{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T05:39:51Z","timestamp":1783057191038,"version":"3.54.6"},"posted":{"date-parts":[[2026,4,24]]},"group-title":"Genetic and Genomic Medicine","reference-count":33,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T00:00:00Z","timestamp":1776988800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Behavioral and psychological symptoms of dementia (BPSD) are common, profoundly troubling to patients and caregivers, and difficult to treat, yet their molecular underpinnings remain poorly understood. Here, we generated a large brain proteomic dataset with nine BPSD domains assessed in life from 376 donors from three cohorts. Protein associations with BPSD were examined using complementary approaches \u2014 domain-specific BPSD, multi-domain BPSD, and latent factor modeling \u2014 and integrated via cross-cohort meta-analysis. Four proteins (NMT1, DCAKD, DNPH1, and HIBADH) were associated with anxiety in dementia and five proteins (ABL1, SAP18, PLXND1, CTRB2, and LDHD) with multi-domain BPSD or BPSD latent factors after adjusting for sex, age, and other covariates (FDR &lt; 0.05). Additionally, eight protein co-expression networks were associated with BPSD across cohorts. Together, these results link BPSD to dysregulation of synaptic signaling, protein folding, and humoral immune response, providing a molecular framework for therapeutic discovery.<\/jats:p>","DOI":"10.64898\/2026.04.23.26351110","type":"posted-content","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T23:00:12Z","timestamp":1777071612000},"source":"Crossref","is-referenced-by-count":1,"title":["Behavioral and psychological symptoms of dementia: insights from a multivariate and network-based brain proteome-wide study"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5616-4184","authenticated-orcid":false,"given":"Selina M.","family":"Vattathil","sequence":"first","affiliation":[{"name":"Department of Neurology, University of California, Davis School of Medicine, Sacramento, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duc M.","family":"Duong","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Emory University School of Medicine, Atlanta, GA"},{"name":"Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marla","family":"Gearing","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA"},{"name":"Goizueta Alzheimer\u2019s Disease Research Center, Emory University School of Medicine, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4507-624X","authenticated-orcid":false,"given":"Nicholas T.","family":"Seyfried","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Emory University School of Medicine, Atlanta, GA"},{"name":"Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA"},{"name":"Goizueta Alzheimer\u2019s Disease Research Center, Emory University School of Medicine, Atlanta, GA"},{"name":"Department of Neurology, Emory University School of Medicine, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert S.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Rush Alzheimer\u2019s Disease Center, Rush University Medical Center, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Rush Alzheimer\u2019s Disease Center, Rush University Medical Center, Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0755-9846","authenticated-orcid":false,"given":"Randall L.","family":"Woltjer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Oregon Health and Science University, Portland, OR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7679-6282","authenticated-orcid":false,"given":"Thomas S.","family":"Wingo","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of California, Davis School of Medicine, Sacramento, CA"},{"name":"Alzheimer\u2019s Disease Research Center, University of California, Davis, Sacramento, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6360-6726","authenticated-orcid":false,"given":"Aliza P.","family":"Wingo","sequence":"additional","affiliation":[{"name":"VA Northern California Healthcare System, Mather, CA"},{"name":"Department of Psychiatry, University of California, Davis, Sacramento, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026042709451359000_2026.04.23.26351110v1.1","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.3233\/JAD-215198","article-title":"Behavioral and psychological symptoms of dementia in different dementia disorders: a large-scale study of 10,000 individuals","volume":"87","year":"2022","journal-title":"Journal of Alzheimer\u2019s Disease"},{"key":"2026042709451359000_2026.04.23.26351110v1.2","doi-asserted-by":"publisher","DOI":"10.1017\/S1041610216001654"},{"key":"2026042709451359000_2026.04.23.26351110v1.3","doi-asserted-by":"publisher","DOI":"10.1093\/geront\/46.1.52"},{"key":"2026042709451359000_2026.04.23.26351110v1.4","doi-asserted-by":"crossref","first-page":"56","DOI":"10.3389\/fnagi.2020.00056","article-title":"Steps towards developing effective treatments for neuropsychiatric disturbances in Alzheimer\u2019s disease: Insights from preclinical models, clinical data, and future directions","volume":"12","year":"2020","journal-title":"Frontiers in aging neuroscience"},{"key":"2026042709451359000_2026.04.23.26351110v1.5","doi-asserted-by":"crossref","first-page":"725","DOI":"10.3233\/JAD-161247","article-title":"Efficacy of antidepressants for depression in Alzheimer\u2019s disease: systematic review and meta-analysis","volume":"58","year":"2017","journal-title":"Journal of Alzheimer\u2019s disease"},{"key":"2026042709451359000_2026.04.23.26351110v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.maturitas.2013.02.009"},{"key":"2026042709451359000_2026.04.23.26351110v1.7","doi-asserted-by":"publisher","DOI":"10.1136\/ip.2005.011015"},{"key":"2026042709451359000_2026.04.23.26351110v1.8","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1001\/jamapsychiatry.2014.3018","article-title":"Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm","volume":"72","year":"2015","journal-title":"JAMA