Apolipoprotein E Mimetic Peptide CN-105 and Postoperative Delirium in Older Patients

Importance: The apolipoprotein E (APOE) gene ε4 allele leads to increased Alzheimer disease risk and neuroinflammation and is also believed to play a role in postoperative delirium. However, the safety and feasibility of modulating apoE protein signaling to reduce postoperative neuroinflammation and delirium in older adults are unclear. Objective: To assess the safety and feasibility of the apoE mimetic peptide CN-105 for reducing delirium incidence and severity and neuroinflammation after noncardiac or nonintracranial surgery in older adults. Design, Setting, and Participants: This triple-blind, escalating dose, phase 2 randomized clinical trial enrolled patients from April 17, 2019, to December 28, 2022, at a tertiary academic medical center. Included patients were 60 years or older and scheduled for a noncardiac or nonintracranial surgery. Exclusion criteria were incarceration, planned chemotherapy within 6 weeks after surgery, or inability to undergo lumbar punctures. Data analyses were based on a modified intention-to-treat approach and were performed from August 14, 2023, to August 22, 2025. Interventions: Patients were randomly assigned 3:1 to the CN-105 group or placebo group. The CN-105 group received intravenous CN-105 doses of 0.1, 0.5, or 1 mg/kg starting within 1 hour before surgery and administered every 6 hours afterward until hospital discharge or 13 doses were received. Patients in the placebo group followed the same administration schedule. Main Outcomes and Measures: The primary outcome was safety-the incidence and number of postoperative adverse events (AEs). Secondary outcomes included feasibility (rate of drug doses administered within 90 minutes of schedule), postoperative delirium incidence and severity, and postoperative changes in cerebrospinal fluid (CSF) cytokine levels (interleukin [IL] 6, granulocyte-colony stimulating factor [G-CSF], monocyte chemoattractant protein-1 [MCP-1], and IL-8). Results: Among 203 enrolled patients, 186 (mean [SD] age, 68.7 [5.2] years; 119 males [64.0%]) were randomized (137 to the CN-105 group, 49 to the placebo group) and underwent surgery. The rates of grade 2 or higher AEs among patients in the CN-105 and placebo groups were 76.6% and 87.8% (relative risk [RR], 0.87; 95% CI, 0.76-1.00; P = .10). The CN-105 vs placebo group had fewer grade 2 or higher AEs per patient (median [IQR], 1 [1-3] vs 2 [1-5]; P = .03). The percentage of CN-105 doses administered within the time window was 94.6% (860 of 909; 95% CI, 92.9%-96.0%) in the CN-105 group and 93.8% (346 of 369; 95% CI, 90.8%-96.0%) in the placebo group. Among patients in the CN-105 vs placebo group, the postoperative delirium incidence was 19.3% vs 26.5% (odds ratio [OR], 0.66; 95% CI, 0.31-1.42; P = .29); the median (IQR) postoperative delirium severity scores were 1 (1-2) vs 2 (1-2) (P = .19); and the median difference in preoperative to 24-hour postoperative CSF cytokine-level changes were as follows: -0.39 pg/mL (95% CI, -0.93 to 0.14 pg/mL, P = .12) for IL-6, -0.84 pg/mL (95% CI, -3.06 to 1.40 pg/mL; P = .18) for G-CSF,-23.32 pg/mL (95% CI, -94.36 to 44.93 pg/mL; P = .57) for IL-8, and -2.36 pg/mL (95% CI, -58.57 to 58.62 pg/mL; P = .50) for MCP-1. Conclusions and Relevance: In this phase 2 randomized clinical trial of older surgical patients, CN-105 (vs placebo) administration was feasible and did not increase AEs. A phase 3 trial is warranted to further evaluate the efficacy of CN-105 for reducing postoperative AEs and to more precisely determine its effects on postoperative delirium incidence and severity. Trial Registration: ClinicalTrials.gov Identifier: NCT03802396.

