Inheritance of a single copy of the apolipoprotein E (APOE) ɛ4 allele increases risk of Alzheimer’s disease (AD) by 3-4-fold, with homozygosity associated with a 12-16-fold increase in risk, relative to ɛ3 allele homozygosity. There is a decreased risk associated with the APOE ɛ2 allele. The pathological consequence of APOE genotype has led to intense efforts to understand the mechanistic basis of the interplay between APOE status and loss of synapses. Numerous ɛ4 allele-related associations have been reported with the potential relevance of these associations to the pathogenesis of AD unknown at this time. In primarily young subjects, we have reviewed a representative body of literature on ɛ4 allele-associations related to the following: cardiovascular responses; impacts on reproduction and fetal development; co-morbidities; resistance to infectious disease; responses to head injury; biochemical differences possibly related to neural stress; and brain structure-function differences. In addition, the literature on the association between the ɛ4 allele and cognitive performance has been reviewed comprehensively. The weight-of-the-evidence supports the hypothesis that possession of the ancestral ɛ4 allele in youth is associated with improved fitness during fetal development, infancy, and youth relative to the more recently appearing ɛ3 allele, at the expense of decreased fitness in old age, which is substantially improved by the ɛ3 allele. However, possession of the ɛ4 allele is also associated with higher levels of synaptic macromolecular turnover, which likely stresses basic cellular neuroplasticity mechanisms. Clinical trials of potential AD therapeutics should consider APOE status as an enrollment criterion.
Alzheimer’s disease (AD) is a pathological condition adversely affecting the brain. AD has a large genetic component. The neuropathology is characterized by the presence of neurofibrillary tangles (NFTs) and neuritic plaques [1, 2]. The modern conceptualization of AD pathology dates from 1968 when Blessed et al. showed in elderly individuals that the NFTs correlated with the severity of the dementia, though the neuritic plaques, which contain cerebral amyloid-β (Aβ), did not . A major advance in understanding AD pathology was the demonstration that AD pathology predominantly affects the posterior-temporal, inferior parietal, posterior cingulate, and medial temporal region , with a characteristic pattern of progression beginning in the entorhinal cortex involving neurofibrillary (NF) and microtubule associated protein-tau pathology rather than senile plaque and cerebral Aβ pathology , consistent with the earlier findings of Blessedet al. .
Dementia is a condition involving impairment of cognitive function, which has deteriorated from a prior higher level, and causes social impairment. There are a few types of dementia, mostly frontotemporal (rare) and temporal-parietal (common). Patients with temporal-parietal dementia subdivide into approximately one third with pure AD, one third not AD, and one third being mixed, with the prevalence of mixed cases increasing with age. This progression of AD (NF/NFT/tau pathology) is clearly reflected by both altered cerebral blood flow  and cerebral metabolism [6, 7], as well as by PET tracers targeting tau [8, 9], with characteristic regional and stage-specific variations . These changes in the brain are closely related to the impairments of memory function that are so typical of the dementia associated with AD and its progression [10, 11]. This pattern has strongly suggested that AD pathology selectively attacks those neuroplastic brain systems which perform the functions of episodic memory [12, 13]. The neuritic plaques and Aβ are consistent components of AD pathology , which is the predominant cause of dementia. However, the distribution pattern of Aβ pathology, which is found at least as early and diffusely in the neocortex as the tau pathology, is found first in most regions of the neocortex  but is generally not or much less related to cognitive changes than the tau pathology [16–18]. With a slowly progressing condition, mild cognitive impairment is a transition from normal cognition that precedes dementia, and is very poorly described .
Previously, we hypothesized that apolipoprotein E (APOE) ɛ4 allele-associated AD risk is consistent with increased lifetime exposure to a neurotoxic process . Specifically, if the hippocampal neurons of two individuals possess the same susceptibility to an endogenous or exogenous stress factor, the neurons with the highest turnover of proteins, lipids, and other macromolecules might experience a larger integrated dose of detriment. Small differences in pharmacokinetic effects might be amplified by the extremely long pre-symptomatic phase of AD, i.e., average age of presentation for a homozygous ɛ4 is about 68 years of age . Studies conducted across the age spectrum from infancy through senescence have suggested that APOE ɛ4-positive status is associated with increased brain activity and macromolecule turnover in young healthy individuals, with the reverse extant in elderly subjects. In the current study, we extend our analysis from the limited number of studies examined in Smith and Ashford  and attempt herein to comprehensively examine the literature on reported associations between clinical conditions, cognitive performance, and presence or absence of the ɛ4 allele in otherwise healthy young subjects.
The literature on associations between ɛ4 status in otherwise healthy young subjects falls into several categories including: cardiovascular responses (Table 1); reproduction and development (Table 2); co-morbidities (Table 3); resistance to infectious disease (Table 4); responses to head injury (Table 5); biochemical differences possibly related to neural stress (Table 6); brain structure-function (Table 7); and mental performance (Table 8). Possession of the ɛ4 allele is a strong risk factor for development of AD in the elderly, and all individuals possessing the ɛ4 allele are increasingly likely to develop AD the older they live, relative to those without this allele. An understanding of the clinical conditions and cognitive performance characteristics idiosyncratic to healthy young persons who possess the ɛ4 allele might assist in the complex task of disentangling the relative contributions of genetics and lifestyle that appear to play a role in how and when a given individual develops AD .
|Subjects / Age||Sample Size||Sex||Study Scope||Major Finding||Citation||Quality of Evidence|
|Young adult Chinese men and women, approximate mean age = 32||ɛ3/4 (N = 60), ɛ4/4 (N = 13)||Mixed||Association of APOE polymorphism with maximal oxygen uptake after exercise training: a study of Chinese young adult||VO2max after exercise training increased significantly in carriers of ɛ3/ɛ4 in males (OR = 0.60, 95% CI = 0.09,1.11; p = 0.02) and females (OR = 0.62, 95% CI = 0.09, 1.15; p = 0.02)||Yu et al. ||Moderate|
|Children from the Tasmanian Infant Health Survey; ɛ4 carriers, mean age = 8||ɛ4 carriers (N = 75)||Mixed||APOE genotype and cardio-respiratory fitness interact to determine adiposity in 8-year-old children||ɛ4 carriers had a lower BMI (mean difference –0.90 kg/m2) [95% CI –1.51, –0.28; p = 0.004] and the effect was more evident among the less fit (mean difference –1.78 kg/m2) [95% CI –2.74, –0.83; p < 0.001]||Ellis et al. ||Moderate|
|Subjects from a supervised exercise training program in Black and White men and women, average age approximately 35||ɛ3/ɛ4 (N = 101), ɛ4/ɛ4 (N = 7)||Mixed||Association of APOE polymorphism with blood lipids and maximal oxygen uptake in the sedentary state and after exercise training (HERITAGE Family Study)||APOE polymorphism was not associated with VO2max [maximal oxygen uptake] levels either in the sedentary state nor the VO2max response to exercise training||Leon et al. ||Moderate|
|Healthy 13-month-old Finnish children||16 ɛ4 children and 20 ɛ3/ɛ3 children (N = 36)||Mixed||APOE phenotype regulates cholesterol absorption in healthy 13-month-old children (The STRIP Study)||16 ɛ4 children had 30% to 50% higher cholesterol-adjusted campesterol and sitosterol concentrations in serum than 20 ɛ3/3 children (p = 0.002 and p = 0.02, respectively)||Tammiet al. ||Moderate|
|7- and 13-month-old Finnish infants||ɛ4/ɛ4 (N = 36), ɛ3/ɛ4 (N = 209)||Mixed||APOE4 phenotype increases non-fasting serum triglyceride concentration in infants (The STRIP Study)||Triglyceride concentrations were higher in infants with ɛ4/ɛ4 or ɛ3/ɛ4 than in those with ɛ3/ɛ3 (p-value for difference 0.01 and 0.009, respectively)||Tammiet al. ||High|
|Caucasian males in Perth, Australia, eight pairs of ɛ3/ɛ3 and ɛ4/ɛ4 subjects matched for age and serum lipid levels; average age =ɛ3/ɛ3 = 45 and ɛ4/ɛ4 = 42||ɛ3/ɛ3, N = 16 and ɛ4/ɛ4, N = 16||Males||Comparison of the LDL-receptor binding of VLDL and LDL from APOE4 and APOE3 homozygotes||Inheritance of APOE4 was associated with an increased affinity of VLDL particles for LDL receptors on hepatocytes||Mamotte et al. ||Low|
|Finnish infants||ɛ4 carriers (N = 44)||Mixed||APOE phenotype determines serum cholesterol in infants during both high-cholesterol breast feeding and low-cholesterol formula feeding||In infants fed high-fat, high-cholesterol human milk, the total and LDL-cholesterol concentrations and the LDL apoB concentration of those with the APOE phenotype ɛ4/4 or ɛ3/4 rose faster and to higher levels than in other infants||Kallioet al. ||Moderate|
|Healthy Finnish boys, 16 years old||ɛ4 carriers (N = 11); Controls N = 17||Males||APOE phenotypes and cardiovascular responses to experimentally induced mental stress in adolescent boys||ɛ3/ɛ2 or ɛ3/ɛ3 showed marginally significant greater heart rate reactivity and significantly greater task levels of heart rate and heart rate variability during mental stress than ɛ4/ɛ2, ɛ4/ɛ3, or ɛ4/ɛ4||Ravajaet al. ||Low|
|Healthy Finnish boys and girls, 16 years old||ɛ2/ɛ4 carriers (N = 28), ɛ3/ɛ4 carriers (N = 470), ɛ4/ɛ4 carriers (N = 49)||Mixed||The effect of physical activity on serum total and LDL cholesterol concentrations varies with APOE phenotype in male children and young adults (The Cardiovascular Risk in Young Finns Study)||Physical exercise does not affect LDL cholesterol, total cholesterol, or HDL/total cholesterol in ɛ4 carriers||Taimelaet al. ||High|
|Finnish male and female newborns and 3-year-old children||ɛ2/ɛ4 (N = 5), ɛ3/ɛ4 (N = 147), ɛ4/ɛ4 (N = 8)||Mixed||APOE phenotypes and serum lipids in newborns and 3-year-old children: (The Cardiovascular Risk in Young Finns Study)||In 3-year-olds, the concentrations of serum total cholesterol and LDL cholesterol increased with APOE phenotype in the order of ɛ3/ɛ2, ɛ3/ɛ3, ɛ4/ɛ3, and ɛ4/ɛ4, in both males and females (p < 0.001)||Lehtimaki et al. ||Moderate|
|Finnish boys and girls ages 3, 6, 9, 12, 15, and 18.||ɛ2/ɛ4 carriers (N = 28), ɛ3/ɛ4 carriers (N = 483), ɛ4/ɛ4 carriers (N = 50)||Mixed||APOE phenotypes in Finnish youths: a cross-sectional and 6-year follow-up study||The concentrations of serum total cholesterol, LDL cholesterol, and apoB increased with APOE phenotype in the order of ɛ2/ɛ2, ɛ3/ɛ2, ɛ4/ɛ2, ɛ3/ɛ3, ɛ4/ɛ3, and ɛ4/ɛ4||Lehtimaki et al. ||High|
APOE, apolipoprotein E; BMI, body mass index; 95% CI, 95% confidence interval; HDL, high-density lipoprotein; LDL, low-density lipoprotein; OR, odds ratio; VLDL, very-low-density lipoprotein.
|Subjects / Age||Sample Size||Sex||Study Scope||Major Finding||Citation||Quality of Evidence|
|100 women with a history of at least 2 first-trimester recurrent miscarriages in Tabriz, Iran, and 100 healthy women with at least 2 successful pregnancies and no miscarriages were the control group; Age not specified||N = 100 (Test Subjects) ɛ4 (N = 31); N = 100 (Control Subjects)||Female||Effect of APOE ɛ4 allele on survival and fertility in an adverse environment||ɛ4 was associated with higher fertility in women exposed to high pathogen levels. Compared with women not carrying an ɛ4 allele; those carrying one ɛ4 had on average one more child and those carrying two ɛ4 alleles had 3.5 more children (p = 0.018)||van Exel et al. ||Moderate|
|White, Black, and Hispanic neonates and infants||(N = 87) All ɛ4 carriers||Not specified||Validation of association of the APOE ɛ2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants||The ɛ2 allele was associated with a lower Psychomotor Development Index (p = 0.038)||Gaynor et al. ||Moderate|
|100 Iranian women with at least 2 first trimester recurrent miscarriages and 100 Iranian women with at least two successful pregnancies with no miscarriages; Age not specified||N = 100 (Test Subjects); ɛ4 (N = 31); N = 0 (Control Subjects)||Female||APOE genotyping in women with recurrent pregnancy loss: an in silico and experimental hybrid study||ɛ4 carriers and the frequency of the ɛ4 allele in the case group were statistically significantly higher than those in the control group (p < 0.05)||Zonouzzi et al. ||Low|
|81 Iranian women with 2 or more pregnancy losses; Age not specified||N = 81; ɛ4 Carriers (N = 22)||Female||Positive association of APOE E4 polymorphism with recurrent pregnancy loss in Iranian patients||Allelic frequency for ɛ4 was 13.5% in the patients with recurrent pregnancy loss and only 1% in the non-recurrent pregnancy loss group||Asgari et al. ||Low|
|90 Turkish women (45 women with >2 consecutive spontaneous abortions and no successful pregnancies and 45 fertile women with at least one live birth); Age not specified||N = 90, 45 Test, 45 Controls; ɛ4 Carriers (N = 16 in patients, N = 18 in controls)||Female||Study on potential role of APOE in recurrent pregnancy loss||ApoE genotypes and ɛ2, ɛ3, and ɛ4 allele frequency distribution were observed among recurrent pregnancy loss patients and controls||Korkmazeret al. ||Moderate|
|Meta-analysis of seven studies with combined ɛ4 carriers; Age not specified||N = 323 for the cases; N = 70 for the controls)||Female||Association between APOE gene polymorphism and the risk of recurrent pregnancy loss||Meta-analysis suggests an association [OR = 1.98, 95% CI 1.14–3.43] between ɛ4 and increased risk of recurrent pregnancy loss||Meng et al. ||High|
|Pregnant Romanian women, average age 28||ɛ4 Carriers (N = 46)||Female||APOE polymorphism as a risk factor in Romanian pregnant women with preeclampsia||Pregnant women with the ɛ4 allele were at increased risk to develop Pregnancy Induced Hypertension (OR 4.14, p = 0.013) and severe preeclampsia (OR 4.43, p = 0.019)||Procopciucet al. ||Moderate|
|Indian women with a history of three spontaneous abortions (mean 4, range 3–7) and no previous history of successful pregnancy, average age 28.4||ɛ4 Carriers (N = 11 in patients; N = 4 in controls)||Female||A case-control study of recurrent pregnancy loss and APOE gene polymorphisms in women from North India||Similar APOE genotypes and ɛ2, ɛ3, and ɛ4 allele frequency distribution were found among recurrent pregnancy loss patients and controls||Agarwal et al. ||Low|
|160 Italian women with recurrent pregnancy loss; Age not specified||ɛ4 Carriers (N = 23)||Female||The association between APOE polymorphisms and recurrent pregnancy loss||No association was seen between ɛ4 and recurrent pregnancy loss||Bianca et al. ||Low|
|Turkish women, average age 35||ɛ4 Carriers (N = 33)||Female||The apparent association of APOE codon 112 polymorphisms with recurrent pregnancy loss||Significantly more ɛ3/ɛ4 and ɛ4/ɛ4 genotypes were seen among individuals experiencing recurrent pregnancy loss and deep vein thrombosis than fertile controls (p < 0.05)||Ozornek et al. ||Low|
|69 American women with recurrent loss of pregnancy (average age 34.7), 69 control women, Average age 37||ɛ4 Carrier patients (N = 15), ɛ4 controls (N = 2)||Female||The association of APOE polymorphisms with recurrent pregnancy loss||Patients experiencing recurrent pregnancy loss had a significantly higher prevalence of APOE ɛ3/ɛ4, ɛ4/ɛ4 genotypes (21.7%) compared with control women (5.4%) (p = 0.036)||Goodman et al. ||Low|
|Scottish perinatal deaths||ɛ4 Carriers (N = 3 ɛ4/ɛ4; N = 16 ɛ2/ɛ4; N = 51 ɛ3/ɛ4)||Not specified||The distribution of APOE alleles in Scottish perinatal deaths||ɛ4 prevalence was raised in healthy liveborn infants (19%) compared with stillbirths (12%, OR = 1.59, 95% CI 1.11 to 2.26)||Becher et al. ||Moderate|
|CSF collected from 107 healthy Japanese subjects (70 males, 37 females) aged 1–86; 67 <20 years and 40 >20 years old||N = 107 (70 males, 37 females)||Mixed||Effect of APOE phenotype on the APOE content of CSF-HDL in children <20 years old||APOE phenotype does not affect composition or concentration of CSF HDL in children <20 years old||Hirayama et al. ||Moderate|
|Afro-Ecuadorian and Cayapa Indian women, average age 39||ɛ4 Carriers (ɛ3/4 = 16; ɛ4/4 = 6; ɛ4/2 = 5)||Female||A study of APOE polymorphism and fertility in pre-industrial populations||ɛ3/ɛ4 genotype frequency (0.50) in African-Ecuadorian women with 9–17 children was about 3-fold that of women with 0–8 children (0.14) (p = 0.02)||Corbo et al. ||Low|
|Asian, Black, and White, male and female infants under 6 months undergoing cardiac surgery in Philadelphia||ɛ4 Carriers (N = 52)||Mixed||APOE genotype and neurodevelopmental sequelae of infant cardiac surgery||Patients with an ɛ2 allele had approximately a 7-point decrease in the Psychomotor Developmental Index [Bayley Scales of Infant Development] (p = 0.036)||Gaynor et al. ||Moderate|
|81 Spontaneously aborted embryos and 100 adult controls from Crete; Age of adults not specified||N = 81 (4 ɛ3ɛ4) Test; N = 100 adult controls (17 ɛ3ɛ4)||Not applicable||Influence of the APOE ɛ4 allele on human embryonic development||ɛ4 allele was less frequent in the spontaneous abortion group than in the control group (p = 0.009), while the frequency of ɛ3 was increased (p = 0.005)||Zetterberg et al. ||Moderate|
|40-year-old married men residing in Aarhus, Denmark||ɛ4 Carriers (ɛ3/ɛ4 = 93; ɛ4/ɛ4 = 12; ɛ4/ɛ2 = 9); ɛ3 Carriers (ɛ3/ɛ3 = 212; ɛ3/ɛ4 = 93; ɛ3/ɛ2 = 48); ɛ2 Carriers (ɛ2/ɛ2 = 5)||Men||The fertility of men carrying the apolipoprotein ɛ4- or ɛ2 allele versus ɛ3/ɛ3 genotypes||Men with the ɛ3/ɛ3 genotype (n = 212) had 1.93 children, men with the ɛ3/ɛ4 or ɛ2/ɛ2 genotypes (n = 53) had 1.66 children (p = 0.0026), and men with the ɛ3/ɛ2 or ɛ2/ɛ2 genotypes (n = 53) had 1.66 children||Gerdes et al. ||Moderate|
APOE, apolipoprotein E; 95% CI, 95% confidence interval; CSF, cerebrospinal fluid; HDL, high-density lipoprotein; OR, odds ratio.
