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

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.