOE</i> 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.