{"doi":"10.1101/2024.10.01.616097","title":"Interrogating the plasma proteome of repetitive head impact exposure and chronic traumatic encephalopathy","abstract":"ABSTRACT Background Exposure to repetitive head impacts (RHI) is associated with increased risk for chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy, and other neuropathological changes. Biological drivers of RHI-related neurodegeneration are not well understood. We interrogated the plasma proteome in aging adults with prior RHI compared to healthy controls (CTL) and individuals with Alzheimer’s disease (AD), including a subset characterized neuropathologically at autopsy. Methods Proximity extension assay (Olink Explore®) quantified 2,779 plasma proteins in 22 RHI patients (all AD-biomarker negative), 39 biomarker-confirmed AD, and 44 CTL. A subset of participants went to autopsy (N=16) allowing for comparisons of the antemortem plasma proteome between autopsy-confirmed CTE+ (N=7) and CTE-(N=9). Differential abundance and co-expression network analyses identified plasma proteomic signatures of RHI, which were functionally annotated using gene ontology and cell type enrichment analysis. Nonparametric correlations examined plasma proteomic associations with orthogonally-measured plasma biomarkers, global cognitive function, and semi-quantitative ratings of neuropathology burden at autopsy. Results Differential abundance analysis revealed 434 increased (vs. 6 decreased) proteins in RHI vs. CTL and 193 increased (vs. 14 decreased) in RHI vs. AD. Network analysis identified 9 protein co-expression modules (M1-M9), of which 7 were elevated in RHI compared to AD or CTL. Modules with increased abundance in RHI were enriched for mitochondrial/metabolic, cell division, and immunovascular (e.g., cell adhesion, TNF-signaling) processes. RHI-related modules exhibited strong and selective correlations with immunoassay-based plasma IL-6 in RHI cases, including the M2 TNF-signaling/cell adhesion module which harbored proteins that strongly tracked with cognitive function. RHI-related plasma protein signatures were similar in the subset of participants with autopsy-confirmed CTE, including immune and metabolic modules that positively correlated with medial temporal lobe tau and TDP-43 burden. Conclusions Molecular pathways in plasma most consistently implicated in RHI were tied to immune response, mitochondrial function, and cell metabolism. RHI-related proteomic signatures tracked with antemortem cognitive severity and postmortem neuropathological burden, providing converging evidence for their role in disease progression. Differentially abundant proteins and co-expression modules in RHI may inform mechanisms linking RHI to increased dementia risk, thus guiding diagnostic biomarker and therapeutic development for at-risk populations.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":492046,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9131,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":329465,"name":"Kaitlin B. Casaletto","orcid":"0000-0001-5000-7604","position":1,"is_corresponding":false},{"id":289793,"name":"Sruti Rayaprolu","orcid":"0000-0002-5212-3745","position":2,"is_corresponding":false},{"id":232924,"name":"Paramita Chakrabarty","orcid":"0000-0002-6226-3776","position":3,"is_corresponding":false},{"id":336095,"name":"Jose F. Abisambra","orcid":"0000-0001-6341-679X","position":4,"is_corresponding":false},{"id":260466,"name":"Salvatore Spina","orcid":"0000-0003-3570-9143","position":5,"is_corresponding":false},{"id":109118,"name":"Lea T. Grinberg","orcid":"0000-0002-6809-0618","position":6,"is_corresponding":false},{"id":32591,"name":"William W. Seeley","orcid":"0000-0003-1410-2027","position":7,"is_corresponding":false},{"id":58513,"name":"Bruce L. Miller","orcid":"0000-0002-2152-4220","position":8,"is_corresponding":false},{"id":253924,"name":"Joel H. Kramer","orcid":"0000-0002-2917-8297","position":9,"is_corresponding":false},{"id":230947,"name":"Gil D. Rabinovici","orcid":"0000-0002-3626-4265","position":10,"is_corresponding":false},{"id":329464,"name":"Breton M. Asken","orcid":"0000-0001-8419-142X","position":11,"is_corresponding":false},{"id":471936,"name":"Rowan Saloner","orcid":"0000-0002-1351-6183","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:08:49.768795Z","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":[]}