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

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.

Advances in the Understanding of the Genetic Determinants of Congenital Heart Disease and Their Impact on Clinical Outcomes

“…There are multiple isotypes of ApoE (ε2, ε3, ε4) with different functional properties. Individuals with at least 1 copy of the ε4 allele are at higher risk of Alzheimer disease and worse outcomes after traumatic brain injury . In patients with CHD, the ApoE ε2 allele is associated with worse early ND performance in patients with CHD, a deficit that persists as patients age and that has been replicated in a similar but distinct patient cohort .…”

Role of Sulfonylurea Receptor 1 and Glibenclamide in Traumatic Brain Injury: A Review of the Evidence

“…It follows that the host-response is a key factor in regulating secondary injury processes such as cerebral edema and contusion expansion that significantly influence outcome after TBI. Genetic variation is increasingly recognized as an important contributor to variability in post-traumatic host response [28,[115][116][117][118][119][120][121][122][123][124]. adjacent gene KCNJ11 (encoding KIR6.2).…”

Apolipoprotein E Epsilon 4 Genotype, Mild Traumatic Brain Injury, and the Development of Chronic Traumatic Encephalopathy

“…APOE genotype was not found to be a predictor of impairment at either time point; however ε4-positive patients, as with positive computed tomography (CT) findings, associated with reduced improvement in performance at 6 months [ 54 ]. In Yue et al, 2017, a prospective cohort of 114 MTBI patients (mean age 43 years, 28% with ε4 allele), verbal memory evaluation using the CVLT-II at 6 months post-injury revealed impaired long-delay free and cued recall for ε4 carriers, along with marginally decreased short-delay cued recall [ 55 ]. Yang et al, 2015, a retrospective cohort of 27 individuals with MTBI (mean age 54 years for those without dementia, 60 years with dementia, MTBI history 6 years ago, 30% with ε4 allele) and 10 age-matched controls, found the highest APOE-ε4 frequency in subjects with MTBI history plus development of dementia (0.250 vs. 0.143 for MTBI without dementia vs. 0.050 for controls) [ 56 ].…”

“…In fact, up to 30% of MTBI patients who are CT-negative can be MRI-positive for intracranial injury, specifically axonal shear and gliding contusions [ 77 ]. Yue et al, 2017 found that 25% of MTBI patients had intracranial pathology on initial head CT scan within 24 h of injury, and APOE-ε4 did not accurately predict the presence of acute CT-positive lesions [ 55 ]. Casson et al, 2014 conducted extensive MRI studies with susceptibility weighted imaging (SWI) and diffusion tensor imaging (DTI) in a cohort of retired professional football players experiencing a mean total of nineconcussions over their lifespan, 38% of whom were ε4 carriers [ 41 ].…”

“…Cognitive scores in concussed collegiate athletes (using the Brief Visuospatial Memory Test-Revised) and former athletes (using CogState battery and Cambridge Brain Science) did not differ in any subdomains by APOE genotype, except for ε4-athletes having greater score variability [ 44 ] and ε4-alumni self-reporting more psychiatric complaints [ 45 ]. When the CVLT-II was used; however, APOE-ε4 carriers suffering MTBI presenting to Level I trauma centers [ 55 ] and in the military [ 49 ] exhibited worse long-delay verbal memory compared to patients without ε4. Other notable differences include manipulative dexterity in motor function and auditory processing and flexibility at 3 weeks post-injury [ 52 ], and a global index incorporating these measures predicted less improvement in ε4 carriers at 6 months [ 54 ].…”