Postoperative cognitive dysfunction (POCD) and delirium occur in up to 40% of the ≥16 million Americans over age 65 who undergo anesthesia and non-cardiac surgery each year, and each is associated with decreased quality of life, increased 1 year mortality, long term cognitive decline and a possible increased dementia risk. POCD and delirium may be caused by neuro-inflammation and an exacerbation of pre-existing Alzheimer's disease (AD) pathology (i.e. Abeta and tau), because after anesthesia and surgery in older adults, we and other have found significant increases in cerebrospinal fluid (CSF) neuroinflammatory and AD biomarkers. The most common genetic variant associated with late onset AD is ApoE4, which acts by accelerating A and tau pathology and increasing neuro-inflammation. ApoE4 carriers also have worsened long term cognitive trajectories after anesthesia and surgery. Over the past 20 years, have developed an ApoE4 based peptide drug (CN-105), which blocks both AD pathologic progression and neuroinflammatory changes in multiple mouse brain injury models. We have also recently completed a phase I clinical trial, which showed that intravenous CN-105 can safely be given to humans at 100-fold the therapeutic dose identified in mice. Here, we will conduct a phase II clinical trial to determine whether CN-105 treatment decreases POCD and delirium rates in older orthopedic surgery patients, and whether it blocks the increases in CSF neuroinflammatory and AD biomarkers, and brain function changes we have previously found in patients with POCD and delirium.