|Subjects / Age||Sample Size||Sex||Study Scope||Major Finding||Citation||Quality of Evidence|
|Meta-analysis of 28 studies on schizophrenia; Age of subjects not specified||Not specified||Mixed||Determine the association between APOE and schizophrenia: evidence of systematic review and updated meta-analysis||Protective effect was found for ɛ3 in the Asian population (OR = 0.73, 95% CI = 0.54–0.98)||Gonzalez-Castro et al. ||Moderate|
|Infants with hypoxic-ischemic encephalopathy||ɛ4 Carriers (N = 41)||Mixed||APOE genotype and outcome in infants with hypoxic-ischemic encephalopathy||Disability was not associated with APOE genotype in this cohort of hypoxic-ischemic encephalopathy patients||Cotton et al. ||Moderate|
|Pooled analysis of 15 studies on the association of APOE alleles with age-related macular degeneration; Age not specified||Not specified||Mixed||Evidence of association of APOE with age-related macular degeneration–a pooled analysis of 15 studies||Decrease in risk associated with each copy of ɛ4 in all age-related macular degeneration sub-phenotypes (Neovascular: OR = 0.74, CI 0.66–0.83; Geographic Atrophic: OR = 0.65, CI 0.55–0.77; Geographic Atrophic Neovascular: OR = 0.71, CI 0.59–0.85; early Age-Related Macular Degeneration: OR = 0.84, CI 0.77–0.92||McKay et al. ||High|
|Male and female patients, average age 46, from the dermatology clinic at Hospital Universitario Central Asturias, Spain||ɛ3/ɛ4 (N = 54), ɛ4/ɛ4(N = 3), ɛ2/ɛ4(N = 5)||Mixed||APOE4 allele is associated with psoriasis severity||ɛ4 carriers were significantly more common in patients with severe psoriasis compared to controls (p = 0.003) and to non-severe psoriasis (p = 0.017)||Coto-Segura et al. ||Moderate|
|Children in Brasilia Brazil with and without CP; Age not specified||ɛ4 Carriers (N = 139)||Mixed||Association of APOE genotype and CP||Presence of ɛ2 raised the probability of having cerebral palsy (OR 3.2; 95% CI 1.27–8.27). The presence of ɛ4 was not significantly different among groups||Braga et al. ||Moderate|
|Infants in Edinburgh Scotland||ɛ4 Carriers (N = 95)||Mixed||APOE ɛ4 and its prevalence in early childhood death due to sudden infant death syndrome or to recognized causes||Percentage of children with at least one ɛ4 allele was lower in non-SIDS compared to SIDS (p = 0.016)||Becher et al. ||Moderate|
|Caucasian (70%) and African-American children (30%) from Louisville, KY, area, average age 6.4 years||ɛ4 Carriers (N = 19)||Mixed||APOE ɛ4 allele, cognitive dysfunction, and obstructive sleep apnea in children||ɛ4 allele is more frequent in children with obstructive sleep apnea and particularly in children who develop neurocognitive deficits||Gozal et al. ||Low|
|White, Black, and Hispanic children from the Chicago area; Age not specified||ɛ4 Carriers (N = 25 patients; N = 9 controls)||Mixed||Association of APOE genotype and CP in children||Overall risk for CP was elevated 3.4-fold among children carrying an ɛ4 allele||Kuroda et al. ||Low|
|40 patients with CP and 40 without, in S’ao Paulo, Brazil; Age not specified||Total N = 80, 40 with CP, 40 without CP; ɛ4 Carriers (N = 13 patients; N = 4 controls)||Mixed||Presence of APOE ɛ4 allele in CP||OR for correlation between CP and ɛ4 allele = 4.333||de Barros et al. ||Low|
APOE, apolipoprotein E; 95% CI, 95% confidence interval; CP, cerebral palsy; OR, odds ratio; SIDS, sudden infant death syndrome.
|Subjects / Age||Sample Size||Sex||Study Scope||Major Finding||Citation||Quality of Evidence|
|Patients from Charite Berlin and University of Leipzig with either chronic or self-limited HCV infection, average age = 48.7||ɛ4 Carriers (N = 205) in two cohorts combined||Mixed||APOE allele frequencies in chronic and self-limited hepatitis C suggest a protective effect of APOE4 in the course of HCV infection||ɛ4 alleles are underrepresented in chronically hepatitis C-infected patients (10.2%) compared to 13% in healthy controls (p = 0.001)||Mueller et al. ||High|
|Seven APOE ɛ4/ɛ4 and six APOE ɛ3/ɛ3 donors from Cleveland, OH, area; Age not specified (only adults)||ɛ4/ɛ4 Donors N = 7 and ɛ3/ɛ3 donors N = 6||Not specified||APOE ɛ4 prevents growth of malaria at the intraerythrocyte stage: implications for differences in racial susceptibility to AD||Human plasma samples from ɛ4/ɛ4 but not ɛ3/ɛ 3 donors inhibited growth and disrupted morphology of P. falciparum||Fujioka et al. ||Low|
|Male and female Caucasian Italian patients with chronic hepatitis C, median age = 41||ɛ2/4 Carriers (N = 3), ɛ3/4 Carriers (N = 21), ɛ4/4 Carriers (N = 1)||Mixed||APOE genotypes modulate fibrosis progression in patients with chronic hepatitis C and persistently normal transaminases||Patients not carrying ɛ3, as well as carriers of a single ɛ3 with serum cholesterol concentration >190 mg/dL were more likely to have a favorable outcome regarding fibrosis progression with chronic hepatitis C||Fabris et al. ||Low|
|British and Irish Caucasian hepatitis C patients; Age not specified||ɛ2 Carriers (N = 48), ɛ4 Carriers (N = 84), 11 Carriers were both, i.e. ɛ2/ɛ4||Mixed||APOE ɛ3 allele is associated with persistent HCV infection||ɛ2 and ɛ4 alleles were both associated with a reduced likelihood of chronic hepatitis C infection. For ɛ2, OR = 0.39[95% CI = 0.211–0.728] (p = 0.003), and for ɛ4, OR = 0.6[95% CI = 0.38–0.96] (p = 0.032)||Price et al. ||Moderate|
|Italian male and female patients who underwent a cadaveric orthotopic liver transplantation, median age 55||ɛ4 Carriers (N = 34)||Mixed||The relationship with the blood lipid profile and low fibrosis progression of recurrent hepatitis C in APOE E4 carriers||Possession of an APOE ɛ4 allele is associated with low fibrosis progression in recurrent hepatitis C infection, and with an idiosyncratic APOE-associated lipid profile.||Fabris et al. ||Low|
|Gambian children, ages 1–10||ɛ4 Carriers (N = 244)||Mixed||Common APOE polymorphisms and risk of clinical malaria in the Gambia||For severe malaria cases subdivided into clinical categories, ɛ3/ɛ4 was more common in children with both cerebral malaria and severe malarial anemia (42.9%) than in controls (24.8%) and mild malaria cases (27.2%). When a correction factor is calculated for the number of clinical groups (4) compared with controls, this finding loses statistical significance||Aucan et al. ||High|
|24 male and female patients, median age = 53.5, with recurrent hepatitis C following cadaveric orthotopic liver transplantation||ɛ4 Carriers (N = 12) of 48 donors, ɛ4 carriers (N = 17) of 48 recipients||Mixed||Carriage of the APOE ɛ4 allele and histologic outcome of recurrent hepatitis C after antiviral treatment||Recipient (but not donor) carriage of at least 1 ɛ4 allele was associated with improvement in staging score due exclusively to the contribution from male recipients||Toniutto et al. ||Low|
|Article is a commentary||Article is a commentary||Article is a commentary||Commentary on APOE polymorphisms and risk of malaria||APOE might compete with pathogens for entry into cells. Differences in isoform affinity for the binding sites/receptors could affect competition and pathogen entry, spread, and damage. APOE isoforms do have different affinities for certain cells. This might explain why a specific allele is protective in some cases but harmful, or else neutral, in others. Competition between APOE and the protozoon might be a factor also in very severe malaria.||Wozniak et al. ||Not applicable|
|Infants from Prampram 50 km east of Accra on south coast of Ghana||ɛ2/ɛ2 Carriers (N = 4), ɛ4 carriers (N = 47)||Mixed||The influence of APOE polymorphism on susceptibility to malaria||ɛ2 homozygotes became infected with malaria at an earlier age than those carrying other genotypes||Wozniak et al. ||Moderate|
|British men and women with HCV infection, mean age = 41||ɛ4 Carriers (N = 42)||Mixed||APOE ɛ4 protects against severe liver disease caused by HCV||In chronically HCV-infected patients grouped according to extent of fibrosis, necroinflammation, and total Knodell score, an overrepresentation of ɛ4 was found in those whose livers were mildly affected. ɛ4 protects against severe liver damage induced by HCV||Wozniak et al. ||Moderate|
|The study samples were specimens from the brain or spleen of 14 UK patients with HSE and from the CSF of seven UK patients with HSV1 in their CSF as detected by PCR; Age not specified||N = 14 for HSE samples; N = 7 for CSF||Mixed||HSE: involvement of APOE genotype||ɛ3 and ɛ4 allele frequencies did not differ significantly between the two groups. ɛ2 is a risk factor for HSE||Lin et al. ||Low|
APOE, apolipoprotein E; 95% CI, 95% confidence interval; CSF, cerebrospinal fluid; HCV, hepatitis C virus; HSE, herpes simplex encephalitis; HSV, herpes simplex virus; OR, odds ratio.
|Subjects / Age||Sample Size||Sex||Study Scope||Major Finding||Citation||Quality of Evidence|
|Male football and male and female soccer players at University of South Carolina, Jacksonville University, Benedict College, College of Charleston, average age 19.85||All ɛ4 carriers (N = 35)||Mixed||A multicenter prospective cohort study on genetic polymorphisms associated with the risk of concussion in 1,056 college athletes||IL-6R cytokine was associated with a 3-fold greater concussion risk and ɛ4 with a 40% lower risk||Terrell et al. ||Low|
|Collegiate male football players and female soccer players, average age 19.7; [N.B. Participants completed a researcher-assisted paper and pencil assessment to indicate the athlete’s concussion history.]||ɛ4 Carriers (N = 62)||Mixed||APOE genotype and concussion in college athletes||No significant association between carrying the ɛ4 allele and history of concussion was found||Tierney et al. ||Moderate|
|APOE genotype and concussion in college athletes||ɛ4 Carriers (N = 79)||Mixed||A prospective cohort study to determine if APOE ɛ4 allele predisposes varsity athletes to concussion||The unadjusted hazard ratio for concussion for ɛ4 carriers was 1.18 (95% CI: 0.52, 2.69) compared to non-carriers. Adjustment for sex, weight, height, and team type resulted in a similar hazard ratio of 1.06 (95% CI: 0.41, 2.72), showing little effect from confounding factors||Kristman et al. ||Low|
|Black and White, male and female, college athletes from 23 schools, average age 19.7; [N.B. Subjects self-report concussion history over the previous eight years]||ɛ3/ɛ4 (N = 225), ɛ4/ɛ4 (N = 20)||Mixed||APOE, APOE promoter, and tau genotypes and risk for concussion in college athletes||Substantial evidence of an association between history of concussion and APOE genotypes and haplotypes was not seen. Cell sizes for some of the APOE genotypes were small. Compared to those with ɛ3/ɛ3, those with ɛ2/ɛ3 were at a 60% higher risk for concussion. Results were not statistically significant (OR, 1.6; 95% CI, 0.5 to 4.8)||Terrell et al. ||Moderate|
|Active duty personnel with a recent history of mild to moderate traumatic brain injury, average age 22.6||ɛ4 Carriers (N = 16)||Mixed||APOE and traumatic brain injury in a military population: evidence of a neuropsychological compensatory mechanism||Comparable performances were seen on most neuropsychological measures and better performances by ɛ4 carriers on select measures of attention, executive functioning, and episodic memory encoding||Han et al. ||Low|
|Review paper of the childhood literature on APOE and brain injury up through 2005||Review paper||Review paper||APOE and brain injury: implications for children||Contrary to the adult experience, in children ɛ4 seemed to confer protection for the brain whereas ɛ2 posed a risk||Blackman et al. ||Review paper Not applicable|
|Consecutive head injury admissions (men and women) to a regional neurosurgical unit in West Scotland, average age 35||ɛ4 Carriers (N = 324)||Mixed||The association between APOE ɛ4, age and outcome after head injury: a prospective cohort study||No overall association between APOE genotype and outcome, with 36% of ɛ4 carriers having an unfavorable outcome compared with 33% of non-carriers of ɛ4||Teasdale et al. ||High|
|Subjects recruited from Canadian traumatic brain injury clinic who experienced mild to moderate traumatic brain injury, mean age 33||ɛ3/ɛ4 (N = 16)||Mixed||Six-month recovery from mild to moderate traumatic brain injury: the role of APOE ɛ4 allele||No association was found between the presence of the ɛ4 allele and poor outcome across all measures||Chamelian et al. ||Low|
|Prospectively recruited series of patients admitted to West Scotland neurosurgical unit following head injury, median age 38||N = 89; 30 patients with ɛ4 and 59 patients without ɛ4||Mixed||Association of APOE polymorphism with outcome after head injury||17 (57%) of 30 patients with ɛ4 had an unfavorable outcome including death, vegetative state, or severe disability, compared with 16 (27%) of the 59 patients without ɛ4 (adjusted p = 0.024)||Teasdale et al. ||Low|
APOE, apolipoprotein E; 95% CI, 95% confidence interval; OR, odds ratio.
|Subjects / Age||Sample Size||Sex||Study Scope||Major Finding||Citation||Quality of Evidence|
|Subjects and ages varied. Original articles, systematic reviews, and meta-analyses of omega-3 studies in AD that were published before August 20, 2016.||Variable||Mixed||Association of DHA supplementation with AD stage in APOE ɛ4 carriers||Randomized clinical trials of omega-3 in symptomatic AD have had negative findings. Observational and clinical trials of omega-3 in the pre-dementia stage of AD suggest that omega-3 supplementation may slow early memory decline in ɛ4 carriers||Yassine et al. ||Review paper, not applicable|
|Middle-aged healthy adults (mean age 35 years, range 19–65 years)||N = 22||Mixed||DHA brain uptake and APOE ɛ4 status: a PET study with [1-11C]-DHA||Mean global gray matter DHA incorporation coefficient, k*, was significantly higher (16%) among ɛ4 carriers (n = 9) than among non-carriers (n = 13, p = 0.046)||Yassine et al. ||Moderate|
|Mini-review of APOE genotype and stress responses||Variable||Mixed||APOE genotype and stress response – a mini review||Oxidative stress and, correspondingly, mitochondrial function is affected in an APOE isoform-dependent manner with ɛ4 usually showing an increased stress response||Dose et al. ||Review paper, not applicable|
|Autopsy specimens from young adults (18–39 years old)||11 ɛ 3/ɛ3 Carriers; 1 ɛ2/ɛ3 heterozygote; 11 ɛ3/ɛ4 heterozygotes; 2 ɛ4/ɛ4 homozygotes||Mixed||Altered energy metabolism pathways in the posterior cingulate in young adult APOE ɛ4 carriers||The authors state that their results suggest the presence of dysregulation of energy metabolism in young ɛ4 carriers. They noted that young adult ɛ4 carriers displayed upregulation of specific glucose (GLUT2, GLUT3) and moncarboxylate (MCT2) transporters, the glucose metabolism enzyme hexokinase, the SCOT &AACS enzymes involved in ketone metabolism, and complexes 1, II, and IV of the mitochondrial electron transport chain. The monocarboxylate transporter (MCT4) was found to be downregulated in ɛ4 carriers||Perkins et al. ||Low|
|21 young and middle-aged participants with FAD and 12 Controls.||Six had the APOE ɛ2/ɛ3, 6 had the ɛ3/ɛ4, [Controls] and 21 had the ɛ3/ɛ3 genotype [Test]||Mixed||A study of the effect of familial AD mutations and APOE genotype on plasma signaling protein levels||Plasma levels of APOE and superoxide dismutase 1 were highest in ɛ2 carriers, lowest in ɛ4 carriers, and intermediate in ɛ3 carriers. Levels of multiple interleukins among the ɛ4 carriers demonstrated significant negative correlations with age||Ringman et al. ||Low|
|699 Subjects from Kiel Germany representing the general population of middle-aged adults, Age 63± years old. A sub-group of 93 subjects from the general population with Metabolic Syndrome; Age 45±11 years||For N = 699 Population - APOE ɛ4 = 195 and No APOE ɛ4 = 504; For N = 93 sub-group - APOE ɛ4 = 30 and No APOE ɛ4 = 63||Mixed||APOE ɛ4 is associated with higher vitamin D levels in targeted replacement mice and humans||Multivariate adjusted models calculated a positive association of the ɛ4 allele with 25(OH)D [vitamin D] levels in a subset of human subjects (n = 93; p = 0.072) and a general population sample (n = 699; p = –0.003)||Huebbe et al. ||High|
|Human brain tissue was obtained from the Douglas Hospital Research Centre Brain Bank, Canada, average age 75–79||ɛ4 Carriers (N = 18)||Mixed||Oxidative insults are associated with APOE genotype in AD brain||Within AD cases, the levels of thiobarbituric acid-reactive substances were higher among ɛ4 carriers while APOE protein concentrations were lower||Ramassamy et al. ||Low|
AD, Alzheimer’s disease; APOE, apolipoprotein E; DHA, docosahexaenoic acid; PET, positron emission tomography.
