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

Topic: Brain proteins, microglia and lab models

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.

@article{timko2026-41931297,
  author  = {Timko, Noah J. and Wright, Mary Cooter and Reese, Melody A. and Boykin, Piper C. and Emerson, Jacqueline M. and Woldorff, Marty G. and Eleswarpu, Sarada and Herbert, J. Taylor and others},
  title   = {{Apolipoprotein E Mimetic Peptide CN-105 and Postoperative Delirium in Older Patients}},
  journal = {JAMA Network Open},
  year    = {2026},
  doi     = {10.1001/jamanetworkopen.2026.2289},
  pmid    = {41931297},
  url     = {https://doi.org/10.1001/jamanetworkopen.2026.2289}
}

Key findings

• 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.

Why it matters

In this phase 2 randomized trial of older surgical patients, the drug CN-105 did not significantly reduce postoperative delirium compared to placebo. The study was small and preliminary, and the results do not support CN-105 as an effective treatment for delirium in this population.

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Study details

• Study designclinical trial
• Effect size64.0%; 76.6%; 87.8%
• Evidence strengthHigh

Read the original

• DOI: 10.1001/jamanetworkopen.2026.2289
• PubMed: 41931297
• Original source →
• Free full text: JAMA Network Open →

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Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU) JAMA · 2001-12-01 · usefulness score 72/100 · Getting a diagnosis
• 3D-CAM: derivation and validation of a 3-minute diagnostic interview for CAM-defined delirium: a cross-sectional diagnostic test study Annals of internal medicine · 2014-10-01 · usefulness score 64/100 · Getting a diagnosis
• Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease Nature genetics · 1994-06-01 · usefulness score 60/100 · Genetics
• The inter-relationship between delirium and dementia: the importance of delirium prevention Nature reviews. Neurology · 2022-08-26 · usefulness score 59/100 · Prevention and risk

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• Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease Proceedings of the National Academy of Sciences of the United States of America · 1993-09-01 · usefulness score 54/100
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