psychiatry"},{"key":"2026042709451359000_2026.04.23.26351110v1.9","first-page":"100892","article-title":"Unlocking the therapeutic potential of protein kinase inhibitors in neurodegenerative and psychiatric disorders","volume":"3","year":"2025","journal-title":"Exploration of Drug Science"},{"key":"2026042709451359000_2026.04.23.26351110v1.10","doi-asserted-by":"crossref","first-page":"4314","DOI":"10.1038\/s41467-022-31873-5","article-title":"Shared mechanisms across the major psychiatric and neurodegenerative diseases","volume":"13","year":"2022","journal-title":"Nature communications"},{"key":"2026042709451359000_2026.04.23.26351110v1.11","doi-asserted-by":"crossref","first-page":"3075","DOI":"10.1038\/s41380-022-01544-4","article-title":"Integrating human brain proteomes with genome-wide association data implicates novel proteins in post-traumatic stress disorder","volume":"27","year":"2022","journal-title":"Molecular psychiatry"},{"key":"2026042709451359000_2026.04.23.26351110v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-021-00832-6"},{"key":"2026042709451359000_2026.04.23.26351110v1.13","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.21020162"},{"key":"2026042709451359000_2026.04.23.26351110v1.14","doi-asserted-by":"crossref","first-page":"e70549","DOI":"10.1002\/alz.70549","article-title":"Leveraging multiomic approaches to elucidate mechanisms of heterogeneity in Alzheimer\u2019s disease: Neuropsychiatric symptoms, co-pathologies, and sex differences","volume":"21","year":"2025","journal-title":"Alzheimer\u2019s & Dementia"},{"key":"2026042709451359000_2026.04.23.26351110v1.15","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1038\/s41398-024-02878-z","article-title":"Unique transcriptional signatures correlate with behavioral and psychological symptom domains in Alzheimer\u2019s disease","volume":"14","year":"2024","journal-title":"Translational psychiatry"},{"key":"2026042709451359000_2026.04.23.26351110v1.16","doi-asserted-by":"publisher","DOI":"10.1093\/geronb\/59.2.P75"},{"key":"2026042709451359000_2026.04.23.26351110v1.17","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.23.1.56"},{"key":"2026042709451359000_2026.04.23.26351110v1.18","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts034"},{"key":"2026042709451359000_2026.04.23.26351110v1.19","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq340"},{"key":"2026042709451359000_2026.04.23.26351110v1.20","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-9-559"},{"key":"2026042709451359000_2026.04.23.26351110v1.21","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M201708200"},{"key":"2026042709451359000_2026.04.23.26351110v1.22","doi-asserted-by":"crossref","unstructured":"Wingo, A. P. et al. Multiancestry brain pQTL fine-mapping and integration with genome-wide association studies of 21 neurologic and psychiatric conditions. Nature Genetics, 1\u201310 (2025).","DOI":"10.1038\/s41588-025-02291-2"},{"key":"2026042709451359000_2026.04.23.26351110v1.23","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.psychres.2018.07.017","article-title":"A genome-wide association study of suicide attempts and suicidal ideation in US military veterans","volume":"269","year":"2018","journal-title":"Psychiatry research"},{"key":"2026042709451359000_2026.04.23.26351110v1.24","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb4542"},{"key":"2026042709451359000_2026.04.23.26351110v1.25","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1186\/s12967-024-05153-3","article-title":"Dissecting the shared genetic landscape of anxiety, depression, and schizophrenia","volume":"22","year":"2024","journal-title":"Journal of translational medicine"},{"key":"2026042709451359000_2026.04.23.26351110v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2021.07.007"},{"key":"2026042709451359000_2026.04.23.26351110v1.27","doi-asserted-by":"crossref","first-page":"237","DOI":"10.4103\/1673-5374.346540","article-title":"c-Abl kinase at the crossroads of healthy synaptic remodeling and synaptic dysfunction in neurodegenerative diseases","volume":"18","year":"2023","journal-title":"Neural Regeneration Research"},{"key":"2026042709451359000_2026.04.23.26351110v1.28","doi-asserted-by":"publisher","DOI":"10.1002\/wps.21034"},{"key":"2026042709451359000_2026.04.23.26351110v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00921-z"},{"key":"2026042709451359000_2026.04.23.26351110v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2010.06.016"},{"key":"2026042709451359000_2026.04.23.26351110v1.31","doi-asserted-by":"crossref","first-page":"601","DOI":"10.3233\/JAD-130632","article-title":"Protein disulfide isomerase P5-immunopositive inclusions in patients with Alzheimer\u2019s disease","volume":"38","year":"2013","journal-title":"Journal of Alzheimer\u2019s disease"},{"key":"2026042709451359000_2026.04.23.26351110v1.32","doi-asserted-by":"crossref","unstructured":"Medinas, D. B. , Rozas, P. & Hetz, C. Critical roles of protein disulfide isomerases in balancing proteostasis in the nervous system. Journal of Biological Chemistry 298 (2022).","DOI":"10.1016\/j.jbc.2022.102087"},{"key":"2026042709451359000_2026.04.23.26351110v1.33","first-page":"e12442","article-title":"Longitudinal associations of apathy and regional tau in mild cognitive impairment and dementia: Findings from the Alzheimer\u2019s Disease Neuroimaging Initiative","volume":"10","year":"2024","journal-title":"Alzheimer\u2019s & Dementia: Translational Research & Clinical Interventions"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.04.23.26351110","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T16:45:24Z","timestamp":1777308324000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.04.23.26351110"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,24]]},"references-count":33,"URL":"https:\/\/doi.org\/10.64898\/2026.04.23.26351110","relation":{},"subject":[],"published":{"date-parts":[[2026,4,24]]},"subtype":"preprint"}}