{"doi":"10.1101/2025.09.17.25335728","title":"Clonal expansion of cytotoxic CD8 <sup>+</sup> T cells in lecanemab-associated ARIA","abstract":"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.","journal":"medRxiv","year":2025,"id":575462,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9542,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1382261,"name":"Kai Saito","orcid":null,"position":1,"is_corresponding":false},{"id":1405676,"name":"Akhil V. Pallerla","orcid":null,"position":2,"is_corresponding":false},{"id":354525,"name":"Jessica L. Funnell","orcid":"0000-0003-1971-6028","position":3,"is_corresponding":false},{"id":1483738,"name":"Ashley Ezzo","orcid":null,"position":4,"is_corresponding":false},{"id":1483739,"name":"Chelsea L Song","orcid":null,"position":5,"is_corresponding":false},{"id":741897,"name":"Douglas A. Harrison","orcid":"0000-0003-2892-1023","position":6,"is_corresponding":false},{"id":1483740,"name":"Noah L Norton","orcid":null,"position":7,"is_corresponding":false},{"id":1483741,"name":"Lauren C. Moore","orcid":null,"position":8,"is_corresponding":false},{"id":245008,"name":"Linda J. Van Eldik","orcid":"0000-0002-8139-6400","position":9,"is_corresponding":false},{"id":244999,"name":"David W. Fardo","orcid":"0000-0002-7207-4696","position":10,"is_corresponding":false},{"id":1483742,"name":"Gregory E. Cooper","orcid":null,"position":11,"is_corresponding":false},{"id":318260,"name":"Josh M. Morganti","orcid":"0000-0002-4183-0049","position":12,"is_corresponding":false},{"id":278179,"name":"Lance A. Johnson","orcid":"0000-0003-0134-7586","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T02:57:48.486077Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}