|Subjects / Age||Sample Size||Sex||Study Scope||Major Finding||Citation||Quality of Evidence|
|A total of 97 participants (48 women/49 men) between 20 and 35 years of age (Medium age = 24.3 years) with 12–20 years of education||ɛ4 Carriers (N = 29)||Mixed||APOE ɛ4 is positively related to spatial performance but unrelated to hippocampal volume in healthy young adults||Two significant patterns observed: 1) specific structural covariance of the anterior hippocampus and posterior hippocampus in all other groups co-varied with frontal, parietal and cerebellar areas; and 2) opposite structural covariance of the posterior hippocampus in ɛ4 carriers and the anterior hippocampus of ɛ4 non-carriers co-varying with motor areas and the middle frontal gyrus||Stening et al. ||Low|
|Young group (average age 21) and a mid-age group (average age 50), right-handed males and females; ɛ4 carriers in young group (N = 21) and in mid-age group (N = 17)||ɛ4 Carriers in young group (N = 21) and in mid-age group (N = 17)||Mixed||Structural and resting-state MRI detects regional brain differences in young and mid-age healthy APOE- ɛ4 carriers||There were no detectable genotype-dependent differences in hippocampal volume for either the young or mid-aged adults. The cuneas appeared to be an important locus for genotype differences with greater functional connectivity among young ɛ3/ɛ3 individuals and greater white matter volume in young ɛ4+ individuals. Subtle cortical thickness measures in the parahippocampus of our young ɛ4+ individuals positively correlated with performance in a memory task||Dowell et al. ||Moderate|
|Right-handed subjects aged 20–40, average age 24, were recruited in Oxfordshire, UK||N = 18, all ɛ4||Mixed||Reduced cerebrovascular reactivity in young adults carrying the APOE ɛ4 allele||ɛ4 Carriers had the highest task-related hippocampal BOLD signal relative to non-carriers||Suri et al. ||Low|
|93 healthy young participants were recruited (age, 20; range 18–30; 64 women, 29 men), right-handed Caucasian undergraduates at the University of Sussex||Split population of young ɛ4 and homozygous ɛ3 carriers; exact N not specified||Mixed||MRI of carriers of the APOE ɛ4 allele-evidence for structural differences in normal-appearing brain tissue in ɛ4+ relative to ɛ4- young adults||Employing voxel-based morphometry of high-resolution structural MR images, a higher white matter volume ratio in ɛ4 relative to homozygous ɛ3 carriers was observed||Dowell et al. ||Moderate|
|33 healthy young German students, average age 24, carrying either the APOE ɛ2 or the ɛ4 allele||ɛ2/ɛ3 (N = 15), ɛ2/ɛ2 (N = 2), ɛ3/ɛ4 (N = 12), ɛ4/ɛ4 (N = 4)||Mixed||Hippocampal volume differences between healthy young APOE ɛ2 and ɛ4 carriers||Healthy young ɛ4 carriers have statistically smaller hippocampal volumes than ɛ2 carriers, while no differences were detected between the two groups in memory performance||Alexopoulos et al. ||Low|
|Hemispheric and lateral ventricular volumes of 144 healthy individuals, aged 19–35 years, were measured using high resolution MRI and data were correlated with BDNF and APOE genotypes.||ɛ4 carriers (N = 20); ɛ4 Non-carriers (N = 124); BDNF Val homozygotes (N = 92); BDNF Met carriers (N = 52)||Mixed||Influence of brain-derived neurotrophic factor and APOE genetic variants on hemispheric and lateral ventricular volume of young healthy adults||No correlations between BDNF or APOE genotype and hemispheric or lateral ventricular volumes were seen||Sidiropoulos et al. ||Moderate|
|Students from University of Sussex, average age = 20.92||ɛ4 Carriers (N = 28); 26 non-ɛ4 carriers||Mixed||Disrupted neural activity patterns to novelty and effort in young adult APOE ɛ4 carriers performing a subsequent memory task||In ɛ4 carriers only, subsequently remembered words were linked to increased hippocampal activity. In the recognition phase, genotype status also modulated hippocampal activity. ɛ4 Carriers failed to show the conventional pattern of greater hippocampal activity to novel words||Evans et al. ||Moderate|
|Young healthy male and female subjects, age range 20–35 years||18 APOE ɛ4 carriers and 18 matched non-carriers||Mixed||Distinct patterns of brain activity in young carriers of the APOE ɛ4 allele||Resting fMRI imaged increased default mode network (involving retrosplenial, medial temporal, and medial-prefrontal cortical areas) co-activation in ɛ4 carriers relative to non-carriers. The encoding task induced higher hippocampal activation in ɛ4 carriers relative to non-carriers||Filippini et al. ||Low|
|Forty-one non-demented, HIV-1 seropositive adults, mean age = 45||15 ɛ4 Carriers and 26 ɛ4 non-carriers||Mixed||The APOE ɛ4 allele and memory performance in HIV-1 seropositive subjects: differences at baseline but not after acute oral lorazepam challenge||Acute lorazepam administration produced dose- and time-dependent impairments in measures of verbal recall. However, the ɛ4 allele did not modulate these adverse effects. An APOE ɛ4 group by time interaction was also found such that the APOE ɛ4-positive subjects had significantly better immediate and delayed verbal recall than the negative subjects at baseline assessment, but the groups did not significantly differ at any subsequent time point.||Pomara et al. ||Low|
|Healthy right-handed adults recruited from Lebanon, NH, median age = 63||ɛ4 Carriers (N = 13)||Mixed||Increased brain activation during working memory in cognitively intact adults with the APOE ɛ4 allele||The ɛ3/ɛ4 group displayed greater activity during working memory in medial frontal and parietal regions bilaterally and in the right dorsolateral prefrontal cortex||Wishart et al. ||Low|
|20 healthy young adults performing non-verbal memory tasks, age 19 to 28 years||4 ɛ4 Carriers and 16 non-ɛ4 carriers||Mixed||APOE related alterations in cerebral activation even at college age||Using PET imaging, specific brain regions were imaged where ɛ4 carriers showed significantly lower or higher activation than non-carriers||Scarmeas et al. ||Low|
|Normal male and female volunteers, age was 20 to 39 years||12 ɛ4 heterozygotes, all with the ɛ3/ɛ4 genotype, and 15 noncarriers of the ɛ4 allele, 12 of whom were individually matched for sex, age, and educational level||Mixed||Functional brain abnormalities in young adults at genetic risk for late-onset AD||The young adult ɛ4 carriers and noncarriers did not differ significantly in their sex, age, educational level, clinical ratings, or neuropsychological test scores. Like previously studied patients with probable AD and late-middle-aged ɛ4 carriers, the young ɛ4 carriers had abnormally low rates of glucose metabolism bilaterally in the posterior cingulate, parietal, temporal, and prefrontal cortex.||Reiman et al. ||Low|
AD, Alzheimer’s disease; APOE, apolipoprotein E; BDNF, brain-derived neurotrophic factor; BOLD, blood-oxygenation-level-dependent; fMRI, functional magnetic resonance imaging; HIV-1, human immunodeficiency virus-1; MRI, magnetic resonance imaging; PET, positron emission tomography.
|Subjects / Age||Sample Size||Sex||Study Scope||Major Finding||Citation||Quality of Evidence|
|Older Korean adults at risk for AD and 44 subjects with AD, Exact age not specified||N = 441 General population; N = 44 with AD||Mixed||Explore whether the size of the difference between carriers and noncarriers is a function of how well the tests measure general intelligence, so whether there are Jensen effects||On some neurocognitive tests, there are smaller differences between ɛ4 carriers and non-carriers, while other tests show larger differences. The method of correlated vectors on 441 Korean older adults at risk for AD and 44 with AD was used. Correlations between APOE status and test scores ranged from –0.05 to 0.11 (normal), and –0.23 to 0.54 (AD). The differences between carriers and non-carriers were Jensen effects (general intelligence): r = 0.31 and r = 0.54, respectively. A composite neurocognitive score may show a clearer contrast between APOE carriers and non-carriers than a large number of scores of single neurocognitive tests||Nijenhuis et al. ||Moderate|
|A total of 97 participants (48 women/49 men) between 20 and 35 years of age (Medium age = 24.3) with 12–20 years of education||ɛ4 Carriers (N = 29)||Mixed||Specific patterns of whole-brain structural covariance of the anterior and posterior hippocampus in young APOE ɛ4 carriers||ɛ4 Carriers performed better compared to non-carriers on Spatial Function and Memory (F  = 6.67, p < 0.05), but there no ɛ4-related differences on the Episodic Memory composite measure were observed||Stening et al. ||Moderate|
|Amazonian children from 28 villages aged 6–18.||ɛ4 Carriers (N = estimated 31 from 25% of 124 children)||Mixed||APOE ɛ4 is associated with improved cognitive function in Amazonian forager-horticulturists with a high parasite burden||After controlling for age, sex, education, and Spanish fluency, ɛ4 was positively associated with visual scan (p = 0.037) and spatial forward tasks (p = 0.032), and positively but not significantly associated with 6/8 cognitive outcomes in 124 children aged 6–18||Trumble et al. ||Moderate|
|Healthy men and women selected from the Oxford Biobank, Oxfordshire (mean age 45.5)||ɛ4 carriers (N = 20 ɛ3/4; N = 20 ɛ4/4)||Mixed||Sex and APOE: a memory advantage in male APOE ɛ4 carriers in midlife||Memory decay (forgetting) was slower in ɛ4 carriers, as measured by localization error and after controlling for misbinding errors. ɛ4 carriers made less misbinding errors. Findings were specific to male carriers only||Zokaei et al. ||Moderate|
|British male and female 18-year-olds||ɛ3/ɛ4 Carriers N = 542, ɛ4/ɛ4 Carriers N = 43||Mixed||Investigation of possible association of APOE genotype with working memory in young adults||There was no evidence of a genotype effect on accuracy when the two difficulty levels were examined separately. There was some evidence to support a deleterious effect of the ɛ4 allele on n-back accuracy in the multi-level regression. There was weak evidence that the ɛ2/ɛ2 group were less accurate, but the numbers were very low in this group. The ɛ3/ɛ4 group had faster reaction times than the reference ɛ3/ɛ3 group in all adjusted analyses but the ɛ4/ɛ4 group were only faster in the 3-back condition in multi-level analyses||Sinclair et al. ||Moderate|
|Young adults (mean age 23.8) recruited from Uppsala University||ɛ4 Carriers (N = 40)||Mixed||APOE ɛ4 is positively related to spatial performance but unrelated to hippocampal volume in healthy young adults||ɛ4 Carriers showed positive effects on spatial function and memory and object location memory, but no effect on word recognition||Stening et al. ||Moderate|
|Male and female college students from Oregon, average age = 19||ɛ4 Carriers (N = 40)||Mixed||Sex, but not APOE polymorphism, differences in spatial performances in young adults||No significant differences related to APOE types was observed on mental rotation, spatial span, and the Memory Island spatial navigation task||Yasen et al. ||Moderate|
|93 healthy young participants were recruited (age, 20; range 18–30; 64 women, 29 men), right-handed Caucasian undergraduates at the University of Sussex||Not specified||Mixed||MRI of carriers of the APOE ɛ4 allele-evidence for structural differences in normal-appearing brain tissue in ɛ4+ relative to ɛ4– young adults||In a verbal fluency task, ɛ4 carriers generated more words than non-carriers in the first two time periods for the second and third, but not the first, letter. Comparisons of means confirmed these differences to be significant only for the final letter [t(38) = 2.00, 1.70 for first and second time bins, respectively; p < 0.03, 0.05; one-tailed]||Dowell et al. ||Low|
|Subjects were aged between 19 and 24 years (Medium = 20.2 years, 14 male and 26 females).||From the 98 volunteers, 40 volunteers were selected for further study. 20 of these were either homozygous or heterozygous for ɛ4. 20 were homozygous for ɛ3. Among the ɛ4 carriers, two participants were homozygous ɛ4 carriers.||Mixed||APOE ɛ4 carriers show prospective memory enhancement under nicotine, and evidence for specialization within medial BA10||fMRI explored performance on a PM task in young adults (age 18–30) using and not using nicotine using a within-subjects design. Participants performed an ongoing task while retaining a PM instruction to respond to specific stimuli embedded in the task. Nicotine effects varied according to APOE allelic status. Reaction times to the PM cue improved under nicotine in ɛ4 carriers, but not in ɛ3 carriers||Evans et al. ||Low|
|Dutch men and women (mean age = 57)||ɛ4 Carriers (N = 116)||Mixed||APOE ɛ4 differentially influences change in memory performance depending on age (The SMART-MR Study)||In persons ≤57, ɛ4+ showed increase in immediate recall and delayed recall||Jochemsen et al. ||Moderate|
|Poor Brazilian children with below median height (mean age = 8.6)||ɛ4 Carriers (N = 37)||Mixed||APOE ɛ4 influences growth and cognitive responses to micronutrient supplementation in shantytown children from northeast Brazil||ɛ4+ children receiving glutamine supplementation presented improved short-term gains in HAZ, WAZ, and WHZ that were correlated with better performance in long-term cognitive testing||Mitter et al. ||Low|
|Males and females, Caucasian Australians, age 20–24||ɛ4 Carriers (N = 530)||Mixed||Examine if the possession of APOE ɛ4 benefits cognitive function in healthy young adults||The ɛ4 allele did not benefit cognitive performance in younger persons, nor accompany cognitive deficits in older persons||Bunce et al. ||High|
|Predominately male, HIV seronegative, mean age 46 from Hawaii||ɛ4 Carriers (N = 16)||Male||Determine the impact of APOE ɛ4 and HIV on cognition and brain atrophy: antagonistic pleiotropy and premature brain aging||ɛ4+ seronegative controls scored higher (better) than APOE- seronegative controls on the Auditory Verbal Learning Test immediate recall (p = 0.01), memory domain (p = 0.03), and trends for better performance on the learning (p = 0.09) and fluency (p = 0.10) domains||Chang et al. ||Low|
|Students of the Friedrich-Alexander University of Erlangen-Nuremberg, average age = 24.1||ɛ4 Carriers (N = 18)||Mixed||Influence of brain-derived neurotrophic-factor and APOE genetic variants on hippocampal volume and memory performance in healthy young adults||Differences in memory function between participants possessing the ɛ4 allele and those without it were not detected||Schmidinger et al. ||Low|
|Avon Longitudinal Study of Parents and Children||ɛ3/ɛ4 = 709, ɛ4/ɛ4 = 58||Mixed||IQ, educational attainment, memory and plasma lipids: associations with APOE genotype in 5,995 children||IQ was 3.6 points higher for children who carried ɛ2/ɛ2 compared with those who carried ɛ3/ɛ3 and 2.6 points higher for ɛ4/ɛ4 compared with ɛ3/ɛ3. There was a consistent pattern that ɛ2/ɛ2 and ɛ4/ɛ4 girls had higher IQ scores (from 3 to 7 points) compared with ɛ3/ɛ3 girls||Taylor et al. ||High|
|Healthy 7-10-year-old boys and girls from Oregon||ɛ4 carriers (N = 12)||Mixed||APOE ɛ4 and sex affect neurobehavioral performance in primary school children||ɛ4+ subjects were ten times more likely to be placed in an ICU after birth. ɛ4+ subjects did not show a target preference in the Memory Island paradigm. Vocabulary score on WASI and immediate and visual recall on the Family Pictures assessment was better in ɛ4+ subjects||Acevedo et al. ||Low|
|Subjects from San Diego area charter middle and high schools (average age = 13.3)||ɛ4 Carriers (N = 33)||Mixed||APOE genotype is associated with left-handedness and visuospatial skills in children||Significant differences were found on the Rey-Osterrieth Complex Figure Test, with ɛ2-positive children (29.2%) relative to ɛ3/ɛ3 (8.9%) and ɛ4-positive children (6.1%; p = 0.12)||Bloss et al. ||Moderate|
|Healthy nonsmokers aged 18–30 recruited from Sussex University||ɛ4 Carriers (N = 27)||Mixed||Positive effects of cholinergic stimulation favor young APOE ɛ4 carriers||ɛ4 allele conferred a cognitive advantage on tasks mediated by the frontal lobe. Young carriers of the ɛ4 allele showed larger cognitive benefit from procholinergic nicotinic stimulation||Marchant et al. ||Low|
|Patients with PTA||Patients with the APOE ɛ4 [N = 17 in the PTA group and N = 9 in the out of PTA group]||Mixed||Patients with the APOE ɛ4 [N = 17 in the PTA group and N = 9 in the out of PTA group]||ɛ4+ patients showed enhanced verbal memory recovery during and after emergence from post-traumatic amnesia||Noe et al. ||Low|
|Brazilian shantytown children (mean age = 8.7)||ɛ4 Carriers (N = 31)||Mixed||APOE polymorphisms and diarrheal outcomes in Brazilian shanty town children||ɛ4 protected shanty town children against heavy diarrhea outcomes, and among those with heavy diarrhea it protected against long-term sequelae||Oria et al. ||Low|
|Urban Spanish adolescents aged 13–18.5||ɛ4 Carriers (N = 76)||Mixed||Individual and combined effects of APOE and MTHFR 677C/T polymorphisms on cognitive performance in Spanish adolescents (The AVENA Study)||ɛ4 alone is not associated with cognitive performance on the Spanish version of the SRA-Test of Educational-Ability||Ruiz et al. ||Moderate|
|Lothian Birth Cohort 1936 comprising 1,091 surviving participants of the Scottish Mental Survey 1947||ɛ4 Carriers (N = 299)||Mixed||Cognitive ability at age 11 and 70 years, information processing speed, and APOE variation: The Lothian Birth Cohort 1936 Study||No significant difference seen between those with and without a copy of the ɛ4 allele in MHT IQ at age 11 years. The cognitive tests measured non-verbal endpoints||Luciano et al. ||High|
