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

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 therapies improve Alzheimer’s disease outcomes but are constrained by ARIA, a serious immune–vascular complication with unclear etiology. By integrating single-cell, clonotype, and metabolomic profiling, we show that ARIA is associated with glycolysis-driven expansion of cytotoxic CD8 TEM/TEMRA subsets that engage monocyte and endothelial signaling axes. These findings identify a peripheral immune program that may inform biomarker development and therapeutic strategies to mitigate ARIA risk. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by the National Institutes of Health, National Institute on Aging (R01AG081421 (LAJ), R01AG080589 (LAJ)), National Institute of Neurological Disorders and Stroke (RF1NS118558 (JMM)), National Center for Advancing Translational Sciences (TL1TR001997 (AVP)), the CNS Metabolism COBRE P20GM148326 (JMM, LAJ), and the Alzheimers Association (LAJ, JMM). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Board of University of Louisville gave ethical approval for this work (Approval #42.007) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors