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.
Data availability
The single-cell RNA sequencing, CITE-seq, and V(D)J data generated in this study have been deposited in the Gene Expression Omnibus (GEO) database under accession code GSE316096. Processed count matrices are publicly available; raw sequencing data are not available due to patient privacy considerations. Interactive data browsers for this study can be accessed at https://www.morgantilab.com/datasets. The metabolomics data generated in this study have been deposited in Metabolomics Workbench under accession code ST004524. The brain single-nucleus RNA sequencing data from lecanemab-treated patients used for cross-modal integration in this study are available in the GEO database under accession code GSE263079. Source data are provided with this paper.
Code availability
Customized analysis scripts used in this study are available from the corresponding author upon reasonable request.
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Acknowledgements
We are deeply grateful to the patients and their caregivers who generously participated in this study. Their willingness to contribute time and effort, often under challenging circumstances, made this work possible. We thank them for their trust and commitment to advancing our understanding of Alzheimer’s disease and treatment-related complications. 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).
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L.A.J.: Conceptualization; Methodology; Investigation; Supervision; Writing-original draft; Writing-review & editing; Funding acquisition. K.S.: Formal analysis; Software; Visualization; Data curation; Writing-review & editing. A.V.P.: Investigation; Data curation; Writing-review & editing. J.L.F.: Investigation; Data curation; Writing-review & editing. A.R.E.: Resources; Investigation; Project administration; Writing-review & editing. C.L.S.: Resources; Investigation; Project administration; Writing-review & editing. D.A.H.: Methodology; Investigation; Data curation; Writing-review & editing. N.J.N.: Investigation; Data curation; Writing-review & editing. L.C.M.: Investigation; Data curation; Writing-review & editing. L.J.V.E.: Resources; Writing-review & editing. D.W.F.: Methodology; Writing-review & editing. G.E.C.: Conceptualization; Resources; Project administration; Writing-review & editing. J.M.M.: Conceptualization; Methodology; Investigation; Data curation; Formal analysis; Visualization; Writing-original draft; Writing-review & editing; Supervision; Funding acquisition.
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Johnson, L.A., Saito, K., Pallerla, A.V. et al. Clonal expansion of cytotoxic CD8⁺ T cells in lecanemab-associated ARIA. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68921-3
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DOI: https://doi.org/10.1038/s41467-026-68921-3
