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

Authors

• Lance A. Johnson, University of KentuckyFollow
• Kai Saito, University of Kentucky
• Akhil V. Pallerla, University of Kentucky
• Jessica L. Funnell, University of Kentucky
• Ashley R. Ezzo, Norton Healthcare
• Chelsea M. Song, Norton Healthcare
• Douglas A. Harrison, University of KentuckyFollow
• Noah J. Norton, University of Kentucky
• Lauren C. Moore, University of Kentucky
• Linda J. Van Eldik, University of KentuckyFollow
• David W. Fardo, University of KentuckyFollow
• Greg E. Cooper, Norton Healthcare
• Josh M. Morganti, University of KentuckyFollow

Abstract

Amyloid-related imaging abnormalities (ARIA) are the principal safety concern limiting anti-amyloid therapies for Alzheimer’s disease, yet their biology remains unclear. Here we show, through multi-omic profiling of peripheral blood from three ARIA+ patients and matched controls, that ARIA is associated with coordinated reprogramming of CD8 + T cells. CD8+ effector memory (TEM) and terminally differentiated (TEMRA) subsets were expanded, clonally enriched, and transcriptionally primed for cytotoxicity and vascular trafficking. Transcription factor inference and metabolomics converged on glycolytic reprogramming favoring short-lived effector function. Ligand-receptor modeling revealed enhanced monocyte-to-T cell signaling through antigen presentation, adhesion, and chemokine axes, while integration with a cerebrovascular atlas confirmed that ARIA-associated TEMRAs are transcriptionally “addressed” for vascular engagement. Together, these findings identify a peripheral immune signature linking metabolic reprogramming, clonal CD8+ expansion, and altered intercellular communication to ARIA, with implications for biomarker development and risk mitigation pending validation in larger cohorts.

Document Type

Article

Publication Date

2026

Notes/Citation Information

© The Author(s) 2026

Digital Object Identifier (DOI)

https://doi.org/10.1038/s41467-026-68921-3

Funding Information

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 Alzheimer’s Association ABA-25-1376140 (LAJ, JMM).

Repository Citation

Johnson, Lance A.; Saito, Kai; Pallerla, Akhil V.; Funnell, Jessica L.; Ezzo, Ashley R.; Song, Chelsea M.; Harrison, Douglas A.; Norton, Noah J.; Moore, Lauren C.; Van Eldik, Linda J.; Fardo, David W.; Cooper, Greg E.; and Morganti, Josh M., "Clonal expansion of cytotoxic CD8⁺ T cells in lecanemab-associated ARIA" (2026). Sanders-Brown Center on Aging Faculty Publications. 218.
https://uknowledge.uky.edu/sbcoa_facpub/218