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

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Objectives/Goals: The goal of this study was to determine if there are the peripheral immune system changes in persons undergoing treatment with lecanemab, and whether those changes are associated with the incidence of amyloid-related imaging abnormalities (ARIA), in order to identify strategies for improving the safety profile of anti-amyloid antibodies. Methods/Study Population: Three pairs of age, sex, APOE genotype, and infusion-matched individuals were selected from a study population at Norton Neuroscience Institute Memory Center (NNI-MC), based on the development of ARIA. Peripheral blood mononuclear cells isolated from these case–control subjects were collected and cryopreserved. Thawed cells were run through a deep sequencing pipeline, including single-cell RNAseq, CITEseq TCR clonality (V(D)Jseq), metabolomics, and lipidomics. Multi-omic data was integrated and analyzed using R (scRNAseq, CITEseq, and V(D)Jseq) and MetaboAnalyst (Metabolomics and Lipidomics). Deidentified clinical data was obtained to correlate to sequencing findings, including cognitive exam scores, MRI scans, and relevant lab values. Results/Anticipated Results: We noted an increase in lymphocytes in ARIA-positive subjects, with expansion in CD8+ T-cells – particularly CD45-RA expressing T-effector memory (TEMRA) subsets. These TEMRA cells expressed large clonal expansions in cells programmed for antigen response, cytotoxicity, and metabolic shifts. We found that in ARIA+ subjects, there was a pro-inflammatory glycolytic shift, accompanied by CD8-driven lipidomic changes. To determine potential effects of TEMRAs on the CNS, we mapped our data onto previously published ARIA+ patient brain transcriptomes (van Olst et al., 2025). TEMRA CD8s from our dataset showed increases in in silico communication with the vascular endothelium, indicating priming of these cells for cerebrovascular engagement. Discussion/Significance of Impact: Together, this first-of-its-kind data in human subjects receiving lecanemab infusions may point to peripheral immunity as a driving factor – and potential biomarker and therapeutic target for – ARIA pathogenesis, allowing for increased safety of these drugs in the highest risk AD populations.

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