Table 1.

Summary of included studies and findings for APOE allelic variants.

Search Criteria [Title/Abstract/MeSH Terms]: (Chronic Traumatic Encephalopathy or Mild Traumatic Brain Injury or Concussion) and Apolipoprotein E
MTBI in Athlete Cohorts (8 Studies)
Author and Year	Study Type	N	Sex; Age	Description	Outcome Measures	Results
Cochrane et al., 2018	MTBI, prospective, athletes	250 collegiate athletes (95 football, 58 baseball/softball, 67 soccer, 18 basketball, 2 cross-country/track and field)	184 male, 66 female; 19.0 ± 1.3 years old	APOE-ε2 carriers (n = 28), APOE-ε3 carriers (n = 128), APOE-ε4 carriers (n = 68), 24% self-reported a history of prior concussion.	Self-reported history of concussions and neurocognitive performance from Immediate Post-concussion Assessment and Cognitive Testing (ImPACT).	Apo-ε4 carriers had significantly slower reaction time (p = 0.002) as measured by the ImPACT.
Kristman et al., 2008	MTBI, prospective, athletes	318 collegiate athletes (43 football, 26 field hockey, 32 basketball, 23 ice hockey, 45 lacrosse, 49 rugby, 53 soccer, 47 volleyball)	164 male, 154 female, mean age 20.5 ± 2.4 years (range 17–31)	79 (24.8%) APOE-ε4(+) athletes	Concussions in athletes were diagnosed by the sport-medicine team and verified by a sport-medicine physician.	In the proportional hazards model, presence of the APOE-ε4 was not significantly associated with concussion (p = 0.68).
Merritt et al., 2016	MTBI, prospective, athletes	42 collegiate athletes (sports not defined)	35 male, 7 female; subjects with mild concussions (14.3% LOC); ε4 carriers aged 19.9 ± 1.4 years, noncarriers aged 20.0 ± 1.6 years	15 (35.7%) APOE-ε4(+) athletes, and 27 (64.3%) APOE-ε4(−) athletes	Team physicians determined TBI and concussed athletes were referred for neuropsychological testing post-injury. The Post-Concussion Symptom Scale was used to evaluate self-report symptoms. Physical and cognitive symptom clusters were each dichotomized into “symptoms present” versus “symptoms absent” groups	ε4-carriers associated with “symptoms present” group; ε4(+) athletes more likely to endorse physical symptoms than ε4(−) athletes (odds ratio (OR) = 5.25 (1.33–20.76); p = 0.015)). For cognitive symptoms, ε4-carriers associated with “symptoms present” group; ε4(+) athletes more likely to endorse cognitive symptoms than ε4(−) athletes, (OR = 4.75 (1.23–18.41), p = 0.020)
Merritt et al., 2018	MTBI, prospective, athletes	57 collegiate athletes (16 football, 11 basketball, 8 lacrosse, 7 rugby, 7 hockey, 4 soccer, 2 wresting, 2 other).	44 males, 13 females; ε4 carriers 20.3 ± 1.4 years old, ε4 noncarriers 20.3 ± 1.4 years old	20 athletes (35.1%) APOE-ε4(+); 37 athletes (64.9%) APOE-ε4(−)	Neurocognitive test battery including learning and memory, attention, processing speed, and executive functions: Brief Visuospatial Memory Test, Hopkins Verbal Learning Test; Symbol-Digit Modalities Test; Vigil Continuous Performance Test; Digit Span Test from the WAIS-III; Trail-Making Test; Penn State University Cancellation Test; Stroop Color-Word Test; ImPACT.	No significant differences were seen between athletes with and without the APOE-ε4 allele when examining mean neurocognitive scores (all p > 0.05). However, ε4(+) subjects were more likely to show a greater number of impaired neurocognitive scores post-injury compared to ε4(−) athletes (p < 0.05). More ε4+ athletes (40.0%; 8 of 20) fell in the impaired group compared with ε4- athletes (16.2%; 6 of 37; p = 0.046). APOE-ε4(+) athletes demonstrated greater neurocognitive variability than athletes without APOE-ε4 (p < 0.05).
