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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月30日

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

摘要

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.