APOE ε4–associated downregulation of the IL‐7/IL‐7R pathway in effector memory T cells: Implications for Alzheimer's disease

Abstract INTRODUCTION The apolipoprotein E ( APOE ) ε4 allele exerts a significant influence on peripheral inflammation and neuroinflammation, yet the underlying mechanisms remain elusive. METHODS The present study enrolled 54 patients diagnosed with late‐onset Alzheimer's disease (AD; including 28 APOE ε4 carriers and 26 non‐carriers). Plasma inflammatory cytokine concentration was assessed, alongside bulk RNA sequencing (RNA‐seq) and single‐cell RNA sequencing (scRNA‐seq) analysis of peripheral blood mononuclear cells (PBMCs). RESULTS Plasma tumor necrosis factor α, interferon γ, and interleukin (IL)‐33 levels increased in the APOE ε4 carriers but IL‐7 expression notably decreased. A negative correlation was observed between plasma IL‐7 level and the hippocampal atrophy degree. Additionally, the expression of IL‐7R and CD28 also decreased in PBMCs of APOE ε4 carriers. ScRNA‐seq data results indicated that the changes were mainly related to the CD4+ Tem (effector memory) and CD8+ Tem T cells. DISCUSSION These findings shed light on the role of the downregulated IL‐7/IL‐7R pathway associated with the APOE ε4 allele in modulating neuroinflammation and hippocampal atrophy. Highlights The apolipoprotein E ( APOE ) ε4 allele decreases plasma interleukin (IL)‐7 and aggravates hippocampal atrophy in Alzheimer's disease. Plasma IL‐7 level is negatively associated with the degree of hippocampal atrophy. The expression of IL‐7R signaling decreased in peripheral blood mononuclear cells of APOE ε4 carriers Dysregulation of the IL‐7/IL‐7R signal pathways enriches T cells.