|Healthy Caucasian subjects from NY, Rhode Island, Nijmegen, Sydney, and Adelaide Australia, mean age = 27.4||ɛ4 Carriers (N = 91)||Mixed||The contribution of APOE alleles on cognitive performance and dynamic neural activity over six decades||ɛ4 group scored consistently higher on verbal fluency tasks than the ɛ3 group, across all age-bands||Alexander et al. ||Moderate|
|Young Swiss adults, average age 23||ɛ4 Carriers (N = 80 ɛ3/4; N = 6 ɛ4/4)||Mixed||Better memory and neural efficiency in young APOE ɛ4 carriers||ɛ4 carriers had better performance in delayed but not immediate recall of 30 studied words (OR = 1.6, p = 0.009). fMRI on 13 ɛ4+ subjects showed decreased brain activity over 3 runs while other alleles show increased brain activity||Mondadori et al. ||Moderate|
|Review paper on Brazilian shantytown children||Variable||Mixed||Role of APOE ɛ4 in protecting children against early childhood diarrhea outcomes and implications for later development||ɛ4 was important for cognitive development under the stress of heavy diarrhea||Oria et al. ||Review paper, Not applicable|
|Poor Brazilian children average age 10||ɛ4 Carriers (N = 21)||Mixed||APOE ɛ4 protects the cognitive development in children with heavy diarrhea burdens in northeast Brazil||ɛ4+ children with heavy diarrhea burdens showed protected cognitive development||Oria et al. ||Low|
|Han Chinese female nursing students aged 19–21||ɛ4 Carriers (N = 32)||Females||Personality traits in young female APOE ɛ4 and non-ɛ4 carriers||ɛ4+ status did not affect tridimensional personality questionnaire scores||Tsai et al. ||Low|
|Young Finnish men and women (mean age = 28)||ɛ4 Carriers (N = 20)||Mixed||The combined effects of APOE polymorphism and LDL cholesterol on cognitive performance in young adults||ɛ4+ status was associated with good performance in mental arithmetic and the association was dependent on LDL cholesterol level||Puttonen et al. ||Low|
|Infants in Mexico City||ɛ4 Carriers (N = 53)||Mixed||APOE genotype predicts 24-month Bayley Scales Infant Development Score||ɛ4+ status had 4.4 point higher 24-month Mental Development Index on Bayley Scale||Wright et al. ||Moderate|
|Czech men and women aged 25–64||ɛ4 Carriers (N = 23)||Mixed||A possible role of APOE polymorphism in predisposition to higher education||87% of ɛ4+ carriers reached higher education||Hubacek et al. ||Low|
|Caucasian children from Cleveland area||ɛ4 Carriers (N = 52)||Mixed||Study explored the hypothesis that variation in the gene encoding APOE is a factor modifying general cognitive ability||No association between APOE polymorphisms and general cognitive ability in children||Turic et al. ||Moderate|
|Han Chinese female nursing students aged 19–21||ɛ4 Carriers (N = 31)||Females||Intelligence and event-related potentials for young female human volunteer APOE ɛ4 and non-ɛ4 carriers||Modest increase in performance IQ and N100 amplitude||Yu et al. ||Moderate|
|Finnish children, adolescents, and young adults||ɛ4/ɛ3 Carriers (N = 483) and ɛ4/ɛ4 carriers (N = 50)||Mixed||Dependence between APOE phenotypes and temperament in children, adolescents, and young adults||Motor activity (even hyperactivity) in childhood and mental vitality in adolescence and young adulthood increased significantly with APOE phenotype in the order of ɛ2/ɛ2, ɛ3/ɛ2, ɛ4/ɛ2, ɛ3/ɛ3, ɛ4/ɛ3, and ɛ4/ɛ4.||Jarvinen et al. ||High|
AD, Alzheimer’s disease; APOE, apolipoprotein E; fMRI, functional magnetic resonance imaging; HAZ, height for age z-scores; HIV, human immunodeficiency virus; ICU, intensive care unit; IQ, intelligence quotient; LDL, low-density lipoprotein; MRI, magnetic resonance imaging; OR, odds ratio; PM, prospective memory; PTA, post-traumatic amnesia; WASI, Wechsler Abbreviated Scale of Intelligence; WAZ, weight for age z-scores; WHZ, weight for height z-scores.
The mechanism through which inheritance of an allele of a protein associated with cholesterol metabolism, i.e., ɛ4, exerts an increased risk for the development of AD later in life is not understood. One current hypothesis emphasizes that vulnerability to AD is based on the very high rate of formation and removal of synapses in the brain. In healthy individuals, the number of synapses formed and actively removed is estimated to be one trillion per day, presumably associated with constant learning and establishment of new memories. The amyloid-beta protein precursor (AβPP) plays a central role in this aspect of neuroplasticity . A considerable amount of evidence has related AβPP to AD , including a relationship between its Aβ product and APOE genotype . AβPP can be cleaved either by the α-secretase, which leads to increased local synapse production and prevents formation of the synapto-toxic Aβ molecule or by the β-secretase, followed by γ-secretase, which leads to the removal of the affected synapse . The control of the delicate balance between synapse creation and destruction is critical for learning and involves numerous mechanisms, with a positive neuronal action culminating in activation of the α-secretase, while activation failure leads to the default action, β-secretase cleavage, then γ-secretase cleavage of the AβPP, with the end-products being fatal to that synapse. Note that the γ-secretase appears to act only on the β-secretase product and not on the α-secretase product, producing both the Aβ and an AβPP intracellular domain (AICD) . The AICD protein, acting intracellularly, leads to hyperphosphorylation of the critical structural protein of neuronal processes, microtubule associated protein tau . The hyperphosphorylated tau appears to disrupt the normal flow in neuronal processes, leading to amputation . The initial memory impairment of AD is likely due to the failure of the process for establishing new memory, while the dementia appears to develop when synaptic slaughter destroys large numbers of synapses , and loss of synapses is the factor most closely associated with the late progression of dementia . Cholesterol metabolism, transport and processing might play a role in this process by affecting the composition of the neuronal synaptic membrane thereby altering its thickness. The extracellular region of AβPP is much longer than the intracellular region. Small differences in the availability of enzymatic cleavage sites influenced by membrane thickness might have profound effects on the ultimate production of AβPP sub-fragments [29, 30].
IMPORTANCE OF THE APOE GENOTYPE
The APOE genotype accounts for the vast majority of AD risk [31, 32]. There are three common alleles of the APOE gene, i.e., APOE ɛ2, APOE ɛ3, and APOE ɛ4 . In the general US population, the ɛ4 allele prevalence is approximately 13% , constituted by about 2% being ɛ4 homozygous (2% of the US population) and 11% being heterozygous (22% of the US population). Possession of one ɛ4 allele increases the risk of developing AD by 3 to 4-fold, and possession of two ɛ4 alleles increases risk by 15-fold, as compared with the ɛ3/ɛ3 genotype, with a large part of the variation being related to substantially early age of onset, and over 60% of patients with non-familial AD carry the ɛ4 allele [35, 36].
This profound difference in AD risk results from only minor changes in the structure of the APOE molecule. The three isoforms of APOE differ in amino acid sequence at only chain positions 112 and 158: the APOE ɛ2 allele has cysteine at both positions; the APOE ɛ4 allele has arginine at both positions; and the APOE ɛ3 allele has cysteine at position 112 and arginine at 158 . These small changes in amino acid sequence alter the biological activity of the APOE proteins in multiple ways, one of which is increased liver catabolism of the APOE ɛ4 lipoprotein as compared with the APOE ɛ3 lipoprotein [38, 39].
The strong positive association between possession of the ɛ4 allele and the development of late-onset AD has stimulated extensive investigation on young, healthy subjects differing in APOE allele status. Numerous ɛ4 allele-related associations have been reported in a series of epidemiological and clinical investigations on a variety of conditions, with the potential relevance of these associations to the pathogenesis of AD poorly understood at this time. Over the last several decades, numerous and elaborate interactions have been demonstrated between the nervous, immune, and endocrine systems . This sophisticated system of sometimes centrally mediated biochemical cross-talk opens the possibility that an association between possession of the ɛ4 allele and a particular clinical characteristic, condition, susceptibility or outcome might provide mechanistic information as to why allelic variation in a cholesterol metabolism gene is so strongly associated with the loss of synapses in the brain.
In primarily young subjects, we have attempted to review a representative body of literature on ɛ4 allele-associations related to the following: cardiovascular responses; impacts on reproduction and fetal development; co-morbidities; resistance to infectious disease; responses to head injury; biochemical differences possibly related to neural stress; and brain structure-function differences. In addition, the literature on the association between the ɛ4 allele and cognitive performance has been reviewed comprehensively. In each summary table, the ethnic composition, age, clinical diagnosis, and number of ɛ4 carriers of the cohort studied are included.
LITERATURE SEARCH STRATEGY
Using Google and PubMed of the National Library of Medicine, the search terms apolipoprotein E or ɛ4 allele were cross-matched against the terms: infant, youth, child, children, adolescent, or young. This initial search gathered a large number of potentially relevant citations that were categorized by clinical condition including cardiovascular responses; reproduction and development; co-morbidities; resistance to infectious disease; responses to head injury; biochemical differences possibly related to neural stress; brain structure-function; and mental performance. Each citation was physically collected, and the reference sections were manually checked for additional relevant citations until no further citations were found. No papers on the relevant topics were excluded. A few studies on middle age subjects not yet presenting with mild cognitive impairment were included with the aberrant age ranges clearly marked in the tables. The studies in the tables were not amenable to meta-analysis as the protocols were too heterogeneous. There were four referenced articles ([15, 47, 53, 130]) that included a meta-analysis. Some of the individual papers in the meta-analyses were also separately included in the review because the details in the individual papers were important.
METHOD FOR GRADING QUALITY OF EVIDENCE
As noted previously, the literature on associations between ɛ4 status in otherwise healthy young subjects can be subdivided into several categories including: cardiovascular responses (Table 1); reproduction and development (Table 2); co-morbidities (Table 3); resistance to infectious disease (Table 4); responses to head injury (Table 5); biochemical differences possibly related to neural stress (Table 6); brain structure-function (Table 7); and mental performance (Table 8). Each table contains seven headings including sequentially: Subject/Age; Sample Size; Sex; Study Scope; Major Finding; Citation; and Quality of Evidence. The first six headings summarize the study characteristics, its results, and citation. The seventh heading provides the reader an estimate of the quality of evidence in the study based on a recognized evidence-based rating system.
A system developed by the Grading of Recommendations Assessment, Development and Evaluation Working Group (GRADE) for ranking the quality of evidence and the strength of recommendations of scientific literature and clinical practice guideline was applied to rate the studies found in Tables 1–8 . The method described by Adkins et al.  was used to estimate the degree of confidence that can be placed on the evidence from research and clinical studies. The studies in the tables of this review represent a wide range of data (high to low) based on quality of evidence regarding main outcomes. The quality of evidence for each study was evaluated based on the following criteria.
• Study design (e.g., observational versus randomized trials);
• Study quality (i.e., detailed study methods and execution);
• Consistency (similarity of estimates of effects across like studies); and
• Directness (i.e., the extent to which the subjects, interventions, and outcomes measures are similar to those of interest).
The following definitions from the GRADE Working Group were used in grading the quality of the evidence based on the criteria above :
• High = Further research is very unlikely to change our confidence in the estimate of effect.
• Moderate = Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
• Low = Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
• Very low = Any estimate of effect is very uncertain.
It should be recognized that the ranking system is based on the quality of the evidence and not on the quality of the research, as all of the cited literature in this review was peer-reviewed.
CARDIOVASCULAR RESPONSES IN YOUNG APOLIPOPROTEIN ɛ4 CARRIERS (Table 1)
The relationship between APOE allele type and cardiovascular risk factors and responses has been extensively studied. In a large study on Finnish boys and girls (Table 1), ages 3, 6, 9, 12, 15, and 18, including 28 ɛ2/ɛ4 carriers, 483 ɛ3/ɛ4 carriers, and 50 ɛ4/ɛ4 carriers, the concentrations of serum total cholesterol, low density lipoprotein cholesterol, and apolipoprotein B increased with APOE phenotype in the order of ɛ2/ɛ2, ɛ3/ɛ2, ɛ4/ɛ2, ɛ3/ɛ3, ɛ4/ɛ3, and ɛ4/ɛ4 . In a follow-up study on Finnish male and female newborns and 3-year-old children including five ɛ2/ɛ4, 147 ɛ3/ɛ4, and eight ɛ4/ɛ4 carriers, the concentrations of serum total cholesterol and LDL cholesterol increased with APOE phenotype in the order of ɛ3/ɛ2, ɛ3/ɛ3, ɛ4/ɛ3, and ɛ4/ɛ4, in both males and females (p < 0.001) in the 3-year-olds . Another large study in 7- and 13-month-old Finnish infants included 36 ɛ4/ɛ4 and 209 ɛ3/ɛ4 carriers and reported that triglyceride concentrations were higher in infants with APOE ɛ4/ɛ4 or ɛ3/ɛ4 than in those with APOE ɛ3/ɛ3 (p-value for difference 0.01 and 0.009, respectively) . A smaller follow-up study was conducted on healthy 13-month-old Finnish children and reported that 16 APOE ɛ4 children had 30% to 50% higher cholesterol-adjusted campesterol and sitosterol concentrations in serum than 20 APOE ɛ3/ɛ3 children (p = 0.002 and p = 0.02, respectively) . In 44 ɛ4 carrier Finnish infants, fed high-fat, high-cholesterol human milk, the total and LDL-cholesterol concentrations and the LDL APOB concentration of those with the APOE phenotype ɛ4/ɛ4 or ɛ3/ɛ4 rose faster and to higher levels than in other infants . In a large study on 16-year-old Finnish boys and girls including 28 ɛ2/ɛ4 carriers, 470 ɛ3/ɛ4 carriers, and 49 ɛ4/ɛ4 carriers, physical exercise did not affect LDL cholesterol, total cholesterol, or HDL/total cholesterol in APOE ɛ4 carriers . In 1999, a study on Caucasian males in Perth, Australia, including eight pairs of ɛ3/ɛ3 and ɛ4/ɛ4 subjects matched for age and serum lipid levels, average age for the ɛ3/ɛ3 = 45 and ɛ4/ɛ4 = 42, suggested that inheritance of APOE ɛ4 is associated with an increased affinity of VLDL particles for LDL receptors on hepatocytes .
Cardiovascular endpoints in addition to blood lipid levels have also been examined. ɛ3/ɛ2 or ɛ3/ɛ3 carriers showed marginally significantly greater heart rate reactivity and significantly greater task levels of heart rate and heart rate variability during mental stress than ɛ4/ɛ2, ɛ4/ɛ3, or ɛ4/ɛ4 carriers among 28 healthy 16-year-old Finnish boys. The number of ɛ4 carriers in this study was limited at only 11 . Ellis et al.  studied 8-year-old children from the Tasmanian Infant Health Survey including 75 ɛ4 carriers and found that the ɛ4 carriers had a lower body mass index and the effect was more evident among the less fit. In addition, Yu et al.  studied young adult Chinese men and women with an approximate mean age = 32; ɛ3/ɛ4 (N = 60), ɛ4/ɛ4 (N = 13). These authors found that VO2max after exercise training increased significantly higher in carriers of ɛ3/ɛ4 in males (OR = 0.60, 95% CI = 0.09–1.11; p = 0.02) and females (OR = 0.62, 95% CI = 0.09–1.15; p = 0.02). In summary, as compared with ɛ3 carriers, young subjects possessing one or more ɛ4 alleles show significant differences in total serum cholesterol, LDL, triglycerides, heart rate variability during mental stress, and VO2max. The directionality of the reported ɛ4-associated lipid profiles is consistent with an increased risk of atherosclerosis later in life.
Possible relationship of ɛ4-related cardiovascular responses and AD
As noted in the Introduction, cholesterol metabolism might play a role in slightly altering the thickness of the synaptic membrane. Synaptic membrane thickness could potentially affect the location of the cleavage site for γ-secretase [29, 30] AβPP sub-fragments possibly being more potent for synaptic remodeling and learning, including playing a role in tau phosphorylation for synapse retraction, could also possess increased pathogenicity for the elderly, leading to tau hyperphosphorylation, the creation of paired-helical filaments, neuropil threads, and NFTs, with amputations of neuritic processes and massive destruction of synapses.