Abrahams et al., 2017	MTBI retrospective, athletes (rugby)	288 rugby athletes (121 high school, 116 club, 51 professional)	Males; controls younger than concussed group (19.2 ± 3.5 years vs. 20.5 ± 4.4 years; p = 0.008)	The concussed group (N = 160) reported 1.9 ± 1.0 prior concussions (45%: 1; 34.4%: 2; 8.8%: 3; 11.9%: 4 concussions)	Self-reported duration of symptoms (<1 week versus ≥1 week)	APOE-ε4 isoforms did not differ significantly between concussion and control groups. APOE-ε4 isoform frequency distribution did not differ significantly between duration of symptoms groups
Casson et al., 2014	Chronic brain damage, retrospective cross-sectional, athletes	45 retired National Football League (NFL) players	45 males; 45.6 ± 8.9 years old (range, 30–60 years)	Athletes reported 6.9 ± 6.2 concussions (maximum 25) throughout their careers	MMSE, dysarthria, pyramidal system dysfunction, extrapyramidal system dysfunction, cerebellar dysfunction, depression, PHQ9, ImPACT. susceptibility weighted imaging (SWI) and diffusion tensor imaging (DTI) evaluation for brain injuries	APOE-ε4 allele present in 38% of players, a larger number than expected in the general male population (23–26%). No association of the APOE-ε4 genotype with anatomical magnetic resonance imaging (MRI), clinical neurologic, depression, or neuropsychological test results
Esopenko et al., 2017	MTBI, retrospective, alumni athletes	33 retired National Hockey League (NHL) players	53 males; alumni athletes 54.3 ± 10.4 years old, controls 53.4 ± 10.2 years old,	Concussions in athletes were 4.8 ± 2.7; in controls were 0.6 ± 0.8; 9 alumni and 4 controls were ε4(+); 1 ε4/ε4, 2 ε2/ε4, rest were ε2/ε3 or ε3/ε3	Self-reported history of concussion, cognitive function and questionnaires on psychosocial/psychiatric function	ε4-carriers associated with increased psychiatric complaints (p = 0.009) but not objective cognitive performance. Executive function associated with number of concussions after accounting for confounders (β = −0.55 and −0.39, p = 0.005 and p = 0.039 for concussion and age, respectively)
Tierney et al., 2010	MTBI, retrospective, athletes	196 collegiate athletes (163 football; 33 soccer)	163 male football and 33 female soccer athletes, age was 19.7 ± 1.5 years old	48 (24.5%) with 1 concussion, 9/48 (4.6%) with >1 concussions. ε2 and ε4 present in 35 (17.7%) and 62 (31.9%) athletes.	Self-reported history of concussions.	No association between ε4 and ε2 carriers and history of concussion. Significant association (OR = 9.8; p = 0.05) between carrying APOE rare alleles and prior concussions.
MTBI in Military Cohorts (5 Studies)
Author	Study Type	N	Sex; Age	Description	Outcome Measures	Results
Dretsch et al., 2017	MTBI, retrospective, active-duty military	458 military members from two brigade combat teams preparing to deploy to Iraq and Afghanistan	430 male, 28 female; age was 26.0 ± 7.0 years	History of concussion in 36.5%, with 10.7% having 3+ concussions. 38% (162/430) of men with 1+ concussions, vs. 18% (5/28) of women	Self-reported history of concussions	APOE not associated with risk for concussions. Of ε3/ε4 or ε4/ε4 soldiers, 44.1% (41/93) had a history of one or more prior concussions compared with 34.5% (126/365) of the comparison group (OR = 1.50; p = 0.087)
Emmerich et al., 2016	MTBI, retrospective, active-duty military	120 demographically matched soldiers with prior deployment to Iraq or Afghanistan (21 with TBI, 34 with posttraumatic stress disorder (PTSD); 13 with TBI + PTSD; 52 controls)	120 males; TBI subjects’ age was 25.9 ± 1.4 years, PTSD subjects’ age was 26.4 ± 1.3 years, TBI + PTSD subjects’ age was 29.9 ± 1.6 years old; control subjects’ age was 26.7 ± 1.0 years	85 APOE-ε4(−) (control n = 37, TBI n = 16, PTSD n = 24, TBI + PTSD n = 8); APOE-ε4(+) n = 35 (control n = 15, TBI = 5, PTSD = 10, TBI + PTSD n = 5)	Self-reported history of TBI, including military-associated injury and all other traumas; alcohol use; medical history; prior deployments; current medications; PTSD symptoms; and depression. Blood samples for lipidomic analysis.	ε4(+) subjects exhibited higher plasma phospholipids levels than their ε4(−) counterparts within diagnostic groups. ε4 noncarriers showed decreased saturated fatty acids (SFA)- and monounsaturated fatty acids (MUFA)-containing phosphatidylethanolamine (PE) species for TBI, PTSD, and TBI+PTSD groups, compared with controls. ε4 carriers showed no significant differences between TBI and PTSD groups for SFA- and MUFA. Interaction between ε4-carriers and diagnosis of TBI+PTSD on MUFA-containing lysophosphatidylcholine (LPC) and lysophosphatidylethanolamide (LPE) species.