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JAMA Network Open
Published
2026-04-03
DOI
https://doi.org/10.1001/jamanetworkopen.2026.2289
Primary Topic
Intensive Care Unit Cognitive Disorders
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article

Apolipoprotein E Mimetic Peptide CN-105 and Postoperative Delirium in Older Patients

Bethany J. Hsia, David H. Harpole, Rachel A. Greenup, Alisan Fathalizadeh et al.
JAMA Network Open
Intensive Care Unit Cognitive Disorders
article

Apolipoprotein E Mimetic Peptide CN-105 and Postoperative Delirium in Older Patients

Bethany J. Hsia, David H. Harpole, Rachel A. Greenup, Alisan Fathalizadeh, Oke Anakwenze, Donna Crabtree, Detlev Erdmann, Michael N. Ferrandino, Christopher S. Klifto, Brian E. Brigman, Roberto Cabeza, Mark J. Gage, Paula S. Lee, Samuel Bruce Adams, Keith W. VanDusen, Russel Kahmke, Leah Acker, David Ryu, Isaac O. Karikari, Walter T. Lee, Amie Kawasaki, Howard W. Francis, Brittany Anne Davidson, Andrew Berchuck, Michael P. Bolognesi, James K. DeOrio, Billy Lan, Jeffrey R. Gingrich, Michael J. Devinney, Jacob A. Klapper, Marty G. Woldorff, Hadiza S. Kazaure, Brian Colin, Sarada Eleswarpu, Jacqueline M. Emerson, Brant A. Inman, Mitchell W. Cox, Rebecca Y. Klinger, Jeff Gadsden, Ralph Abi Hachem, Tyler H. Reekes, K. Blennow, Pallavi Avasarala, Thomas Bunning, Ashraf S. Habib, Scott Thomas Hollenbeck, Josiane Kerbage, Matthew Galen Hartwig, Noah J. Timko, Mitchell T. Heflin, Chakib M. Ayoub, William A. Jiranek, Stuart J. Knechtle, Daniel T. Laskowitz, Laura Jean Havrilesky, Frank W. Rockhold, Cindy L. Amundsen, Sandhya Lagoo-Deenadayalan, Matthew D. Barber, Thomas J. Hopkins, Howard Levinson, Thomas A. D’Amico, Michael R. Abern, R. Brassard, Eugene W. Moretti, Mark E. Easley, John C. Haney, Summer Granger, M. S. Berger, Piper C. Boykin, Nicholas Kathrein, Arun Ganesh, Peter J. Allen, Matthew Fuller, Henrik Zetterberg, J. Taylor Herbert, Tarrah Henley, Ashley E. Hall, Clay Elliott, Daniel G. Blazer, David W. Jang, Janet L. Huebner, Zhong Li, Ayesha Syed, Lori Cole-Freiburger, Mary Cooter Wright, Soren K. Christensen, Bonita L. Hilliard, W.M. Bullock, Robert D. Fitch, Jeffrey N. Browndyke, Jaleesa Garner, Julia Hoang, Christine Ha, Catharina C. Eisdorfer, Deborah R. Kaye, MARBLE Study Investigators, Melissa M. Erickson, Melody R. Smith, Morgan A. Caldwell
article en

