Interleukin-6, CD8+ T cells, and Alzheimer’s disease: unraveling neuroimmune crosstalk via genetic and mechanistic insights

Alzheimer’s disease (AD) is a neurodegenerative disorder with complex interplay between neuroinflammation and immune dysfunction. Interleukin-6 (IL-6), a pleiotropic cytokine, has emerged as a controversial player in AD pathogenesis, with conflicting roles reported in inflammation and neuroprotection. This review synthesizes genetic and mechanistic evidence linking IL-6 to AD, focusing on the mediating role of peripheral immune cells—particularly CD8 + T cell subsets like CD28 + CD45RA − CD8br absolute counts (AC). We discuss how Mendelian randomization (MR) studies, including our recent work, have clarified causal relationships between IL-6, immune cell phenotypes, and AD risk. Additionally, we explore underlying mechanisms, such as IL-6-driven T cell activation, blood–brain barrier (BBB) modulation, and neuroinflammation resolution. Current controversies, including ethnic heterogeneity in genetic effects and the dual nature of IL-6 in systemic vs. central immunity, are highlighted. Finally, we address translational implications, such as immune cell-based biomarkers and targeted anti-inflammatory therapies, offering perspectives for future research.