{"doi":"10.1101/2025.11.26.690872","title":"Proteomic Analysis in Alzheimer’s Disease with Psychosis Reveals Separate Molecular Signatures for Core AD Proteinopathy and Postsynaptic Density Disruption","abstract":"BACKGROUND AND HYPOTHESIS: Alzheimer's disease with psychosis (AD+P) is a subgroup of AD patients with more rapid cognitive deterioration. While our previous study showed that AD+P is associated with loss of prefrontal cortex postsynaptic density (PSD) proteins, identifying proteins in the broader cellular environment that influence PSD loss addresses a critical knowledge gap about synaptic dysfunction mechanisms in early disease stages. STUDY DESIGN: We conducted a proteomic analysis comparing prefrontal grey matter cortex tissue homogenates from elderly normal controls (n=18), individuals with AD+P (n=61), and individuals with AD-P (n=48), all with Braak stages 3-5. STUDY RESULTS: AD+P showed the most pronounced alterations relative to controls (178 proteins with q<0.05), although alterations in AD-P and AD+P relative to controls were highly similar (R²=0.965, p<0.001). Weighted-gene correlation network analysis (WGCNA) identified four modules significantly associated with disease status comparing AD subjects to controls, but none differed significantly between AD+P and AD-P. We identified 15 proteins significantly correlated with PSD yield across all samples, including ENPP6, linked to AD+P by GWAS. Additionally, PSD yield-associated proteins showed minimal overlap with altered AD proteins (1 of 137). WGCNA revealed one module significantly correlated with PSD yield across all samples, enriched for inflammatory terms. CONCLUSIONS: Our findings suggest a model in which AD+P arises from the combination of quantitative alterations within a shared AD proteome profile and a superimposed set of protein alterations correlated with PSD yield that are largely independent of the shared AD proteome, conferring distinct mechanisms of synaptic vulnerability and psychosis risk.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":585134,"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":0.9619,"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":237068,"name":"Steven J. Mullett","orcid":"0009-0005-6971-9288","position":1,"is_corresponding":false},{"id":1322821,"name":"Z. Sui","orcid":null,"position":2,"is_corresponding":false},{"id":1115385,"name":"Li Zeng","orcid":"0000-0003-3242-2286","position":3,"is_corresponding":false},{"id":263119,"name":"Ying Ding","orcid":"0000-0003-1352-1000","position":4,"is_corresponding":false},{"id":559460,"name":"Anastasia K. Yocum","orcid":"0000-0002-1592-0825","position":5,"is_corresponding":false},{"id":50994,"name":"Marcy E. MacDonald","orcid":null,"position":6,"is_corresponding":false},{"id":1015227,"name":"Stacy L. Gelhaus","orcid":null,"position":7,"is_corresponding":false},{"id":98,"name":"Julia Kofler","orcid":"0000-0003-4298-7328","position":8,"is_corresponding":false},{"id":71006,"name":"Robert A. Sweet","orcid":"0000-0001-9154-9709","position":9,"is_corresponding":false},{"id":1333329,"name":"Taeyun Ku","orcid":"0000-0001-9447-7579","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:59:20.067334Z","pmid":"41383762","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":[]}