Han et al., 2009	Mild to moderate TBI, retrospective, active-duty military	53 military personnel	42 male, 4 female; Mean age of APOE-ε4(+) was 22.6 ± 3.8 years, mean age of APOE-ε4(−) was 25.2 ± 6.1 years	16 APOE-ε4(+), 30 APOE-ε4(−)	Job change (reduction in duties for any reason e.g., medical hold, rehabilitation or assignment to light/limited duties (n = 24), reduction due to TBI (n = 3), referral to Medical Board (n = 3), or administrative separation (n = 1)), using neuropsychological assessments	In ε4-carriers, job status was determined by a long-delay free recall on the CVLT-II. If the percent change between long-delay free recall and short-delay free recall (defined as ((long-delay free recall raw score) minus (short-delay free recall raw score))/(short-delay free recall raw score)) >3.55%, subjects correctly predicted as no change in work status (85.7% accuracy). If the percentage change was <3.55%, subjects were correctly predicted to have a change in their job status with 88.9% accuracy
Hayes et al., 2017	MTBI, retrospective, veterans	160 veterans of OEF/OIF and/or New Dawn	149 male, 11 female; non-MTBI aged 32.9 ± 8.9 years, MTBI aged 30.6 ± 8.1 years	55 with no MTBI, 105 with MTBI. ε4(+): 10/55 with no MTBI, 27/105 with MTBI	Linear models examined the main effect of APOE (ε4-carriers, n = 37; non-ε4 carriers, n = 123) and MTBI × APOE interaction factor on cortical thickness.	No main effect of APOE on cortical thickness; no MTBI/APOE interaction.
Nielsen et al., 2018	MTBI, retrospective, veterans	87 veterans with or without MTBI	Demographics not published	47 veterans with MTBI and 40 controls	Hierarchical linear regression to evaluate the association between DNA methylation, MTBI, and APOE genotype with plasma APOE, controlling for age, sex, population structure, depression and PTSD	Plasma APOE associated with PTSD severity (p = 0.013). Higher APOE levels in ε3/ε3 compared to ε4 carriers (p = 0.031). Plasma APOE was associated with DNA methylation at CpG sites −877 (p = 0.021), and −775 (p = 0.014). The interaction factor ε4 × PTSD was associated with DNA methylation at CpG −675 (p = 0.009)
MTBI in Population-Based Cohorts (6 Studies)
Author	Study Type	N	Sex; Age	Description	Outcome Measures	Results
Lee et al., 2017	MTBI, prospective, population-based	189 patients from emergency departments (ED) of three hospitals	76 male, 113 female; Mean age of ε4(+) was 42.2 ± 14.7 years and ε4(−) was 40.1 ± 15.2 years	35 ε4(+), 154 ε4(−)	1st week post-mTBI and 6th week post-mTBI) sleep assessments, using the Pittsburgh Sleep Quality Index (PSQI)	No difference in PSQI at baseline and week 6 between ε4-carriers and noncarriers. Both ε4 carriers and noncarriers exhibited improvement in overall PSQI scores between baseline and week 6 follow-up (carrier: baseline 8.3 ± 3.9, 6th week: 7.4 ± 4.9, p = 0.05; noncarrier: baseline 8.5 ± 4.4, 6th week: 8.1 ± 3.8, p = 0.03)
Liberman et al., 2002	MTBI, prospective, population-based	87 adult patients presenting with mild or moderate TBI to a shock trauma center	48 males, 32 females; <30 years of age (n = 25), 30–49 years old (n = 28) and ≥50 years old (n = 27)	18 ε4(+), 62 ε4(−)	13 neuropsychological tests administered twice at 3 and 6 weeks post-injury	90% with MTBI; 18 (22.5%) ε4-carriers, who had lower scores on 12 of 13 neuropsychological outcomes at visit 1 compared to noncarriers, 2 were significant (grooved pegboard test, p = 0.005; paced auditory serial addition task 2.8-s trial, p = 0.004). At visit 2, ε4(+) had lower adjusted mean scores on 11/13 neuropsychological outcomes, though none were statistically significant.
