The MARBLE Study Protocol: Modulating ApoE Signaling to Reduce Brain Inflammation, DeLirium, and PostopErative Cognitive Dysfunction

Keith W. Vandusen, Sarada Eleswarpu, Eugene W. Moretti, Michael J. Devinney, Donna M. Crabtree, Daniel T. Laskowitz, Marty G. Woldorff, Kenneth C. Roberts, John Whittle, Jeffrey N. Browndyke, Mary Cooter, Frank W. Rockhold, Oke Anakwenze, Michael P. Bolognesi, Mark E. Easley, Michael N. Ferrandino, William A. Jiranek, Miles Berger, Samuel B. Adams, Cindy L. AmundsenPallavi Avasarala, Matthew D. Barber, Andrew Berchuck, Daniel G. Blazer, Rachele Brassard, Brian E. Brigman, Victor Cai, Soren K. Christensen, Mitchel W. Cox, Brittany A. Davidson, James K. Deorio, Detlev Erdmann, Melissa M. Erickson, Bonita L. Funk, Jeffrey Gadsden, Mark J. Gage, Jeff R. Gingrich, Rachel A. Greenup, Christine Ha, Ashraf Habib, Ralph Abi Hachem, Ashley E. Hall, Matthew G. Hartwig, Laura J. Havrilesky, Mitchell T. Heflin, Courtney Holland, Scott T. Hollenbeck, Thomas J. Hopkins, Brant A. Inman, David W. Jang, Russel R. Kahmke, Isaac Karikari, Amie Kawasaki, Jacob A. Klapper, Christopher S. Klifto, Rebecca Klinger, Stuart J. Knechtle, Sandhya A. Lagoo-Deenadayalan, Walter T. Lee, Howard Levinson, Brian D. Lewis, Michael E. Lidsky, Michael E. Lipkin, Christopher R. Mantyh, Shelley R. McDonald, John Migaly, Timothy E. Miller, Suhail K. Mithani, Paul J. Mosca, Judd W. Moul, Thomas L. Novick, Steven A. Olson, Theodore N. Pappas, John J. Park, Andrew C. Peterson, Brett T. Phillips, Thomas J. Polascik, Peter Potash, Glenn M. Preminger, Rebecca A. Previs, Cary N. Robertson, Charles D. Scales, Kevin N. Shah, Randall P. Scheri, Nazema Y. Siddiqui, Shayan Smani, Kevin W. Southerland, Michael T. Stang, Ayesha Syed, Alicja Szydlowska, Julie K.M. Thacker, Niccolò Terrando, Yanne Toulgoat-Dubois, Anthony G. Visco, Alison C. Weidner, Mamata Yanamadala, Sabino Zani, Catherine Price

Research output: Contribution to journalArticlepeer-review


Background: Perioperative neurocognitive disorders (PND) are common complications in older adults associated with increased 1-year mortality and long-term cognitive decline. One risk factor for worsened long-term postoperative cognitive trajectory is the Alzheimer's disease (AD) genetic risk factor APOE4. APOE4 is thought to elevate AD risk partly by increasing neuroinflammation, which is also a theorized mechanism for PND. Yet, it is unclear whether modulating apoE4 protein signaling in older surgical patients would reduce PND risk or severity. Objective: MARBLE is a randomized, blinded, placebo-controlled phase II sequential dose escalation trial designed to evaluate perioperative administration of an apoE mimetic peptide drug, CN-105, in older adults (age≥60 years). The primary aim is evaluating the safety of CN-105 administration, as measured by adverse event rates in CN-105 versus placebo-treated patients. Secondary aims include assessing perioperative CN-105 administration feasibility and its efficacy for reducing postoperative neuroinflammation and PND severity. Methods: 201 patients undergoing non-cardiac, non-neurological surgery will be randomized to control or CN-105 treatment groups and receive placebo or drug before and every six hours after surgery, for up to three days after surgery. Chart reviews, pre-and postoperative cognitive testing, delirium screening, and blood and CSF analyses will be performed to examine effects of CN-105 on perioperative adverse event rates, cognition, and neuroinflammation. Trial results will be disseminated by presentations at conferences and peer-reviewed publications. Conclusion: MARBLE is a transdisciplinary study designed to measure CN-105 safety and efficacy for preventing PND in older adults and to provide insight into the pathogenesis of these geriatric syndromes.

Original languageEnglish (US)
Pages (from-to)1319-1328
Number of pages10
JournalJournal of Alzheimer's Disease
Issue number4
StatePublished - 2020
Externally publishedYes


  • Alzheimer's disease
  • Apolipoprotein E
  • Apolipoprotein E4
  • delirium
  • inflammation
  • neurocognitive disorders
  • surgery

ASJC Scopus subject areas

  • General Neuroscience
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health


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