REPRODUCTION AND DEVELOPMENT IN APOLIPOPROTEIN ɛ4 CARRIERS (Table 2)
A limited number of studies have examined potential associations between APOE ɛ4 carrier status and fertility. In 2017, van Exel et al.  studied 100 women with a history of at least two first-trimester recurrent miscarriages in Tabriz, Iran, and 100 healthy women with at least two successful pregnancies and no miscarriages. This study incorporated 31 ɛ4 carriers and showed that APOE ɛ4 was associated with higher fertility in women exposed to high pathogen levels. In 2004, Corbo et al.  reported similar results in a population of Afro-Ecuadorian and Cayapa Indian women, average age 39; ɛ4 carriers (ɛ3/ɛ4 = 16; ɛ4/ɛ4 = 6; ɛ4/ɛ2 = 5). These authors reported that the ɛ3/ɛ4 genotype frequency (0.50) in the African-Ecuadorian women with 9–17 children was about three times that of the women with 0–8 children (0.14) (p = 0.02). In contrast with these reportedly positive effects on fertility in populations without access to birth control methods, Gerdeset al.  studied a cohort of 40-year-old married men residing in Aarhus Denmark; ɛ4 carriers (ɛ3/ɛ4 = 93; ɛ4/ɛ4 = 12; ɛ4/ɛ2 = 9) and found that on average, men with the ɛ3/ɛ3 genotype (n = 212) had 1.93 children, men with the ɛ3/ɛ4 or ɛ2/ɛ2 genotypes (n = 53) had 1.66 children. The potential confounding effects of the widespread availability of birth control methods in Denmark and the low average number of children per couple questions the clinical relevancy of these findings as per the association of the ɛ4 allele and fertility.
Several studies have investigated the possible relationship between APOE ɛ4 carrier status and occurrence of fetal miscarriages. A single study has reported a protective effect of the ɛ4 allele . Some studies do not report an association between ɛ4 status and fetal loss [56–58]. At least five studies and one meta-analysis report a positive association between possession of the ɛ4 allele and fetal loss [59–65]. Several additional studies have examined the association between ɛ4 carrier status and a variety of pregnancy-related conditions. Gaynor et al.  studied White, Black, and Hispanic neonates and infants; ɛ4 carriers (N = 87) and reported that the APOE ɛ2 allele was associated with a lower Psychomotor Development Index (p = 0.038). Pregnant women with the ɛ4 allele displayed an increased risk to develop Pregnancy Induced Hypertension (OR 4.14, p = 0.013) and severe preeclampsia (OR 4.43, p = 0.019) in a group of pregnant Romanian women, average age 28; ɛ4 carriers (N = 46) . Cerebrospinal fluid (CSF) was collected from 107 healthy Japanese subjects (70 males, 37 females) aged 1–86 by Hirayama et al.  who showed that the APOE phenotype does not affect the composition or concentration of CSF high density lipoprotein in children. In 2003, Gaynor et al.  studied Asian, Black, and White, male and female infants under 6 months undergoing cardiac surgery in Philadelphia; ɛ4 carriers (N = 52) and reported that patients with the ɛ2 allele had approximately a 7-point decrease in the Psychomotor Developmental Index [Bayley Scales of Infant Development] (p = 0.036).
In summary, the most notable findings related to fertility and the ɛ4 allele suggest a protective effect of ɛ4+ status and reproductive potential in populations exposed to high pathogen levels.
Possible relationship between ɛ-related reproduction and development and AD
The ɛ4 allele is the ancestral allele to the now more common ɛ3 allele. Protective effects on fertility and reproduction might help explain the original predominance of the ɛ4 allele. The impetus for the conversion from ɛ4 to ɛ3 predominance is currently not understood.
CO-MORBIDITIES IN YOUNG APOLIPOPROTEIN ɛ4 CARRIERS (Table 3)
A number of epidemiology studies have reported co-morbidities associated with possession of different APOE alleles (Table 1). Co-morbidities represent an important area of study as co-linearity in prevalence between clinical conditions of known etiology with clinical conditions whose current etiology is unknown (e.g., AD) might provide clues related to causation. A meta-analysis of 28 studies on schizophrenia reported a significant protective effect of ɛ3 in an Asian population . Another meta-analysis found a significant decrease in risk associated with each copy of ɛ4 in all age-related macular degeneration sub-phenotypes . A dermatology clinic in Spain reported that APOE ɛ4 carriers were significantly more frequent in patients with severe psoriasis compared to controls (p = 0.003) and to non-severe psoriasis (p = 0.017). Infants with hypoxic-ischemic encephalopathy did not show an association with APOE allele type . In contrast, the percentage of children with at least one ɛ4 allele was significantly lower in non- Sudden infant death syndrome (SIDS) compared to SIDS (p = 0.016) in a study of infants from Scotland. Several studies have examined the potential relationship between APOE allele type and cerebral palsy. In children seen in Brasilia, Brazil, of whom 139 were ɛ4 carriers, the presence of the ɛ2 allele raised the probability of having cerebral palsy (OR 3.2; 95% CI 1.27–8.27) while the APOE ɛ4 allele was not significantly different among groups . An earlier smaller study on Brazilian children that included only 13 ɛ4 carriers, reported a positive association between the ɛ4 allele and cerebral palsy , as did a study on children from Chicago that included 25 ɛ4 carriers .
Possible relationship between ɛ4-related co-morbidities and AD
The mechanism by which possession of the ɛ4 allele exerts its increase risk of AD is currently unknown. Concomitantly, the mechanistic relationships between co-morbid clinical conditions and the ɛ4 allele, and risk of AD, are also not understood. As mechanistic relationships on AD causation are elucidated in the future, ɛ4-related co-morbidities might provide additional mechanistic insights.
RESISTANCE TO INFECTIOUS DISEASE IN APOLIPOPROTEIN ɛ4 CARRIERS (Table 4)
The potential relationship between resistance to infectious diseases and APOE allele status represents an important area of investigation as this environmental stressor can exert significant evolutionary pressures. The relationship between hepatitis C infection and APOE carrier status has been examined in several studies. Mueller et al.  enrolled 205 ɛ4 carriers in two combined cohorts selected from patients from Charite Berlin and the University of Leipzig diagnosed with either chronic or self-limited hepatitis C virus infection. The average age of the patients was 48.7. These authors found that APOE ɛ4 alleles were underrepresented in chronically hepatitis C-infected patients (10.2%) compared to 13% in healthy controls (p = 0.001).
Male and female Caucasian Italian patients with chronic hepatitis C, median age = 41; ɛ2/ɛ4 carriers (N = 3), ɛ3/ɛ4 carriers (N = 21), ɛ4/ɛ4 carriers (N = 1) were studied by Fabris et al. . They reported that patients not carrying an ɛ3 allele, as well as carriers of a single ɛ3 allele with serum cholesterol concentration >190 mg/dL were more likely to have a favorable outcome regarding fibrosis progression with chronic hepatitis C. In an earlier study, Fabris et al.  investigated Italian male and female patients who underwent a cadaveric orthotopic liver transplantation, median age 55; ɛ4 carriers (N = 34). Their results showed that possession of an APOE ɛ4 allele to be associated with low fibrosis progression in recurrent hepatitis C infection, and with an idiosyncratic APOE-associated lipid profile. Price et al.  found that the APOE ɛ2 and APOE ɛ4 alleles were both associated with a reduced likelihood of chronic infection (hepatitis C virus). For ɛ2, OR = 0.39[95% CI = 0.211–0.728] (p = 0.003), and for ɛ4, OR = 0.6[95% CI = 0.38–0.96] (p = 0.032), in a study population of British and Irish Caucasian hepatitis C patients; ɛ2 carriers (N = 48), ɛ4 carriers (N = 84), 11 carriers were both, i.e., ɛ2/ɛ4. Twenty-four male and female patients, median age = 53.5, with recurrent hepatitis C following cadaveric orthotopic liver transplantation; ɛ4 carriers (N = 12) of 48 donors, ɛ4 carriers (N = 17) of 48 recipients were studied by Toniutto et al. . These authors found that recipient (but not donor) carriage of at least one ɛ4 allele was associated with improvement in the staging score due exclusively to the contribution given by male recipients. Similarly, Wozniak et al.  observed British men and women with hepatitis C viral infection, mean age = 41; ɛ4 carriers (N = 42) and concluded that in chronically hepatitis C virus-infected subjects grouped according to extent of fibrosis, necroinflammation, and total Knodell score, an overrepresentation of the APOE ɛ4 allele was found in those whose livers were mildly affected. These authors suggested that carriage of an APOE4 ɛ4 allele protects against severe liver damage induced by hepatitis C virus.
Although not as extensively studied as hepatitis C infection, the relationship between resistance to malaria and APOE allele status has also been examined in several studies. Fujioka et al.  showed that human plasma samples from APOE ɛ4/ɛ4 but not APOE ɛ3/ɛ3 donors inhibited growth and disrupted morphology of P. falciparum (malaria) in seven APOE ɛ4/ɛ4 and six APOE ɛ3/ɛ3 donors from Cleveland, OH, USA. Aucan et al.  observed Gambian children ages 1–10; ɛ4 carriers (N = 244) and concluded that the APOE ɛ3/ɛ4 genotype was found to be more common in children with both cerebral malaria and severe malarial anemia (42.9%) than in controls (24.8%) and mild malaria cases (27.2%). When corrected for the number of clinical groups (4) compared with controls in this study, this finding was not statistically significant. An earlier study on African infants was reported by Wozniak et al. . This group studied infants from Prampram, 50 km east of Accra on the south coast of Ghana; ɛ2/ɛ2 carriers (N = 4), ɛ4 carriers (N = 47). Based on small numbers, APOE ɛ2 homozygotes became infected with malaria at an earlier age than those carrying other genotypes.
At least one study on a potential relationship between APOE allele status and risk for development of herpes simplex encephalitis has been conducted in the United Kingdom . These authors examined specimens from the brain or spleen of 14 patients with herpes simplex encephalitis and from the CSF of seven patients with HSV1 in their CSF detected by PCR. Lin et al.  concluded that APOE ɛ3 and ɛ4 allele frequencies did not differ significantly between the two groups, and that APOE ɛ2 is a risk factor for herpes simplex encephalitis. In summary, possession of the ɛ4 allele might provide some measure of protection against hepatitis C and malaria.
Possible relationship between ɛ4-related resistance to infectious disease and AD
ɛ4 allele-associated resistance to infectious diseases endemic in prehistoric populations is consistent with the ancestral predominance of the ɛ4 allele. Evolutionary pressures or mechanisms that influenced the conversion of human populations from ɛ4 predominance to ɛ3 predominance remainunexplained.
RESPONSES TO HEAD INJURY IN YOUNG APOLIPOPROTEIN ɛ4 CARRIERS (Table 5)
Several studies have been conducted on the association between APOE allele frequency and either susceptibility to head injury, or recovery from head injury. In a 2018 study by Terrell et al.  on a cohort of male football and male and female soccer players (average age 19.85) from four US southern universities that enrolled 35 ɛ4 carriers, IL-6R CC was associated with a three times greater concussion risk and APOE ɛ4 with a 40% lower risk. In a similar cohort with 62 ɛ4 carriers, Tierney et al.  found no significant association between carrying the ɛ4 allele and history of concussion. However, Tierneyet al.  stated that they assessed the medical history via researcher-assisted paper and pencil assessment, attempting to indicate the athlete’s concussion history. Collegiate student athletes from the University of Toronto, average age 20.5, with 79 ɛ4 carriers were studied by Kristman et al.  with a small statistically significant positive association reported as stated by the authors of an unadjusted hazard ratio for concussion in the APOE ɛ4 carriers of 1.18 (95% CI: 0.52, 2.69) compared to non-carriers. Adjusting for sex, weight, height, and team type resulted in an only slightly lower hazard ratio of 1.06 (95% CI: 0.41, 2.72), indicating little effect from confounding factors. A somewhat larger study that relied upon self-reported concussion history over the previous eight years was conducted by Terrell et al.  on Black and White, male and female, college athletes from 23 schools, average age 19.7; ɛ3/ɛ4 (N = 225), ɛ4/ɛ4 (N = 20). Terrell et al.  summarized their results as showing no substantial evidence of an association between a history of concussion and APOE genotypes and haplotypes. However, the authors also noted that the cell sizes for some of the APOE genotypes were so small that meaningful analysis was not possible. Also, compared to those with the APOE ɛ3/ɛ3 genotype, those with the ɛ2/ɛ3 genotype were at a 60% higher risk for concussion, but the results were not statistically significant (OR, 1.6; 95% CI, 0.5 to 4.8). In summary, the association between possession of the APOE ɛ4 allele and risk of concussion is unclear at this time due to methodological limitations in determination of concussion history and limited sample sizes.
Han et al.  conducted a study on active duty military personnel with a recent history of mild to moderate traumatic brain injury, average age 22.6; ɛ4 carriers (N = 16). Their analysis showed comparable performances on most neuropsychological measures and better performances by ɛ4 carriers on select measures of attention, executive functioning and episodic memory encoding. Merritt et al.  reported data on 53 veterans with a history of mild traumatic brain injury and 46 military controls and found that traumatic brain injury ɛ4 carriers had relative impairments in memory function and speed of processing but not on executive function relative to traumatic brain injury-affected veterans without an ɛ4 allele. However, there was no ɛ4-related difference among the non-traumatic brain injury military controls.
In a relatively large study (ɛ4 carriers N = 324) enrolling consecutive head injury admissions (men and women) to a regional neurosurgical unit in West Scotland, average age 35, Teasdale et al.  found no overall association between APOE genotype and outcome. Thirty-six percent of APOE ɛ4 carriers had an unfavorable outcome compared with 33% of non-carriers of APOE ɛ4. This relatively large study was a follow-up to a smaller study conducted by Teasdale et al. in 1997  on only 30 ɛ4 carriers. Another small study on 16 ɛ3/ɛ4 subjects recruited from a Canadian traumatic brain injury clinic who experienced mild to moderate traumatic brain injury, mean age 33, was conducted by Chamelian et al. . These authors reported no association between the presence of the APOE ɛ4 allele and poor outcome across all measures. In 2005, Blackman et al.  reviewed the childhood literature on APOE and brain injury up through 2005 and concluded that results from the limited studies in children were contrary to the adult experience with ɛ4 seeming to confer protection for the brain whereas ɛ2 posed a risk. Further larger studies are needed to definitively determine the role of APOE status on recovery from brain injury in young subjects.
Possible relationship between ɛ4-related responses to head injury and AD
To date, a definitive relationship between ɛ4 status and recovery from head injury has not been established. If ɛ4 possession was established as associated with poor recovery from head injury, poor recovery could be consistent with an ɛ4-associated increase in neural stress. Damage from accumulated neural stress might be a contributing factor to AD.
BIOCHEMICAL DIFFERENCES POSSIBLY RELATED TO NEURAL STRESS IN APOLIPOPROTEIN ɛ4 CARRIERS (Table 6)
The strongest direct evidence that some of the macromolecular components comprising the synapses of ɛ4 carriers might be turned over at a higher rate than comparable macromolecular synaptic components in non-ɛ4 carriers has been provided by Yassine et al. . This group studied 22 middle-aged healthy adults (mean age 35 years, range 19–65 years) and found that k*, the mean global gray matter DHA incorporation coefficient, was significantly higher (16%) among ɛ4 carriers (n = 9) than among non-carriers (n = 13, p = 0.046). Also in 2017, the same group  reviewed original articles, systematic reviews, and meta-analyses of omega-3 studies in AD that were published before August 20, 2016 and concluded that while randomized clinical trials of omega-3 in symptomatic AD reported negative findings, several observational and clinical trials of omega-3 in the pre-dementia stage of AD suggest that omega-3 supplementation might slow early memory decline in ɛ4 carriers. Tambini et al.  conducted an in vitro experiment whose results are consistent with the increased lipid metabolism observed by Yassine et al. . Using an astrocyte-conditioned media model, this group measured the synthesis of phospholipids and cholesteryl esters and reported a significant increase in cells treated with APOE ɛ4-containing astrocyte-conditioned media as compared to those treated with APOE ɛ3-containing-astrocyte-conditioned media.
Dose et al.  conducted a mini-review of APOE genotype and stress responses. From their analysis of the evidence on APOE isoform-dependent oxidative stress and mitochondrial function these authors concluded that APOE4 is associated with an increased stress response. Ramassamy et al.  conducted a brain tissue study whose results are consistent with the observations of Dose et al. . They obtained human brain tissue from the Douglas Hospital Research Centre Brain Bank, Canada, average age 75–79; ɛ4 carriers (N = 18). Among ɛ4 carriers with AD, the levels of thiobarbituric acid-reactive substances were found to be higher among ɛ4 carriers while the APOE protein concentrations were lower.
At least one small study has examined the potential association between vitamin D and APOE allele status . In a sub-group of 93 subjects from a general population sample of 699 subjects (age of subjects unknown), multivariate adjusted modeling showed a positive association (p = 0.072) of the APOE ɛ4 allele with 25(OH)D [vitamin D] levels. Another small study was conducted in 2012 by Ringman et al.  wherein thirty-three subjects were studied including six ɛ2/ɛ3, six ɛ3/ɛ4, and 21 ɛ3/ɛ4 allele combinations. Plasma levels of APOE and superoxide dismutase 1 were lowest in ɛ4 carriers, intermediate in ɛ3 carriers, and highest in the ɛ2 carriers. In contrast, multiple plasma interleukins were highest in ɛ4 carriers and demonstrated significant negative correlations with age. Larger studies similar to those conducted by Yassine et al. would be helpful in clarifying the association of neural stress/macromolecular turnover rate with allele subtype.