Abstract

Importance: The apolipoprotein E (APOE) gene ε4 allele leads to increased Alzheimer disease risk and neuroinflammation and is also believed to play a role in postoperative delirium. However, the safety and feasibility of modulating apoE protein signaling to reduce postoperative neuroinflammation and delirium in older adults are unclear. Objective: To assess the safety and feasibility of the apoE mimetic peptide CN-105 for reducing delirium incidence and severity and neuroinflammation after noncardiac or nonintracranial surgery in older adults. Design, Setting, and Participants: This triple-blind, escalating dose, phase 2 randomized clinical trial enrolled patients from April 17, 2019, to December 28, 2022, at a tertiary academic medical center. Included patients were 60 years or older and scheduled for a noncardiac or nonintracranial surgery. Exclusion criteria were incarceration, planned chemotherapy within 6 weeks after surgery, or inability to undergo lumbar punctures. Data analyses were based on a modified intention-to-treat approach and were performed from August 14, 2023, to August 22, 2025. Interventions: Patients were randomly assigned 3:1 to the CN-105 group or placebo group. The CN-105 group received intravenous CN-105 doses of 0.1, 0.5, or 1 mg/kg starting within 1 hour before surgery and administered every 6 hours afterward until hospital discharge or 13 doses were received. Patients in the placebo group followed the same administration schedule. Main Outcomes and Measures: The primary outcome was safety-the incidence and number of postoperative adverse events (AEs). Secondary outcomes included feasibility (rate of drug doses administered within 90 minutes of schedule), postoperative delirium incidence and severity, and postoperative changes in cerebrospinal fluid (CSF) cytokine levels (interleukin [IL] 6, granulocyte-colony stimulating factor [G-CSF], monocyte chemoattractant protein-1 [MCP-1], and IL-8). Results: Among 203 enrolled patients, 186 (mean [SD] age, 68.7 [5.2] years; 119 males [64.0%]) were randomized (137 to the CN-105 group, 49 to the placebo group) and underwent surgery. The rates of grade 2 or higher AEs among patients in the CN-105 and placebo groups were 76.6% and 87.8% (relative risk [RR], 0.87; 95% CI, 0.76-1.00; P = .10). The CN-105 vs placebo group had fewer grade 2 or higher AEs per patient (median [IQR], 1 [1-3] vs 2 [1-5]; P = .03). The percentage of CN-105 doses administered within the time window was 94.6% (860 of 909; 95% CI, 92.9%-96.0%) in the CN-105 group and 93.8% (346 of 369; 95% CI, 90.8%-96.0%) in the placebo group. Among patients in the CN-105 vs placebo group, the postoperative delirium incidence was 19.3% vs 26.5% (odds ratio [OR], 0.66; 95% CI, 0.31-1.42; P = .29); the median (IQR) postoperative delirium severity scores were 1 (1-2) vs 2 (1-2) (P = .19); and the median difference in preoperative to 24-hour postoperative CSF cytokine-level changes were as follows: -0.39 pg/mL (95% CI, -0.93 to 0.14 pg/mL, P = .12) for IL-6, -0.84 pg/mL (95% CI, -3.06 to 1.40 pg/mL; P = .18) for G-CSF,-23.32 pg/mL (95% CI, -94.36 to 44.93 pg/mL; P = .57) for IL-8, and -2.36 pg/mL (95% CI, -58.57 to 58.62 pg/mL; P = .50) for MCP-1. Conclusions and Relevance: In this phase 2 randomized clinical trial of older surgical patients, CN-105 (vs placebo) administration was feasible and did not increase AEs. A phase 3 trial is warranted to further evaluate the efficacy of CN-105 for reducing postoperative AEs and to more precisely determine its effects on postoperative delirium incidence and severity. Trial Registration: ClinicalTrials.gov Identifier: NCT03802396.

JAMA Network OpenVol. 9(4)
University of North Carolina at Chapel Hill (US), University of Science and Technology of China (CN), University of Wisconsin–Madison (US), Duke University (US), Sahlgrenska University Hospital (SE), Sorbonne Université (FR), Clinical Research Institute (US), Abterra Biosciences (United States) (US), Duke Medical Center (US), UK Dementia Research Institute (GB), MRC Prion Unit (GB), Stanford Medicine (US), Durham VA Medical Center (US), Institut du Cerveau (FR), Duke University Hospital (US), General Marble (Greece) (GR), University College London (GB), University of Gothenburg (SE)
Alzheimer's Drug Discovery Foundation, Society for Neuroscience in Anesthesiology and Critical Care, National Institutes of Health
Zero hunger
Openalex Percentile: Top 28%
Intensive Care Unit Cognitive Disorders
DOIOpen Access PDFOpenAlex
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