{"doi":"10.1192/bjo.2025.10926","title":"A proof-of-concept study: investigating the impact of COMT genotype and proline on negative symptoms in Alzheimer’s disease","abstract":"Background Negative neuropsychiatric symptoms, such as apathy, are a core feature of Alzheimer’s disease. Previous studies have shown that levels of fasting plasma proline and differential activity of the catechol-O-methyltransferase (COMT) enzyme, which metabolises dopamine, influence negative symptoms in patients with severe psychiatric illness and those at risk for psychosis. For patients with the COMT high activity enzyme (as assessed via the COMT Val 158 Met polymorphism), high plasma proline was associated with less severe negative symptoms. Conversely, high proline was associated with more severe negative symptoms in patients with the low activity COMT enzyme. Aims In this proof-of-concept cross-sectional study, we tested the hypothesis that proline and COMT Val 158 Met interact to modify negative symptom severity across neuropsychiatric disease, specifically now investigating patients with Alzheimer’s disease dementia. Method Least Absolute Shrinkage and Selection Operator regression was employed to model the interaction between proline and COMT on negative symptoms in n = 50 patients with probable Alzheimer’s disease or mild cognitive impairment with underlying Alzheimer’s disease biomarkers. Results The proline × COMT interaction significantly predicted symptoms as assessed via the negative items of the Positive and Negative Symptom Scale, interaction coefficient 0.025, p = 0.031, with a trend toward significance when assessed via the Scale for Assessment of Negative Symptoms in Alzheimer’s disease, interaction coefficient 0.075, p = 0.055. Higher proline was beneficial for both Val/Val and Val/Met dementia patients, but detrimental to patients with the low activity Met/Met COMT enzyme. Conclusions Higher proline also has opposing effects on negative symptoms by COMT genotype in patients with dementia and further supports the development of therapeutics aimed at modulating this interaction pathway across neuropsychiatric disorders.","journal":"BJPsych Open","year":2025,"id":585222,"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":0.9572,"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":992205,"name":"H. Curé","orcid":null,"position":1,"is_corresponding":false},{"id":1499031,"name":"Ashley M. Canizares","orcid":null,"position":2,"is_corresponding":false},{"id":1498600,"name":"Julia Anderson","orcid":"0000-0003-0771-6530","position":3,"is_corresponding":false},{"id":1499032,"name":"Bimala Rawal","orcid":null,"position":4,"is_corresponding":false},{"id":1499033,"name":"Sabrina A. Wong","orcid":null,"position":5,"is_corresponding":false},{"id":890314,"name":"Nancy Kerner","orcid":"0000-0002-4552-6431","position":6,"is_corresponding":false},{"id":233784,"name":"Edward D. Huey","orcid":"0000-0002-8295-5884","position":7,"is_corresponding":false},{"id":108602,"name":"Lawrence S. Honig","orcid":"0000-0002-9703-2265","position":8,"is_corresponding":false},{"id":291364,"name":"Davangere P. Devanand","orcid":"0000-0001-8597-1380","position":9,"is_corresponding":false},{"id":1498601,"name":"Catherine L. Clelland","orcid":"0000-0002-9364-3974","position":10,"is_corresponding":false},{"id":1498599,"name":"James D. Clelland","orcid":"0000-0002-2597-1140","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-19T02:59:20.067334Z","pmid":"41392765","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":[]}