Apolipoprotein E epsilon 4 (APOE-ε4) genotype is associated with decreased 6-month verbal memory performance after mild traumatic brain injury.

John K Yue,Jessica L Nielson,Adam R Ferguson,Jonathan Rosand,Sourabh Sharma,Alex B Valadka,Thomas W Mcallister,Maryse C Cnossen,David O Okonkwo,Pratik Mukherjee,Phiroz E Tarapore,Frederick K Korley,Hester F Lingsma,Esther L Yuh,John F Burke,Ethan A Winkler,Esteban G Burchard,Jason F Talbott,Marco D Sorani,Ramon Diaz‐Arrastia,Geoffrey T Manley,Hansen Deng,Caitlin Robinson ,Kevin Wang ,Gabriela Satris

doi:10.1002/brb3.791

Abstract

IntroductionThe apolipoprotein E (APOE) ε4 allele associates with memory impairment in neurodegenerative diseases. Its association with memory after mild traumatic brain injury (mTBI) is unclear.Methods mTBI patients (Glasgow Coma Scale score 13–15, no neurosurgical intervention, extracranial Abbreviated Injury Scale score ≤1) aged ≥18 years with APOE genotyping results were extracted from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK‐TBI Pilot) study. Cohorts determined by APOE‐ε4(+/−) were assessed for associations with 6‐month verbal memory, measured by California Verbal Learning Test, Second Edition (CVLT‐II) subscales: Immediate Recall Trials 1–5 (IRT), Short‐Delay Free Recall (SDFR), Short‐Delay Cued Recall (SDCR), Long‐Delay Free Recall (LDFR), and Long‐Delay Cued Recall (LDCR). Multivariable regression controlled for demographic factors, seizure history, loss of consciousness, posttraumatic amnesia, and acute intracranial pathology on computed tomography (CT).ResultsIn 114 mTBI patients (APOE‐ε4(−)=79; APOE‐ε4(+)=35), ApoE‐ε4(+) was associated with long‐delay verbal memory deficits (LDFR: B = −1.17 points, 95% CI [−2.33, −0.01], p = .049; LDCR: B = −1.58 [−2.63, −0.52], p = .004), and a marginal decrease on SDCR (B = −1.02 [−2.05, 0.00], p = .050). CT pathology was the strongest predictor of decreased verbal memory (IRT: B = −8.49, SDFR: B = −2.50, SDCR: B = −1.85, LDFR: B = −2.61, LDCR: B = −2.60; p < .001). Seizure history was associated with decreased short‐term memory (SDFR: B = −1.32, p = .037; SDCR: B = −1.44, p = .038).ConclusionThe APOE‐ε4 allele may confer an increased risk of impairment of 6‐month verbal memory for patients suffering mTBI, with implications for heightened surveillance and targeted therapies. Acute intracranial pathology remains the driver of decreased verbal memory performance at 6 months after mTBI.

Highlights

Mild traumatic brain injury is a major cause of cognitive impairment, which may be modulated in part by genetic susceptibility. mTBIs constitute 70%–90% of all traumatic brain injuries (TBI) (Cassidy et al, 2004); it is estimated that 20%–25% of patients experience persistent symptoms and/or cognitive and neuropsychiatric deficits at 6–12 months postinjury (Arciniegas, Anderson, Topkoff, & McAllister, 2005)
As the goal of the current analysis was to investigate the association between the Apolipoprotein E (APOE)-ε4 allele and 6-month verbal memory outcome after mTBI, uncomplicated by massive intracranial trauma [e.g., computed tomography (CT) evidence of mixed density lesions >25 mm, midline shift >5 mm, or evidence of cisternal compression (Marshall et al, 1992)] or polytrauma, patients were included if ≥18 years of age, with Glasgow Coma Scale (GCS) score of 13–15 at ED admission per current definition of mTBI (Teasdale & Jennett, 1974; ), Marshall CT Score 1–2 (Marshall et al, 1992), no acute neurosurgical intervention, and no extracranial injuries greater than “mild” (Abbreviated Injury Scale [AIS] score >1 in any extracranial body region)
In a prospective study examining the association between APOE-ε4 and verbal memory deficits after isolated mTBI, we find that APOE-ε4(+) is independently associated with impaired long-delay free and cued recall at 6 months postinjury when compared with APOE-ε4(−) patients

Summary

Introduction

Mild traumatic brain injury (mTBI) is a major cause of cognitive impairment, which may be modulated in part by genetic susceptibility. mTBIs constitute 70%–90% of all traumatic brain injuries (TBI) (Cassidy et al, 2004); it is estimated that 20%–25% of patients experience persistent symptoms and/or cognitive and neuropsychiatric deficits at 6–12 months postinjury (Arciniegas, Anderson, Topkoff, & McAllister, 2005). MTBIs constitute 70%–90% of all traumatic brain injuries (TBI) (Cassidy et al, 2004); it is estimated that 20%–25% of patients experience persistent symptoms and/or cognitive and neuropsychiatric deficits at 6–12 months postinjury (Arciniegas, Anderson, Topkoff, & McAllister, 2005). Differences in the tertiary structure and in the charge distribution of the APOE isoforms determine the capacity for cholesterol homeostasis through binding to receptors, to other proteins, and through intracellular trafficking pathways and second messengers (Strittmatter & Bova Hill, 2002; Saito et al, 2003). These differences in metabolic regulation may influence the outcome after brain injury. APOE-ε4 is directly associated with mitochondrial toxicity and beta-amyloid deposition contributing to Alzheimer’s Disease (AD) in a dose-dependent manner (ε4 carrier, 5-fold; ε4/ε4: 20-fold) (Blennow, Mattsson, Schöll, Hansson, & Zetterberg, 2015; Hauser & Ryan, 2013)

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