Possible relationship between ɛ4-related biochemical changes related to neural stress and AD
If the hippocampal neurons of two individuals possess the same susceptibility to an endogenous or exogenous stress factor, the neurons with the highest turnover of proteins, lipids, and other macromolecules might experience a larger integrated dose of detriment.
BRAIN STRUCTURE-FUNCTION DIFFERENCES IN YOUNG APOLIPOPROTEIN ɛ4 CARRIERS (Table 7)
Studies on brain structure
Several studies have reported subtle differences in brain structure in association with APOE allele status. Stening et al.  studied 29 ɛ4 carriers in their subject population of 97 participants (48 women/49 men) between 20 and 35 years of age (M = 24.3) with 12–20 years of education (M = 15). These authors reported the emergence of two different patterns. The first pattern showed that specific structural covariance of the anterior hippocampus and posterior hippocampus in all other groups co-varied with frontal, parietal and cerebellar areas. The second pattern displayed an opposite structural covariance of the posterior hippocampus in ɛ4 carriers and the anterior hippocampus of ɛ4 non-carriers co-varying with motor areas and the middle frontal gyrus. Given the small subject numbers, and uncertainty of the clinical significance of these differences in anatomic ratios, the relevance to the development of AD pathology and the later appearance of dementia is unknown.
A young group (average age 21) and a mid-age group (average age 50), of right-handed males and females with 21 ɛ4 carriers in the young group and 17 in the mid-age group (N = 17) was investigated by Dowell et al. . They found no detectable genotype-dependent differences in hippocampal volume for either the young or mid-aged adults. Also, the cuneus appeared to be an important locus for genotype differences with greater functional connectivity among young ɛ3/ɛ3 individuals and greater white matter volume in young ɛ4+ individuals. These authors also reported subtle cortical thickness measures in the parahippocampus in the young ɛ4+ individuals positively correlated with performance in a memory task. This 2016 study was a follow-up to an earlier study published by Dowell et al. . The earlier 2013 study enrolled 93 healthy young participants (age, 20; range 18–30; 64 women, 29 men), right-handed Caucasian undergraduates at the University of Sussex. The authors summarized their results using voxel-based morphometry of high-resolution structural MR images as identifying a higher white matter volume ratio in ɛ4 relative to homozygous ɛ3 carriers.
In 2011, Alexopoulos et al.  reported that healthy young APOE ɛ4 carriers have statistically smaller hippocampal volumes than APOE ɛ2 carriers. No differences were detected between the two groups in memory performance. The study population in Alexopoulos et al.  consisted of 33 healthy young German students, average age 24, carrying either the APOE ɛ2 or the ɛ4 allele: ɛ2/ɛ3 (N = 15), ɛ2/ɛ2 (N = 2), ɛ3/ɛ4 (N = 12), ɛ4/ɛ4 (N = 4).
In a study incorporating 20 ɛ4 carriers, Sidiropoulos et al.  found no correlations between brain derived neurotrophic factor (BDNF) or APOE genotype and hemispheric or lateral ventricular volumes. The study measured the hemispheric and lateral ventricular volumes of 144 healthy individuals, aged 19–35 years, using high resolution magnetic resonance imaging (MRI) and data were correlated with BDNF and APOE genotypes.
Studies on brain function
In addition to imaging studies that have been conducted on brain morphology, several studies have examined brain function in association with ɛ4 carrier status. In 2009, Filippini et al.  conducted resting functional MRI (fMRI) on 18 young healthy male and female APOE ɛ4 carriers and 18 matched non-carriers (age range 20–35). These authors observed increased default mode network (involving retrosplenial, medial temporal, and medial-prefrontal cortical areas) co-activation in ɛ4 carriers relative to non-carriers. Also, the encoding task produced greater hippocampal activation in ɛ4 carriers relative to non-carriers. Scarmeas et al.  studied 20 healthy young adults (age 19 to 28 years; four ɛ4 carriers and 16 non-ɛ4 carriers) during a non-verbal memory task. Using PET imaging, brain regions were identified where ɛ4 carriers showed significantly lower or higher activation than non-carriers. Young ɛ4 carriers had abnormally low rates of glucose metabolism bilaterally in the posterior cingulate, parietal, temporal, and prefrontal cortex in 139 20–39 age range, normal male and female volunteers, average age 31; ɛ4 carriers (N = 12) . The small subject numbers, high cost and labor intensity of imaging modalities, and heterogeneity of protocol design renders definitive interpretation of these structure and function studies problematic. However, lower brain metabolism in association with task performance can reasonably be assumed to represent a lower level of neural stress per unit time. Perhaps protocol design of imaging studies on metabolic demand should consider studying the brain areas recruited for tasks showing the greatest performance differential between ɛ3 and ɛ4 carriers.
Evans et al.  examined students from the University of Sussex, average age = 20.92; ɛ4 carriers (N = 28). In ɛ4 carriers only, these authors found that subsequently remembered words were linked to increased hippocampal activity. Additionally, Evans et al. reported that genotype status modulated hippocampal activity in the recognition phase . Carriers of ɛ4 did not show the conventional pattern of greater hippocampal activity to novelwords.
Dennis et al.  enrolled 24 healthy young adults, 12 carriers and 12 non-carriers of the APOE ɛ4 allele, and scanned them in a subsequent memory paradigm, using event-related fMRI. These authors reported that the APOE ɛ4 allele carriers exhibited greater bilateral medial temporal lobe activity relative to the non-carriers to accomplish the same encoding task. In addition, ɛ4 carriers demonstrated greater functional connectivity of encoding success activity-related medial temporal lobe activity with the posterior cingulate and other peri-limbic regions, with overall connectivity reductions found across anterior and posterior cortices.
Possible relationship between ɛ4-related brain structure and brain function and AD
Preliminary imaging data suggest that certain brain regions related to memory processes might contain fewer neurons in carriers of the ɛ4 allele than in non-carriers. Studies suggest the presence of increased mental performance in young healthy subjects who possess the ɛ4 allele. Increased mental performance elicited from a reduced population of neurons might be exposing the young healthy ɛ4+ brain to neural stress. The process of synaptic formation and normal homeostatic synaptic loss might be adversely impacted by long-term neural stress.
MENTAL PERFORMANCE IN YOUNG APOLIPOPROTEIN ɛ4 CARRIERS (Table 8)
At least 32 studies or meta-analyses have examined mental performance in young APOE ɛ4 carriers. No effect of the APOE allele was reported in six studies [112–117]. All six of the study populations reporting no effect were Caucasian and lived in the United States, United Kingdom, or Western Europe. A single study  on only 33 ɛ4 carriers reported inferior performance associated with possession of ɛ4. Significant differences were found on the Rey-Osterrieth Complex Figure Test, with ɛ2-positive children scoring 29.2% relative to ɛ3/3 at 8.9% and ɛ4-positive children at 6.1% (p = 0.12).
Three studies reported improved performance in spatial tasks in ɛ4 carriers [102, 119, 120]. A large British study (ɛ3/4 = 542, ɛ4/4 = 43) showed faster reaction times in association with the ɛ4 allele . In a series of studies, Oria et al. [122–124] have shown that possession of the ɛ4 allele protects against long-term cognitive deficits associated with severe diarrhea in Brazilian shanty-town children. In young Finnish men and women (mean age = 28), ɛ4 carriers (N = 20), ɛ4+ status was associated with good performance in mental arithmetic and the association was dependent on LDL cholesterol level .
Two studies have reported a higher IQ in ɛ4 carriers. In a large British study , there was a consistent pattern that ɛ2/ɛ2 and ɛ4/ɛ4 girls had higher IQ scores (from 3 to 7 points) compared with ɛ3/ɛ3 girls. A small study (31 ɛ4 carriers) on Han Chinese female nursing students showed a modest increase in performance IQ and N100 amplitude for ɛ4 carriers (p = 0.038 and 0.068, respectively) . Using the same cohort of nursing students reported in Yu et al. , ɛ4+ status did not affect tridimensional personality questionnaire scores . In contrast with the lack of correlation with personality reported in the small cohort of Tsai et al. , a large study on Finnish children, adolescents, and young adults [ɛ4/ɛ3 (N = 483) and ɛ4/ɛ4 (N = 50)] reported that motor activity and even hyperactivity in childhood, and mental vitality in adolescence and young adulthood increased significantly in the order of ɛ2/ɛ2, ɛ3/ɛ2, ɛ4/ɛ2, ɛ3/ɛ3, ɛ4/ɛ3, and ɛ4/ɛ4 . In addition, ɛ4 carriers displayed a wider field of attention in two tasks .
Several studies have reported better performance on memory tasks in young subjects possessing the ɛ4 allele [131–136]. Comparatively enhanced verbal fluency has also been observed in ɛ4 allele carriers [137, 104]. In a study on 53 infants in Mexico City who were ɛ4 carriers, ɛ4+ status had a 4.4 point higher 24-month Mental Development Index on the Bayley Scale . A small study from the Czech Republic on 23 ɛ4+ subjects suggested that early life cognitive advantages might persist through young adulthood as 87% of ɛ4+ carriers reached higher education .
The results from two studies suggest that the cognitive response to particular pharmacologic agents might be affected by APOE ɛ4 status. Twenty-seven ɛ4 carriers who were healthy nonsmokers, aged 18–30 recruited from Sussex University demonstrated that the ɛ4 allele confers a cognitive advantage on tasks mediated by the frontal lobes. In addition, young carriers of the ɛ4 allele show larger cognitive benefit from procholinergic nicotinic stimulation . In the second study, poor Brazilian children with below median height (mean age = 8.6), including 37 ɛ4 carriers reported that ɛ4+ children receiving glutamine supplementation showed short-term gains in HAZ (height for age Z score), WAZ (weight for age Z score) and WHZ (weight for height Z score) that were correlated with better performance in long-term cognitive testing .
In this review of cognition and APOE allele genotype, our emphasis has been on ɛ-related clinical and performance associations in young rather than middle-age subjects. Several recent studies on middle age cohorts might address the issue of transition from ɛ4-associated cognitive advantage to cognitive deficit. In an older cohort with an average age for ɛ4 carriers of 58.0 and non-carriers of 61.4, Caselli et al.  sought to determine the age at presentation of ɛ4-related declines in memory. They enrolled 815 subjects: 317 ɛ4 carriers, 79 of whom were ɛ4/ɛ4 and 238 ɛ3/ɛ4. The non-carrier group contained 498 subjects. Carriers were followed for a longer period (5.3 versus 4.7 years, p = 0.01), with an equivalent duration of formal education (15.4 years) and proportion of women (69%). Longitudinal decline in memory in ɛ4 carriers began before age 60 and showed greater acceleration than in non-carriers (p = 0.03). There was a possible ɛ4 dose effect (p = 0.008). In 2017, Lancaster et al. published a systematic and meta-analytic review of 36 studies on subjects ranging from 35–60 years old investigating APOE-related differences in cognition in mid-adulthood . The average effect size of ɛ4 status was non-significant across cognitive domains. Sinclair et al.  studied 114 participants with the allelic combinations of ɛ3/ɛ3 (39 subjects), ɛ3/ɛ4 (27 subjects), ɛ4/ɛ4 (15 subjects), ɛ3/ɛ2 (26 subjects), and ɛ2/ɛ2 (7 subjects). The primary outcome was performance on the Rey Auditory Verbal Learning Test (RAVLT). ɛ2 carriers displayed slightly better episodic memory performance (p = 0.016), somewhat improved n-back accuracy and better executive functioning (p = 0.005).
Possible relationship between ɛ4-related increases in mental performance and AD
The observation of increased mental performance in young healthy carriers of the ɛ4 allele is consistent with the observation of increased brain lipid metabolism. Taken together, these observations suggest that macromolecular turnover rates related to synapse formation and loss might be elevated in these young ɛ4 carriers. It is possible that a higher rate of synaptic turnover leads to increased accumulation of non-repaired molecular errors.
The weight-of-the-evidence presented in Tables 1–8 supports the hypothesis that the possession of the ɛ4 allele in youth may have a positive differential impact on fitness during different life stages . Young subjects having at least one copy of the ɛ4 allele reportedly possess a number of advantages that might facilitate survival in harsh environments including the following among others: more rapid improvement in VO2max following exercise ; increased fertility at high pathogen burdens [52, 53]; more rapid infant development ; prophylaxis against cognitive deficits associated with severe diarrhea [122–124]; resistance to certain infections, e.g., hepatitis  and malaria ; faster reaction times ; better spatial memory [111, 102, 119, 120]; and slight superiority in direct or indirect measures of IQ [135, 134, 126, 141]. Some of these advantages appear to come at the expense of differences in neural processing that might place higher metabolic demands per unit time on the brains of young ɛ4 carriers [143, 111, 96].
Until 300,000 years ago, ancestors of modern humans were ubiquitously ɛ4/ɛ4 and then the ɛ3 allele mutated from the ancestral ɛ4 allele . The ɛ3 allele displayed a competitive survival advantage sufficiently robust to result in the current predominance of the ɛ3/ɛ3 genotype which is now found in over 60% of the US population, presumably because of its protection for memory loss and dementia in progressively older age ranges . Similarly, the ɛ2 allele mutated from the ɛ3 allele about 200,000 years ago, but this protective allele has remained relatively rare with the homozygous ɛ2/ɛ2 variant less than 1%, and the ɛ3/ɛ2 heterozygote in about 11% of the population .
Given the ancestral primacy of the ɛ4 allele, and the evolutionary trade-off of superior performance in youth versus additional years beyond historical lifespans, the abnormality of the ɛ4 allele is somewhat a matter of perspective. If part of the APOE ɛ4-associated neurotoxic susceptibility is based on pharmacokinetic rather than toxicant receptor interactions on a per mole basis , future therapies that slow down synaptic pruning might carefully consider differential effects based on APOE allele subtype. Current knowledge of potential sources of AD patient heterogeneity is lacking. Reducing at least one important source of inter-subject heterogeneity, i.e., APOE ɛ4 allele carrier status, is advisable. Early attempts at shifting the balance away from synaptic pruning might consider enrolling early stage AD patients possessing at least one ɛ4 allele.
Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/18-1089r3).
Jarvik L (1990) Alzheimer’s original paper. Am J Psychiatry 147, 127.
Blessed G , Tomlinson BE , Roth M (1968) The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects. Br J Psychiatry 114, 797–811.
Brun A , Gustafson L (1976) Distribution of cerebral degeneration in Alzheimer’s disease. A clinico-pathological study. Arch Psychiatr Nervenkr 223, 15–33.
Braak H , Braak E (1996) Evolution of the neuropathology of Alzheimer’s disease. Neurol Scand Suppl 165, 3–12.
Ashford JW , Shih WJ , Coupal J , Shetty R , Schneider A , Cool C , Aleem A , Kiefer VH , Mendiondo MS , Schmitt FA (2000) Single SPECT measures of cerebral cortical perfusion reflect time-index estimation of dementia severity in Alzheimer’s disease. J Nucl Med 41, 57–64.
Small GW , Kuhl DE , Riege WH , Fujikawa DG , Ashford JW , Metter EJ , Mazziotta JC (1989) Cerebral glucose metabolic patterns in Alzheimer’s disease. Effect of gender and age at dementia onset. Arch Gen Psychiatry 46, 527–532.
Langbaum JB , Chen K , Lee W , Reschke C , Bandy D , Fleisher AS , Alexander GE , Foster NL , Weiner MW , Koeppe RA , Jagust WJ , Reiman EM (2009) Categorical and correlational analyses of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Neuroimage 45, 1107–1116.
Schwarz AJ , Yu P , Miller BB , Shcherbinin S , Dickson J , Navitsky M , Joshi AD , Devous MD Sr. , Mintun MS (2018) Regional profiles of the candidate tau PET ligand 18F-AV-1451 recapitulate key features of Braak histopathological stages. Brain 139, 1539–1550.
Tosun D , Landau S , Aisen PS , Petersen RC , Mintun M , Jagust W , Weiner MW (2017) Association between tau deposition and antecedent amyloid-beta accumulation rates in normal and early symptomatic individuals. Brain 140, 1499–1512.
Ashford JW , Kolm P , Colliver JA , Bekian C , Hsu LN (1989) Alzheimer patient evaluation and the mini-mental state: Item characteristic curve analysis. J Gerontol 44, P139–P146.
Ashford JW (2008) Screening for memory disorders, dementia, and Alzheimer’s disease. Aging Health 4, 399–432.
Ashford JW , Jarvik L (1985) Alzheimer’s disease: Does neuron plasticity predispose to axonal neurofibrillary degeneration? N Engl J Med 313, 388–389.
Ashford JW (2015) Treatment of Alzheimer’s disease: The legacy of the cholinergic hypothesis, neuroplasticity, and future directions. J Alzheimers Dis 47, 149–156.
Geddes JW , Tekirian TL , Soultanian NS , Ashford JW , Davis DG , Markesbery WR (1997) Comparison of neuropathologic criteria for the diagnosis of Alzheimer’s disease. Neurobiol Aging 18, S99–105.
Thal DR , Rub U , Orantes M , Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58, 1791–1800.
Nelson PT , Alafuzoff I , Bigio EH , Bouras C , Braak H , Cairns NJ , Castellani RJ , Crain BJ , Davies P , Del Tredici K , Duyckaerts C , Frosch MP , Haroutunian V , Hof PR , Hulette CM , Hyman BT , Iwatsubo T , Jellinger KA , Jicha GA , Kovari E , Kukull WA , Leverenz JB , Love S , Mackenzie IR , Mann DM , Masliah E , McKee AC , Montine TJ , Morris JC , Schneider JA , Sonnen JA , Thal DR , Trojanowski JQ , Troncoso JC , Wisniewski T , Woltjer RL , Beach TG (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: A review of the literature. J Neuropathol Exp Neurol 71, 362–381.