Muller et al., 2009	MTBI, prospective, population-based	59 patients with MTBI	47 male, 12 female; Mean age 35.1 years (range 18–74)	13 APOE-ε4(+), 46 APOE-ε4(−)	GCS in ED, head computed tomography (CT) and MRI, neurophysiological assessments at baseline and 6-months. Serum S100B was measured.	GCS < 15, TBI on CT/MRI, and serum S-100B > 0.14 μg/L predicted impaired cognitive performance at baseline and 6-months while APOE did not. APOE-ε4 genotype was the only independent factor significantly predicting less improvement from baseline to 6-months.
Sundstrom et al., 2007	MTBI, prospective, population-based	31 MTBI patients and 62 matched controls	18 male, 13 female; Mean age 55.2 ± 13.6 years	APOE-ε4 present in 38.7% of MTBI subjects and controls	Self-reported pre and postinjury fatigue, anxiety, depression and sleep disturbance was compared within-group and between groups	In MTBI, fatigue was more commonly reported among ε4 carriers (58%) than noncarriers (32%). MTBI ε4-carriers were more often fatigued than controls with ε4 (58% vs. 17%, p = 0.02). No significant between-group differences between MTBI and controls without ε4
Yang et al., 2015	MTBI, prospective, population-based	21 MTBI patients without dementia, 6 MTBI patients with dementia, and 10 controls without MTBI	15 male, 22 female; (controls: 2 M, 8 F, aged 50.6 ± 6.8 years; MTBI without dementia: 9 M, 12 F, aged 53.7 ± 7.9 years; MTBI with dementia: 4 M, 2 F; aged 60.0 ± 7.5 years)	ε4 carriers: 5 of 21 MTBI without dementia, 4 of 6 MTBI with dementia, 1 of 10 controls	MMSE, amyloid-PET	ε4 frequency high in MTBI patients with dementia (p = 0.049). Linear regression between APOE-ε4 and average amyloid standardized uptake value ratio (SUVR) showed significant correlation for all subjects (p < 0.05)
Yue et al., 2017	MTBI, prospective, population-based	114 MTBI patients	76 male, 38 female; aged 49.6 ± 13.6 for ε4(+); aged 39.7 ± 16.5 years for noncarriers	79 ε4(−), 35 ε4(+)	6-month verbal memory using the CVLT-II, including Short-Delay Free Recall (SDFR), Short-Delayed Cued Recall (SDCR), Long-Delay Free Recall (LDFR), and Long-Delay Cued Recall (LDCR).	ε4-carriers associated with long-delay verbal memory deficits (LDFR: B = −1.17 points, 95% CI (−2.33, −0.01), p = 0.049; LDCR: B = −1.58 (−2.63, −0.52), p = 0.004), and a marginal decrease on SDCR (B = −1.02 (−2.05, 0.00), p = 0.050). CT pathology was the strongest predictor of decreased verbal memory.
