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Cerebrospinal fluid (CSF) exploratory proteomics was employed to identify pharmacodynamic biomarkers of CT1812 in mild to moderate AD from two independent clinical trials.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Unbiased analysis of tandem\u2010mass tag mass spectrometry (TMT\u2010MS) quantitative proteomics, pathway analysis and correlation analyses with volumetric magnetic resonance imaging (vMRI) were performed for the SPARC\ncohort (NCT03493282). Comparative analyses and a meta\u2010analysis with the interim SHINE cohort (NCT03507790; SHINE\u2010A) followed by network analysis (weighted gene co\u2010expression network analysis [WGCNA]) were used to understand the biological impact of CT1812.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>CT1812 pharmacodynamic biomarkers and biological pathways were identified that replicate across two clinical cohorts. The meta\u2010analysis revealed novel candidate biomarkers linked to S2R biology and AD, and network analysis revealed treatment\u2010associated networks driven by S2R.\u00a0<\/jats:p><\/jats:sec><jats:sec><jats:title>DISCUSSION<\/jats:title><jats:p>Early clinical validation of CT1812 candidate biomarkers replicating in independent cohorts strengthens the understanding of the biological impact of CT1812 in patients with AD, and supports CT1812's synaptoprotective mechanism of action and its continued clinical development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Highlights<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>This exploratory proteomics study identified candidate biomarkers of CT1812 in SPARC (NCT03493282)<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Comparative analyses identified biomarkers replicating across trials\/cohorts<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Two independent Ph2 trial cohorts (SPARC and interim SHINE [NCT03507790; SHINE\u2010A]) were used in a meta\u2010analysis<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Amyloid beta (A\u03b2)\u00a0&amp; synaptic biology impacted by CT1812 and volumetric magnetic resonance imaging (vMRI) treatment\u2010related correlates emerge<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Network analyses revealed sigma\u20102 receptor (S2R)\u2010interacting proteins that may be \u201cdrivers\u201d of changes<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.14152","type":"journal-article","created":{"date-parts":[[2024,8,21]],"date-time":"2024-08-21T22:07:04Z","timestamp":1724278024000},"page":"6860-6880","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["CT1812 biomarker signature from a meta\u2010analysis of CSF proteomic findings from two Phase 2 clinical trials in Alzheimer's disease"],"prefix":"10.1002","volume":"20","author":[{"given":"Britney N.","family":"Lizama","sequence":"first","affiliation":[{"name":"Cognition Therapeutics  Pittsburgh Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claire","family":"Williams","sequence":"additional","affiliation":[{"name":"Cognition Therapeutics  Pittsburgh Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hilary A.","family":"North","sequence":"additional","affiliation":[{"name":"Cognition Therapeutics  Pittsburgh Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kiran","family":"Pandey","sequence":"additional","affiliation":[{"name":"Emtherapro Inc Systems Biology  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Duc","family":"Duong","sequence":"additional","affiliation":[{"name":"Emory University School of Medicine, Biochemistry  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Di Caro","sequence":"additional","affiliation":[{"name":"Cognition Therapeutics  Pittsburgh Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam P.","family":"Mecca","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Alzheimer's Disease Research Unit Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[{"name":"Paris Brain Institute ICM Piti\u00e9\u2010Salp\u00eatri\u00e8re Hospital Sorbonne University  Paris France"},{"name":"Neurodegenerative Disorder Research Center Division of Life Sciences and Medicine and Department of Neurology Institute on Aging and Brain Disorders University of Science and Technology of China and First Affiliated Hospital of USTC  Hefei Anhui P.R. China"},{"name":"Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology the Sahlgrenska Academy at the University of Gothenburg, M\u00f6lndal  G\u00f6teborg Sweden"},{"name":"Clinical Neurochemistry Laboratory Sahlgrenska University Hospital, M\u00f6lndal  G\u00f6teborg Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology the Sahlgrenska Academy at the University of Gothenburg, M\u00f6lndal  G\u00f6teborg Sweden"},{"name":"Clinical Neurochemistry Laboratory Sahlgrenska University Hospital, M\u00f6lndal  G\u00f6teborg Sweden"},{"name":"Department of Neurodegenerative Disease UCL Institute of Neurology  London UK"},{"name":"UK Dementia Research Institute at UCL  London UK"},{"name":"Hong Kong Center for Neurodegenerative Diseases  Hong Kong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allan I.","family":"Levey","sequence":"additional","affiliation":[{"name":"Emory University School of Medicine, Neurology  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Grundman","sequence":"additional","affiliation":[{"name":"Global R&amp;D Partners LLC  San Diego California USA"},{"name":"Dept. of Neurosciences University of California  San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher H.","family":"van Dyck","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Alzheimer's Disease Research Unit Yale University School of Medicine  New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony O.","family":"Caggiano","sequence":"additional","affiliation":[{"name":"Cognition Therapeutics  Pittsburgh Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas T.","family":"Seyfried","sequence":"additional","affiliation":[{"name":"Emory University School of Medicine, Biochemistry  Atlanta Georgia USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6782-1853","authenticated-orcid":false,"given":"Mary E.","family":"Hamby","sequence":"additional","affiliation":[{"name":"Cognition Therapeutics  Pittsburgh Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,8,21]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2022.30"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2212948"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12302"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40035\u2010023\u201000358\u2010w"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24076251"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2015.05.007"},{"key":"e_1_2_9_8_1","unstructured":"CavazzioniP FDA's Decision to Approve New Treatment for Alzheimer's Disease 2021. 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