Brier MR , Gordon B , Friedrichsen K , McCarthy J , Stern A , Christensen J , Owen C , Aldea P , Su Y , Hassenstab J , Cairns NJ , Holtzman DM , Fagan AM , Morris JC , Benzinger TL , Ances BM (2016) Tau and Abeta imaging, CSF measures, and cognition in Alzheimer’s disease. Transl Med 8, 338–366.
Farrell ME , Chen X , Rundle MM , Chan MY , Wig GS , Park DC (2018) Regional amyloid accumulation and cognitive decline in initially amyloid-negative adults. Neurology 91, e1809–e1821.
Knopman DS , Petersen RC (2014) Mild cognitive impairment and mild dementia: A clinical perspective. Mayo Clin Proc 89, 1452–1459.
Smith CJ , Ashford JW (2017) APOE ɛ4 allele-associated Alzheimer’s disease risk is consistent with increased lifetime exposure to a neurotoxic process. J Syst Integr Neurosci 3, 1–4.
Vetrano DL , Rizzuto D , Calderón-Larrañaga A , Onder G , Welmer AK , Bernabei R , Marengoni A , Fratiglioni L (2018) Trajectories of functional decline in older adults with neuropsychiatric and cardiovascular multimorbidity: A Swedish cohort study. PLoS Med 15, e1002503.
Eimer WA , Kumar D , Kumar V , Kumar N , Shanmugan N , Breakefield XO , Tanzi RE , Moir RD (2018) Alzheimer’s disease-associated β-amyloid is rapidly seeded byto protect against brain infection. Neuron 99, 56–63.
Jones L , Holmans PA , Hamshere ML , Harold D , Moskvina V , Ivanov D , Pocklington A , Abraham R , Hollingworth P , Sims R , Gerrish A , Pahwa JS , Jones N , Stretton A , Morgan AR , Lovestone S , Powell J , Proitsi P , Lupton MK , Brayne C , Rubinsztein DC , Gill M , Lawlor B , Lynch A , Morgan K , Brown KS , Passmore PA , Craig D , McGuinness B , Todd S , Holmes C , Mann D , Smith AD , Love S , Kehoe PG , Mead S , Fox N , Rossor M , Collinge J , Maier W , Jessen F , Schürmann B , Heun R , Kölsch H , van den Bussche H , Heuser I , Peters O , Kornhuber J , Wiltfang J , Dichgans M , Frölich L , Hampel H , Hüll M , Rujescu D , Goate AM , Kauwe JS , Cruchaga C , Nowotny P , Morris JC , Mayo K , Livingston G , Bass NJ , Gurling H , McQuillin A , Gwilliam R , Deloukas P , Al-Chalabi A , Shaw CE , Singleton AB , Guerreiro R , Mühleisen TW , Nöthen MM , Moebus S , Jöckel KH , Klopp N , Wichmann HE , Rüther E , Carrasquillo MM , Pankratz VS , Younkin SG , Hardy J , O’Donovan MC , Owen MJ , Williams J (2010) Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer’s disease. PloS One 5, e13950.
Flammang B , Pardossi-Piquard R , Sevalle J , Debayle D , Dabert-Gay AS , Thévenet A , Lauritzen I , Checler F (2012) Evidence that the amyloid-β protein precursor intracellular domain, AICD, derives from β-secretase-generated C-terminal fragment. J Alzheimers Dis 30, 145–153.
Ghosal K , Fan Q , Dawson HN , Pimplikar SW (2016) Tau protein mediates ABPP intracellular domain (AICD)-induced Alzheimer’s-like pathological features in mice. PLoS One 11, e0159435.
Ashford JW , Soultanian NS , Zhang SX , Geddes JW (1998) Neuropil threads are collinear with MAP2 immunostaining in neuronal dendrites of Alzheimer brain. Exp Neurol 57, 972–978.
Coleman PD , Yao PJ (2003) Synaptic slaughter in Alzheimer’s disease. Neurobiol Aging 24, 1023–1027.
Scheff SW , Price DA , Ansari MA , Roberts KN , Schmitt FA , Ikonomovic MD , Mufson EJ (2015) Synaptic change in the posterior cingulate gyrus in the progression of Alzheimer’s disease. J Alzheimers Dis 43, 1073–1090.
Song Y , Mittendorf KF , Lu Z , Sanders CR (2014) Impact of bilayer lipid composition on the structure and topology of the transmembrane amyloid precursor C99 protein. J Am Chem Soc 136, 4093–4096.
Winkler E , Kamp F , Scheuring J , Ebke A , Fukumori A , Steiner H (2012) Generation of Alzheimer disease-associated amyloid β42/43 peptide by γ-secretase can be inhibited directly by modulation of membrane thickness. J Biol Chem 287, 21326–21334.
Roses AD (1996) Apolipoprotein E alleles as risk factors in Alzheimer’s disease. Annu Rev Med 47, 387–400.
Raber J , Huang Y , Ashford JW (2004) APOE genotype accounts for the vast majority of AD risk and AD neuropathology. Neurobiol Aging 25, 641–650.
Yassine HN , Braskie MN , Mack WJ , Castor KJ , Fonteh AN , Schneider LS , Harrington MG , Chui HC (2017) Association of docosahexaenoic acid supplementation with Alzheimer disease stage in apolipoprotein E E4 carriers. A review. Neurol 7, 339–347.
Evans DA , Beckett LA , Field TS , Feng L , Albert MS , Bennett DA , Tycko B , Mayeux R (1997) Apolipoprotein E4 and incidence of Alzheimer disease in a community population of older persons. JAMA 277, 822–824.
Ashford JW (2004) APOE genotype effects on Alzheimer’s disease onset and epidemiology. J Mol Neurosci 23, 157–165.
Corder EH , Saunders AM , Strittmatter WJ , Schmechel DE , Gaskell PC , Small GW , Roses AD , Haines JL , Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and risk of Alzheimer’s disease in late onset families. Science 261, 921–923.
Mahley RW , Weisgraber KH , Huang Y (2009) Apolipoprotein E: Structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J Lipid Res 50(Suppl), S183–S188.
Weisgraber KH (1990) Apolipoprotein E distribution among human plasma lipoproteins: Role of the cysteine-arginine interchange at residue 112. J Lipid Res 31, 1503–1511.
Polozova A , Salem N Jr (2007) Role of liver and plasma lipoproteins in selective transport of n-3 fatty acids to tissues: A comparative study of 14C-DHA and 3H-oleic acid tracers. J Mol Neurosci 33, 56–66.
Taub DD (2008) Neuroendocrine interactions in the immune system. Cell Immunol 252, 1–6.
Atkins D , Best D , Briss PA , Eccles M , Falck-Ytter Y , Flottorp S , Guyatt GH , Harbour RT , Haugh MC , Henry D , Hill S , Jaeschke R , Leng G , Liberati A , Magrini N , Mason J , Middleton P , Mrukowicz J , O’Connell D , Oxman AD , Phillips B , Schünemann HJ , Edejer T , Varonen H , Vist GE , Williams JW Jr , Zaza S (2004) Grading quality of evidence and strength of recommendations. BMJ 328, 1490–1493.
Lehtimaki T , Moilanen T , Viikari J , Akerblom HK , Ehnholm C , Rönnemaa T , Marniemi J , Dahlen G , Nikkari T (1990) Apolipoprotein E phenotypes in Finnish youths: A cross-sectional and 6-year follow-up study. J Lipid Res 31, 487–495.
Lehtimaki T , Porkka K , Viikari J , Ehnholm C , Akerblom HK , Nikkari T (1994) Apolipoprotein E phenotypes and serum lipids in newborns and 3-year-old children: The Cardiovascular Risk in Young Finns Study. Pediatrics 94, 489–493.
Tammi A , Ronnemaa T , Viikari J , Jokinen E , Lapinleimu H , Ehnholm C , Simell O (2000) Apolipoprotein E4 phenotype increases non-fasting serum triglyceride concentration in infants – the STRIP study. Atherosclerosis 152, 135–141.
Tammi A , Ronnemaa T , Nissila LR , Miettinen TA , Gylling H , Valsta L , Viikari J , Välimäki I , Simell O (2001) Apolipoprotein E phenotype regulates cholesterol absorption in healthy 13-month-old children – The STRIP Study. Pediatr Res 50, 688–691.
Kallio MJT , Salmenpera L , Siimes MA , Perheentupa J , Gylling H , Miettinen TA (1997) Apolipoprotein E phenotype determines serum cholesterol in infants during both high-cholesterol breast feeding and low-cholesterol formula feeding. J Lipid Res 38, 759–764.
Taimela S , Lehtimaki T , Porkka KVK , Rasanen L , Viikari JSA (1996) The effect of physical activity on serum total and low-density lipoprotein cholesterol concentrations varies with apolipoprotein E phenotype in male children and young adults: The Cardiovascular Risk in Young Finns Study. Metabolism 45, 797–803.
Mamotte CDS , Sturm M , Foo JI , Van Bockxmeer FM , Taylor RR (1999) Comparison of the LDL-receptor binding of VLDL and LDL from APOE4 and APOE3 homozygotes. Am J Physiol 276(3 Pt 1), E553–557.
Ravaja N , Raikkonen K , Lyytinen H , Lehtimake T , Jarvinen LK (1997) Apolipoprotein E phenotypes and cardiovascular responses to experimentally induced mental stress in adolescent boys. J Behav Med 20, 571–587.
Ellis JA , Ponsonby AL , Pezic A , Williamson E , Cochrane JA , Dickinson JL , Dwyer T (2011) APOE genotype and cardio-respiratory fitness interact to determine adiposity in 8-year-old children from the Tasmanian Infant Health Survey. PLoS One 6, e26679.
Yu B , Chen W , Wang R , Qi Q , Li K , Zhang W , Wang H (2014) Association of apolipoprotein E polymorphism with maximal oxygen uptake after exercise training: A study of Chinese young adult. Lipids Health Dis 13, 40.
Van Exel E , Koopman JJE , Bodegom DV , Meij JJ , Knijff P , Ziem JB , Finch CE , Westendorp RGJ (2017) Effect of APOE E4 allele on survival and fertility in an adverse environment. PLoS One 12, e0179497.
Corbo RM , Ulizzi L , Scacchi R , Labarga CM , Stefano GF (2004) Apolipoprotein E polymorphism and fertility: A study in pre-industrial populations. Mol Hum Reprod 10, 617–620.
Gerdes LU , Gerdes C , Hansen PS , Klausen IC , Faergeman O (1996) Are men carrying the apolipoprotein E4- or E2 allele less fertile than E3E3 genotypes? Hum Genet 98, 239–242.
Zetterberg H , Palmer M , Ricksten A , Poirier J , Palmqvist L , Rymo L , Zafiropoulos A , Arvanitis DA , Spandidos DA , Blennow K (2002) Influence of the apolipoprotein E E4 allele on human embryonic development. Neurosci Lett 324, 189–192.
Agarwal M , Parveen F , Faridi RM , Phadke SR , Das V , Agrawal S (2010) Recurrent pregnancy loss and apolipoprotein E gene polymorphisms: A case-control study from North India. Am J Reprod Immunol 64, 172–178.
Bianca S , Barrano B , Cutuli N , Indaco L , Cataliotti A , Milana G , Barone C , Ettore G (2010) No association between apolipoprotein E polymorphisms and recurrent pregnancy loss. Fertil Steril 93, 276.
Korkmazer E , Ustunyurt E , Tekin B , Cilingir O (2013) Study on potential role of apolipoprotein E in recurrent pregnancy loss. Exp Ther Med 5, 1408–1410.
Becher J-C , Keeling JW , Bell J , Wyatt B , McIntosh N (2008) Apolipoprotein E E4 and its prevalence in early childhood death due to sudden infant death syndrome or to recognized causes. Early Hum Dev 84, 549–554.
Becher J-C , Keeling JW , McIntosh N , Wyatt B , Bell J (2006) The distribution of apolipoprotein E alleles in Scottish perinatal deaths. J Med Genet 43, 414–418.
Goodman C , Goodman CS , Hur J , Jeyendran RS , Coulam C (2009) The association of apoprotein E polymorphisms with recurrent pregnancy loss. Am J Reprod Immunol 61, 34–38.
Ozornek H , Ergin E , Jeyendran RS , Ozay AT , Pillai D , Coulam C (2010) Is apolipoprotein E codon 112 polymorphisms associated with recurrent pregnancy loss? Am J Reprod Immunol 64, 87–92.
Asgari N , Akbari MT , Zare S , Babamohammadi G (2013) Positive association of apolipoprotein E4 polymorphism with recurrent pregnancy loss in Iranian patients. J Assist Reprod Genet 30, 265–268.
Meng HX , Qi MG , Yi YY , Liu YP (2013) Association between apolipoprotein E gene polymorphism and the risk of recurrent pregnancy loss: A meta-analysis. J Assist Reprod Genet 30, 1547–1552.
Zonouzi AP , Farajzadeh D , Bargahi N , Farajzadeh M (2014) Apolipoprotein E genotyping in women with recurrent pregnancy loss: An in silico and experimental hybrid study. Gene 549, 209–213.
Gaynor JW , Kim DS , Arrington CB , Atz AM , Bellinger DC , Burt AA , Ghanayem NS , Jacobs JP , Lee TM , Lewis AB , Mahle WT , Marino BS , Miller SG , Newburger JW , Pizarro C , Ravishankar C , Santani AB , Wilder NS , Jarvik GP , Mital S , Russell MW (2014) Validation of association of the apolipoprotein E E2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants. J Thorac Cardiovasc Surg 148, 2560–2568.
Procopciuc LM , Hazi GM , Caracostea G , Nemeti G , Olteanu H , Stamatian F (2011) Apolipoprotein E polymorphism – a risk factor in Romanian pregnant women with preeclampsia. Obstetrics 7, 134–140.
Hirayama S , Miida T , Obayashi K , Yamazaki F , Yamazaki-Sakurai M , Ito M , Saito Y , Hanyu O , Suzuki K , Aizawa Y (2005) Effect of apolipoprotein E (APOE) phenotype on the APOE content of CSF-HDL in children. Clin Chim Acta 356, 110–116.
Gaynor JW , Gerdes M , Zackai EH , Bernbaum J , Wernovsky G , Clancy RR , Newman MF , Saunders AM , Heagerty PJ , D’Agostino JA , McDonald-McGinn D , Nicolson SC , Spray TL , Jarvik GP (2003) Apolipoprotein E genotype and neurodevelopmental sequelae of infant cardiac surgery. J Thorac Cardiovasc Surg 126, 1736–1745.
González-Castro TB , Tovilla-Zárate CA , Hernández-Díaz Y , Fresán A , Juárez-Rojop IE , Ble-Castillo JL , López-Narváez L , Genis A , Hernández-Alvarado MM (2015) No association between APOE and schizophrenia: Evidence of systematic review and updated meta-analysis. Schizophr Res 169, 355–368.
McKay GJ , Patterson CC , Chakravarthy U , Dasari S , Klaver CC , Vingerling JR , Ho L , de Jong PT , Fletcher AE , Young IS , Seland JH , Rahu M , Soubrane G , Tomazzoli L , Topouzis F , Vioque J , Hingorani AD , Sofat R , Dean M , Sawitzke J , Seddon JM , Peter I , Webster AR , Moore AT , Yates JR , Cipriani V , Fritsche LG , Weber BH , Keilhauer CN , Lotery AJ , Ennis S , Klein ML , Francis PJ , Stambolian D , Orlin A , Gorin MB , Weeks DE , Kuo CL , Swaroop A , Othman M , Kanda A , Chen W , Abecasis GR , Wright AF , Hayward C , Baird PN , Guymer RH , Attia J , Thakkinstian A , Silvestri G (2011) Evidence of association of APOE with age-related macular degeneration – a pooled analysis of 15 studies. Hum Mutat 32, 1407–1416.
Cotten CM , Goldstein RF , McDonald SA , Goldberg RN , Salhab WA , Carlo WA , Tyson JE , Finer NN , Walsh MC , Ehrenkranz RA , Laptook AR , Guillet R , Schibler K , Van Meurs KP , Poindexter BB , Stoll BJ , O’Shea TM , Duara S , Das A , Higgins RD , Shankaran S (2014) Apolipoprotein E (APOE) genotype and outcome in infants with hypoxic-ischemic encephalopathy (HIE). Pediatr Res 75, 424–430.
Braga LW , Borigato EV , Speck-Martins CE , Imamura EU , Gorges AM , Izumi AP , Dantas RC , Nunes LG (2010) Apolipoprotein E genotype and cerebral palsy. Dev Med Child Neurol 52, 666–671.
De Barros EMKP , Rodrigues CJ , de Barros TEP , Bevilacqua RG (2000) Presence of apolipoprotein E E4 allele in cerebral palsy. J Pediatr Orthop 20, 786–789.
Kuroda MM , Weck ME , Sarwark JF , Hamidullah A , Wainwright MS (2007) Association of apolipoprotein E genotype and cerebral palsy in children. Pediatrics 119, 306–313.
Mueller T , Fischer J , Gessner R , Rosendahl J , Böhm S , van Bömmel F , Knop V , Sarrazin C , Witt H , Marques AM , Kovacs P , Schleinitz D , Stumvoll M , Blüher M , Bugert P , Schott E , Berg T (2016) Apolipoprotein E allele frequencies in chronic and self-limited hepatitis C suggest a protective effect of APOE4 in the course of hepatitis C virus infection. Liver Int 36, 1267–1274.
Fabris C , Vandelli C , Toniutto P , Minisini R , Colletta C , Falleti E , Smirne C , Pirisi M (2011) Apolipoprotein E genotypes modulate fibrosis progression in patients with chronic hepatitis C and persistently normal transaminases. Hepatology 26, 328–333.
