Clonal expansion of cytotoxic CD8 + T cells in lecanemab-associated ARIA

作者：Lance A. Johnson, Kai Saito, Akhil V. Pallerla, Jessica L. Funnell, Ashley Ezzo, Chelsea L Song, Douglas A. Harrison, Noah L Norton, Lauren C. Moore, Linda J. Van Eldik, David W. Fardo, Gregory E. Cooper, Josh M. Morganti · 发表于：medRxiv · 年份：2025 · DOI：10.1101/2025.09.17.25335728 · 研究领域：CAR-T cell therapy research、Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses

Abstract Amyloid-related imaging abnormalities (ARIA) remain the principal safety concern limiting adoption of anti-amyloid therapies such as lecanemab, yet their underlying biology is poorly defined. To address this, we performed deep multi-omic profiling of peripheral blood mononuclear cells from three Alzheimer’s disease (AD) patients who developed ARIA and three matched controls. Single-cell RNA sequencing, CITE-seq, V(D)J clonotyping, and metabolomic/lipidomic profiling revealed a coordinated reprogramming of the CD8 + compartment in ARIA+ patients. CD8 + TEM and TEMRA subsets were numerically expanded, transcriptionally enriched for cytotoxic and migratory programs, and exhibited increased clonal expansion. Transcription factor inference and metabolomics converged on a glycolytic bias, supporting short-lived effector activity. Ligand–receptor modeling identified ARIA-associated signaling from CD14 + and CD16 + monocytes that augmented antigen presentation, adhesion, and chemokine axes directed toward effector CD8s. Finaly, integration with an external cerebrovascular atlas confirmed that ARIA-associated TEM/TEMRAs are transcriptionally “addressed” for vascular engagement. Together, these findings establish a peripheral immune–vascular axis linking immunometabolic reprogramming, clonal cytotoxic CD8 + expansion, and altered monocyte signaling to ARIA, with implications for biomarker development and risk mitigation during anti-amyloid therapy. Significance Anti-amyloid th...