CTE in Athlete and Military Cohorts (4 Studies)
Author	Study Type	N	Sex; Age	Description	Outcome Measures	Results
Stern et al., 2013	CTE, retrospective, athletes	36 athletes (29 football (22 pro, 4 college, 3 high school), 3 hockey, 1 wrestling, 3 boxing (1 pro, 2 amateur)) with neuropathologically confirmed CTE	All male; aged 56.8 ± 21.9 years (range 17–98)	APOE-ε4 genotype distribution was 3% ε2/ε3, 63% ε3/ε3, 26% ε3/ε4, and 9% ε4/ε4	Next-of-kin interviewed for neuropsychiatric, social/occupational histories, dementia, depression, changes in cognition, behavior, mood, motor function, and ADLs	Proportions of APOE genotypes (i.e., ε4/ε4, ε4 carriers, and ε4 noncarriers) in this CTE sample were significantly different from those found in an age-matched normative sample (p < 0.05). Primary difference between this CTE sample and population norms was a greater proportion of ε4/ε4 in this sample (p < 0.05). More ε4/ε4 in the cognition group than expected (p < 0.05). Relative proportions of APOE in the 10 subjects with dementia did not differ significantly from those seen in Alzheimer’s (p > 0.05)
Mckee et al., 2013	CTE, retrospective, athletes, military veterans, and civilians	80 athletes (22 veterans), 3 military veterans, 1 civilian with history of falls, 1 civilian with history of self-injurious head banging behavior; 18 age- and sex-matched controls	84 males, 1 female; Mean age of 54.2 ± 23.3 years (age range 14–98)	Of all subjects, including controls, 21 were carriers of Apo-ε4, 5 were homozygous for Apo-ε4	Post-mortem brains of subjects with histories of repetitive MTBI were analyzed for evidence of CTE. Hyperphosphorylated tau pathology ranged in severity from focal pathology in the frontal lobe to a more global tauopathy, allowing for a progressive staging of pathology in these subjects. APOE genotyping was performed	In the 68 subjects diagnosed with CTE, the proportion of carrying at least one APOE-ε4 allele was not significantly different than that observed in the general population (p = 0.334)
Omalu et al., 2011	CTE, case series, athlete	14 pro athletes (8 football, 4 wrestling, 1 boxing, 1 mixed martial arts, 3 high school football)	Subjects male; age range 16–52 years	ε3/ε3 in 6 athletes (60%), ε3/ε4 in 2 athletes (20%), ε2/ε3 in 1 athlete (10%), ε2/ε4 (10%) in 1 athlete. 9 of the pro athletes (90%) with at least 1 ε3 allele. 7 of 10 pro athletes with known APOE genotype had CTE (70%). For the 3 deceased high school football players, the APOE genotype in 1 case could not be determined (blood samples were not available), and the genotypes in the other 2 were ε3/ε3 and ε3/ε3	Histochemical and immunohistochemical brain tissue analysis for CTE changes and apolipoprotein E genotyping	Three pro athletes carried APOE-ε4, two of which (ε3/ε4 genotype) were positive for CTE, and the remaining (ε2/ε4 genotype) negative for CTE
Omalu et al., 2011	CTE, case report, military	Case report of a military individual	27-year-old male	The APOE genotype was ε3/ε4	Histochemical and immunohistochemical brain tissue analysis for CTE changes	Autopsy, as well as gross and histomorphological examination of this brain revealed CTE changes similar to those observed in USA athletes
CTE in an Institutionalized Cohort (1 Study)
Author	Study Type	N	Sex; Age	Description	Outcome Measures	Results
Shively et al., 2017	Leucotomy, case series, institutionalized	5 institutionalized patients with schizophrenia and history of surgical leucotomy, with post-diagnosis survival of >40 years	2 male, 3 female; Ages were 67, 70, 77, 87, and 89 years	Three of 5 are APOE-ε4 carriers, with the other 2 having ε3/ε3 genotype	Immunohistochemistry for abnormally hyperphosphorylated tau, beta-amyloid, antigen CD68; H&E stains on tissue sections for general morphology/structure	The three ε4-carriers showed scattered β-amyloid plaques in the overlying gray matter, which were not seen in the two ε3/ε3 patients

APOE: apolipoprotein E gene; CI: confidence interval; CT: computed tomography; LOC: loss of consciousness; MMSE: Mini Mental State Exam; OEF: Operation Enduring Freedom; OIF: Operation Iraqi Freedom; TBI: traumatic brain injury.