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

Abstract

Introduction: The 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).

Results: In 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).

Conclusion: The 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.

Keywords: apolipoprotein E; genetic factors; human studies; outcome measures; traumatic brain injury; verbal memory.

Figure 1

Effects of APOE on Aβ metabolism and postinjury repair. Neuronal injury upregulates astrocyte secretion of ApoE, which clears lipid cell debris and assists in cholesterol delivery for synaptogenesis. APOE is lipidated to form ApoE lipoprotein, and in the extracellular space binds in an isoform‐dependent pattern (APOE‐ε2, ‐ε3 >  APOE‐ε4) to soluble beta‐amyloid protein (Aβ), a peptidic neurotoxin. APOE genotype determines the capacity for Aβ clearance and parenchymal amyloid plaque accumulation. Evidence suggests that relative to APOE‐ε2 and ‐ε3,APOE‐ε4 is preferentially susceptible to proteolytic degradation, thus reducing the capacity to fulfill postinjury needs for membrane repair and synaptogenesis

Figure 2

Six‐month verbal memory performance, by APOE‐ε4 carrier status. Performance on four CVLT‐II subscales (SDFR, Short‐Delay Cued Recall (SDCR), Long‐Delay Free Recall (LDFR), LDCR) at 6 months postinjury are shown for 114 mTBI patients, by APOE‐ε4 carrier status. Raw scores for each CVLT‐II subscale are controlled for age, education, sex, race, prior medical history (PMH) seizures, loss of consciousness, posttraumatic amnesia, and acute intracranial pathology on head CT scan. Multivariable regression means and 95% confidence intervals are shown for APOE‐ε4 groups. APOE‐ε4(−), blue; APOE‐ε4(+), red. APOE, apolipoprotein E; CT, computed tomography; CVLT‐II, California Verbal Learning Test, Second Edition; LDCR, Long‐Delay Cued Recall; LDFR, Long‐Delay Free Recall; mTBI, mild traumatic brain injury; PMH, prior medical history; SDCR, Short‐Delay Cued Recall; SDFR, Short‐Delay Free Recall