Apolipoprotein E4 polymorphism as a genetic predisposition to delirium in critically ill patients* E. Wesley Ely, MD, MPH; Timothy D. Girard, MD; Ayumi K. Shintani, PhD, MPH; James C. Jackson, PsyD; Sharon M. Gordon, PsyD; Jason W. W. Thomason, MD; Brenda T. Pun, RN, MSN, ACNP; Angelo E. Canonico, MD; Richard W. Light, MD; Pratik Pandharipande, MD, MSCI; Daniel T. Laskowitz, MD D elirium is a syndrome of multifactorial etiology that is well recognized as a harbin- ger of poor prognosis affect- ing tens of thousands of patients daily and millions annually. It is defined as an acute change or fluctuation in mental status plus inattention and either disor- ganized thinking or an altered level of consciousness at the time of the evalua- tion (1–3). Numerous studies have de- scribed the incidence and costly impact of delirium with regard to patient outcomes in nursing homes and hospital wards (4, 5), documenting huge intercohort vari- ability in delirium frequency and dura- tion (5–7). More recently, prospective in- vestigations have focused on the highest risk patients—those treated within inten- sive care units (ICUs), a population of patients exposed on average to more than ten delirium risk factors during their ICU stay (8). These ICU cohorts have found a wide range of delirium prevalence from 20% to 80%, with durations ranging from 1 day to several weeks (3, 8 –14). Delirium in ICU patients has been in- dependently associated with poor clinical outcomes including a higher mortality (10, 13), an increased risk of prolonged cognitive dysfunction (15), and longer (8, 10, 16) and more costly hospitalizations (17). Considering these facts, it is imper- ative to determine intrinsic factors that predispose to delirium. Although elegant predictive models in ICU and non-ICU cohorts have been developed to consider a host of risk factors (18 –21), no studies to our knowledge have identified any ge- netic predispositions for either develop- ment or duration of delirium in humans. Apolipoprotein E (APOE gene; ApoE pro- tein) is a 299 amino acid lipid binding protein with multiple biological proper- ties. There are three common human iso- forms of apoE— designated apoE2, Objective: To test for an association between apolipoprotein E (APOE) genotypes and duration of intensive care unit delirium. Design: Prospective, observational cohort study. Setting: A 541-bed, community-based teaching hospital. Patients: Fifty-three mechanically ventilated intensive care unit patients. Interventions: None. Measurements and Main Results: All patients were managed with standardized sedation and ventilator weaning protocols as part of an ongoing clinical trial and were evaluated prospectively for delirium with the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). DNA was extracted from whole blood samples obtained on enrollment, and APOE genotype was determined using polymerase chain reaction followed by restriction enzyme digestion by investigators blinded to the clinical information. Delirium occurred in 47 (89%) patients at some point during the intensive care unit stay. Of the 53 patients, 12 (23%) had an APOE4 allele (APOE4) and 41 (77%) had only APOE2 or APOE3 alleles (APOE4). APOE4 patients were younger (53.2  21.9 vs. 65.4  13.4, p  .08) and less often admitted for pneumonia (0% vs. 29.3%, p  .05) compared with APOE4 patients, yet they had a duration of delirium that was twice as long: median (interquartile range), 4 (3, 4.5) vs. 2 (1, 4) days (p  .05). No other clinical outcomes were significantly different between the APOE4 and APOE4 patients. Using multivariable regression analysis to adjust for age, admission diagnosis of sepsis or acute respiratory distress syndrome or pneumonia, severity of illness, and duration of coma, the presence of APOE4 allele was the strongest predictor of delirium duration (odds ratio, 7.32; 95% con- fidence interval, 1.82–29.51, p  .005). Conclusions: APOE4 allele represents the first demonstrated genetic predisposition to longer duration of delirium in humans. (Crit Care Med 2007; 35:112–117) KEY WORDS: delirium; critical care; sepsis; respiratory failure; aging; apolipoprotein E4 *See also p. 304. From the Department of Medicine, Saint Thomas Hospital, Nashville, TN (AEC, RWL); Departments of Internal Medicine, Divisions of General Internal Medi- cine and Center for Health Services Research and the VA Tennessee Valley Geriatric Research, Education and Clinical Center (GRECC) (EWE, SMG, BTP); Division of Allergy/Pulmonary/Critical Care Medicine (EWE, TDG, JCJ, JWWT, RWL), Department of Anesthesiology (PP), and Department of Biostatistics (AKS), Vanderbilt Uni- versity School of Medicine, Nashville, TN; and the Multidisciplinary Neuroprotection Laboratory and the Departments of Medicine (Neurology) (DTL) and Critical Care, Duke University Medical Center, Durham, NC. Supported, in part, by a grant from the Saint Thomas Foundation, Nashville, TN; the Paul Beeson Faculty Scholar Award from the Alliance for Aging Research (EWE); a K23 from the National Institutes of Health (AG01023-01A1) (EWE); grant 240803 from the Institute for the Study of Aging (DTL); and grant M01 RR00095 from the National Center for Research Re- sources, National Institute of Health. Dr. Ely has received honoraria and grants from Pfizer, Lilly, and Hospira. The remaining authors have not disclosed any potential conflicts of interest. Address requests for reprints to: E. Wesley Ely, MD, MPH, FACP, FCCM, ICU Cognitive Impairment Study Group, Center for Health Services Research, 6th Floor Medical Center East, #6109, Vanderbilt University Medical Center, Nashville, TN 37232-8300. E-mail: wes.ely@vanderbilt.edu. Copyright © 2006 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/01.CCM.0000251925.18961.CA 112 Crit Care Med 2007 Vol. 35, No. 1