Fabris C , Toniutto P , Bitetto D , Minisini R , Smirne C , Caldato M , Pirisi M (2005) Low fibrosis progression of recurrent hepatitis C in apolipoprotein E E4 carriers: Relationship with the blood lipid profile. Liver Int 25, 1128–1135.
Price DA , Bassendine MF , Norris SM , Golding C , Toms GL , Schmid ML , Morris CM , Burt AD , Donaldson PT (2006) Apolipoprotein E3 allele is associated with persistent hepatitis C virus infection. Gut 55, 715–718.
Toniutto P , Fabris C , Fumo E , Apollonio L , Caldato M , Mariuzzi L , Avellini C , Minisini R , Pirisi M (2004) Carriage of the apolipoprotein E-E4 allele and histologic outcome of recurrent hepatitis C after antiviral treatment. Am J Clin Pathol 122, 428–433.
Wozniak MA , Itzhaki RF , Faragher EB , James MW , Ryder SD , Irving WL (2002) Apolipoprotein E-E4 protects against severe liver disease caused by hepatitis C virus. Hepatology 36, 456–463.
Fujioka H , Phelix CF , Friedland RP , Zhu X , Perry EA , Castellani RJ , Perry G (2013) Apolipoprotein E4 prevents growth of malaria at the intraerythrocyte stage: Implications for differences in racial susceptibility to Alzheimer’s disease. J Health Care Poor Underserved 24(4 Suppl), 70–78.
Aucan C , Walley AJ , Hill AVS (2004) Common apolipoprotein E polymorphisms and risk of clinical malaria in the Gambia. J Med Genet 41, 21–24.
Wozniak MA , Faragher EB , Todd JA , Koram KA , Riley EM , Itzhaki RF (2003) Does apolipoprotein E polymorphism influence susceptibility to malaria? J Med Genet 40, 348–351.
Lin WR , Wozniak MA , Esiri MM , Klenerman P , Itzhaki RF (2001) Herpes simplex encephalitis: Involvement of apolipoprotein E genotype. J Neurol Neurosurg Psychiatry 70, 117–119.
Terrell TR , Abramson R , Barth JT , Bennett E , Cantu RC , Sloane R , Laskowitz DT , Erlanger DM , McKeag D , Nichols G , Valentine V , Galloway L (2018) Genetic polymorphisms associated with the risk of concussion in 1056 college athletes: A multicenter prospective cohort study. Br J Sports Med 52, 192–198.
Tierney RT , Mansell JL , Higgins M , McDevitt JK , Toone N , Gaughan JP , Mishra A , Krynetskiy E (2010) Apolipoprotein E genotype and concussion in college athletes. Clin J Sport Med 20, 464–468.
Kristman VL , Tator CH , Kreiger N , Richards D , Mainwaring L , Jaglal S , Tomlinson G , Comper P (2008) Does the apolipoprotein E4 allele predispose varsity athletes to concussion? A prospective cohort study. Clin J Sport Med 18, 322–328.
Terrell TR , Bostick RM , Abramson R , Xie D , Barfield W , Cantu R , Stanek M , Ewing T (2008) APOE, APOE promoter, and TAU genotypes and risk for concussion in college athletes. Clin J Sport Med 18, 10–17.
Han SD , Drake AI , Cessante LM , Jak AJ , Houston WS , Delis DC , Filoteo JV , Bondi MW (2007) Apolipoprotein E and traumatic brain injury in a military population: Evidence of a neuropsychological compensatory mechanism? Neurosurg Psychiatry 78, 1103–1108.
Merritt VC , Clark AL , Sorg SF , Evangelista ND , Werhane ML , Bondi MW , Schiehser DM , Delano-Wood L (2018) Apolipoprotein E (APOE) ɛ4 genotype is associated with reduced neuropsychological performance in military veterans with a history of mild traumatic brain injury. J Clin Exp Neuropsychol 40, 1050–1061.
Teasdale GM , Murray GD , Nicoll JAR (2005) The association between APOE E4, age and outcome after head injury: A prospective cohort study. Brain 128, 2556–2561.
Teasdale GM , Nicoll JAR , Murray G , Fiddes M (1997) Association of apolipoprotein E polymorphism with outcome after head injury. Lancet 350, 1069–1071.
Chamelian L , Reis M , Feinstein A (2004) Six-month recovery from mild to moderate traumatic brain injury: The role of APOE-E4 allele. Brain 127, 2621–2628.
Blackman JA , Worley G , Strittmatter WJ (2005) Apolipoprotein E and brain injury: Implications for children. Dev Med Child Neurol 47, 64–70.
Yassine HN , Croteau E , Rawat V , Hibbeln JR , Rapoport SI , Cunnane SC , Umhau JC (2017) DHA brain uptake and APOE4 status: A PET study with [1-11C]-DHA. Alzheimers Res Ther 9, 23.
Tambini MD , Pera M , Kanter E , Yang H , Guardia-Laguarta C , Holtzman D , Sulzer D , Area-Gomez E , Schon EA (2016) APOE4 upregulates the activity of mitochondria-associated ER membranes. EMBO Rep 17, 27–36.
Dose J , Huebbe P , Nebel A , Rimbach G (2016) APOE genotype and stress response – a mini review. Lipids Health Dis 15, 121.
Ramassamy C , Averill D , Beffert U , Theroux L , Lussier-Cacan S , Cohn JS , Christen Y , Schoofs A , Davignon J , Poirier J (2000) Oxidative insults are associated with apolipoprotein E genotype in Alzheimer’s disease brain. Neurobiol Dis 7, 23–37.
Huebbe P , Nebel A , Siegert S , Moehring J , Boesch-Saadatmandi C , Most E , Pallauf J , Egert S , Müller MJ , Schreiber S , Nöthlings U , Rimbach G (2011) APOE E4 is associated with higher vitamin D levels in targeted replacement mice and humans. FASEB J 25, 3262–3270.
Ringman JM , Elashoff D , Geschwind DH , Welsh BT , Gylys KH , Lee C , Cummings JL , Cole GM (2012) Plasma signaling proteins in persons at genetic risk for Alzheimer disease: Influence of APOE genotype. Arch Neurol 69, 757–764.
Stening E , Persson J , Eriksson E , Wahlund LO , Zetterberg H (2017) Specific patterns of whole-brain structural covariance of the anterior and posterior hippocampus in young APOE E4 carriers. Behav Brain Res 326, 256–264.
Dowell NG , Evans SL , Tofts PS , King SL , Tabet N , Rusted JM (2016) Structural and resting-state MRI detects regional brain differences in young and mid-age healthy APOE-E4 carriers. NMR Biomed 29, 614–624.
Dowell NG , Ruest T , Evans SL , King SL , Tabet N , Tofts PS , Rusted JM (2013) MRI of carriers of the apolipoprotein E E4 allele-evidence for structural differences in normal-appearing brain tissue in E4+ relative to E4–young adults. NMR Biomed 26, 674–682.
Alexopoulos P , Schmidinger TR , Horn M , Maus S , Reichel M , Sidiropoulos C , Rhein C , Lewczuk P , Doerfler A , Kornhuber J (2011) Hippocampal volume differences between healthy young apolipoprotein E E2 and E4 carriers. J Alzheimers Dis 26, 207–210.
Sidiropoulos C , Jafari-Khouzani K , Soltanian-Zadeh H , Mitsias P , Alexopoulos P , Richter-Schmidinger T , Reichel M , Lewczuk P , Doerfler A , Kornhuber J (2011) Influence of brain-derived neurotrophic factor and apolipoprotein E genetic variants on hemispheric and lateral ventricular volume of young healthy adults. Acta Neuropsychiatr 23, 132–138.
Filippini N , MacIntosh BJ , Hough MG , Goodwin GM , Frisoni GB , Smith SM , Matthews PM , Beckmann CF , Mackay CE (2009) Distinct patterns of brain activity in young carriers of the APOE-E4 allele. Proc Natl Acad Sci U S A 106, 7209–7214.
Scarmeas N , Habeck CG , Hilton J , Anderson KE , Flynn J , Park A , Stern Y (2005) APOE related alterations in cerebral activation even at college age. J Neurol Neurosurg Psychiatry 76, 1440–1444.
Reiman EM , Chen K , Alexander GE , Caselli RJ , Bandy D , Osborne D , Saunders AM , Hardy J (2004) Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proc Natl Acad Sci U S A 101, 284–289.
Evans S , Dowell NG , Tabet N , King SL , Hutton SB , Rusted JM (2017) Disrupted neural activity patterns to novelty and effort in young adult APOE-E4 carriers performing a subsequent memory task. Brain Behav 7, e00612.
Dennis NA , Browndyke JN , Stokes J , Need A , Burke JR , Welsh-Bohmer KA , Cabeza R (2010) Temporal lobe functional activity and connectivity in young adult APOE E4 carriers. Alzheimers Dement 6, 303–311.
Turic D , Fisher PJ , Plomin R , Owen MJ (2001) No association between apolipoprotein E polymorphisms and general cognitive ability in children. Neurosci Lett 299, 97–100.
Luciano M , Gow AJ , Harris SE , Hayward C , Allerhand M , Starr JM , Visscher PM , Deary IJ (2009) Cognitive ability at age 11 and 70 years, information processing speed, and APOE variation: The Lothian Birth Cohort 1936 Study. Aging 24, 129–138.
Ruiz JR , Castillo R , Labayen I , Moreno LA , Fuentes MG , Lamuño DG , Alvarez Granda JL , Lucia A , Ortega FB (2010) Individual and combined effects of APOE and MTHFR 677C/T polymorphisms on cognitive performance in Spanish adolescents: The AVENA Study. J Pediatr 156, 978–984.
Bunce D , Anstey KJ , Burns R , Christensen H , Easteal S (2011) Does possession of apolipoprotein E ɛ4 benefit cognitive function in healthy young adults? Neuropsychologia 49, 1693–1697.
Richter-Schmidinger T1 , Alexopoulos P , Horn M , Maus S , Reichel M , Rhein C , Lewczuk P , Sidiropoulos C , Kneib T , Perneczky R , Doerfler A , Kornhuber J (2011) Influence of brain-derived neurotrophic-factor and apolipoprotein E genetic variants on hippocampal volume and memory performance in healthy young adults. J Neural Transm 118, 249–257.
Yasen AL , Raber J , Miller JK , Piper BJ (2015) Sex, but not apolipoprotein E polymorphism, differences in spatial performances in young adults. Arch Sex Behav 44, 2219–2226.
Bloss CS , Delis DC , Salmon DP , Bondi MW (2010) APOE genotype is associated with left-handedness and visuospatial skills in children. Neurobiol Aging 31, 787–795.
Stening E , Persson J , Eriksson E , Wahlund LO , Zetterberg H , Soderland H (2016) Apolipoprotein E E4 is positively related to spatial performance but unrelated to hippocampal volume in healthy young adults. Behav Brain Res 299, 11–18.
Trumble BC , Stieglitz J , Blackwell AD , Allayee H , Beheim B , Finch CE , Gurven M , Kaplan H (2018) Apolipoprotein E4 is associated with improved cognitive function in Amazonian forager-horticulturists with a high parasite burden. FASEB J 31, 1508–1515.
Sinclair LI , Button KS , Munafo MR , Day INM , Lewis G (2015) Possible association of APOE genotype with working memory in young adults. PLoS One 10, e0135894.
Oria RB , Patrick PD , Zhang H , Lorntz B , de Castro Costa CM , Brito GA , Barrett LJ , Lima AA , Guerrant RL (2005) APOE4 protects the cognitive development in children with heavy diarrhea burdens in northeast Brazil. Pediatr Res 57, 310–316.
Oria RB , Patrick PD , Blackman JA , Lima AA , Guerrant RL (2007) Role of apolipoprotein E4 in protecting children against early childhood diarrhea outcomes and implications for later development. Med Hypotheses 68, 1099–1107.
Oria RB , Patrick PD , Oria MO , Lorntz B , Thompson MR , Azevedo OG , Lobo RN , Pinkerton RF , Guerrant RL , Lima AA (2010) APOE polymorphisms and diarrheal outcomes in Brazilian shanty town children. Braz J Med Biol Res 43, 249–256.
Puttonen S , Elovainio M , Kivimaki M , Lehtimaki T , Jarvinen LK (2003) The combined effects of apolipoprotein E polymorphism and low-density lipoprotein cholesterol on cognitive performance in young adults. Neuropsychobiology 48, 35–40.
Taylor AE , Guthrie PAI , Smith GD , Golding J , Sattar N , Hingorani AD , Deanfield JE , Day IN (2011) IQ, educational attainment, memory and plasma lipids: Associations with apolipoprotein E genotype in 5995 children. Biol Psychiatry 70, 152–158.
Yu YWY , Lin CH , Chen SP , Hong CJ , Tsai SJ (2000) Intelligence and event-related potentials for young female human volunteer apolipoprotein E E4 and non-E4 carriers. Neurosci Lett 294, 179–181.
Tsai SJ , Yu YWY , Hong CJ (2004) Personality traits in young female apolipoprotein E (APOE) E4 and non-E4 carriers. Am J Med Genet B Neuropsychiatr Genet 124, B58–60.
Jarvinen LK , Raikkonen K , Lehtimaki T (1993) Dependence between apolipoprotein E phenotypes and temperament in children, adolescents, and young adults. Psychosom Med 55, 155–163.
Rusted JM , Evans SL , King SL , Dowell N , Tabet N , Tofts PS (2013) APOE E4 polymorphism in young adults is associated with improved attention and indexed by distinct neural signatures. Neuroimage 65, 364–373.
Mondadori CR , de Quervain DJ , Buchmann A , Mustovic H , Wollmer MA , Schmidt CF , Boesiger P , Hock C , Nitsch RM , Papassotiropoulos A , Henke K (2007) Better memory and neural efficiency in young apolipoprotein E E4 carriers. Cereb Cortex 17, 1934–1947.
Acevedo SF , Piper BJ , Craytor MJ , Benice TS , Raber J (2010) Apolipoprotein E4 and sex affect neurobehavioral performance in primary school children. Pediatr Res 67, 293–299.
Noe E , Ferri J , Colomer C , Moliner B , Chirivella J (2010) APOE genotype and verbal memory recovery during and after emergence from post-traumatic amnesia. Brain Injury 24, 886–892.
Chang L , Andres M , Sadino J , Jiang CS , Nakama H , Miller E , Ernst T (2011) Impact of apolipoprotein E E4 and HIV on cognition and brain atrophy: Antagonistic pleiotropy and premature brain aging. Neuroimage 58, 1017–1027.
Jochemsen HM , Muller M , van der Graaf Y , Geerlings MI (2012) APOE E4 differentially influences change in memory performance depending on age. The SMART-MR study. Neurobiol Aging 33, 832e15–832e22.
Zokaei N , Giehl K , Sillence A , Neville MJ , Karpe F , Nobre AC , Husain M (2017) Sex and APOE: A memory advantage in male APOE E4 carriers in midlife. Cortex 88, 98–105.
Alexander DM , Williams LM , Gatt JM , Dobson-Stone C , Kuan SA , Todd EG , Schofield PR , Cooper NJ , Gordon E (2007) The contribution of apolipoprotein E alleles on cognitive performance and dynamic neural activity over six decades. Biol Psychol 75, 229–238.
Wright RO , Hu H , Silverman EK , Tsaih SW , Schwartz J , Bellinger D , Palazuelos E , Weiss ST , Hernandez-Avila M (2003) Apolipoprotein E genotype predicts 24-month Bayley Scales Infant Development Score. Pediatr Res 54, 819–825.
Hubacek JA , Pitha J , Skodova Z , Adamkova V , Lanska V , Poledne R (2001) A possible role of apolipoprotein E polymorphism in predisposition to higher education. Neuropsychobiology 43, 200–203.
Marchant NL , King SL , Tabet N , Rusted JM (2010) Positive effects of cholinergic stimulation favor young APOE E4 carriers. Neuropsychopharmacology 35, 1090–1096.
Mitter SS , Oria RB , Kvalsund MP , Pamplona P , Joventino ES , Mota RM , Gonçalves DC , Patrick PD , Guerrant RL , Lima AA (2012) Apolipoprotein E4 influences growth and cognitive responses to micronutrient supplementation in shantytown children from northeast Brazil. Clinics 67, 11–18.
Caselli RJ , Dueck AC , Osborne D , Sabbagh MN , Connor DJ , Ahern GL (2009) Longitudinal modeling of age-related memory decline and the APOE ɛ4 effect. N Engl J Med 361,, 255–263.
Lancaster C , Tabet N , Rusted J (2017) The elusive nature of APOE ɛ4 in mid-adulthood: Understanding the cognitive profile. J Int Neuropsychol Soc 23, 239–253.
Sinclair LI , Pleydell-Pearce CW , Day INM (2017) Possible positive effect of the APOE ɛ2 allele on cognition in early to mid-adult life. Neurobiol Learn Mem 146, 37–46.
Tuminello ER , Han SD (2011) The apolipoprotein E antagonistic pleiotropy hypothesis: Review and recommendations. Int J Alzheimers Dis 2011, 726197.
Fullerton SM , Clark AG , Weiss KM , Nickerson DA , Taylor SL , Stengârd JH , Salomaa V , Vartiainen E , Perola M , Boerwinkle E , Sing CF (2000) Apolipoprotein E variation at the sequence haplotype level: Implications for the origin and maintenance of a major human polymorphism. Am J Hum Genet 67, 881–900.
Farrer LA , Cupples LA , Haines JL , Hyman B , Kukull WA , Mayeux R , Myers RH , Pericak-Vance MA , Risch N , van Duijn CM (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: A meta-analysis. JAMA 278, 1349–1356.
Suri S , Mackay CE , Kelly ME , Germuska M , Tunbridge EM , Frisoni GB , Matthews PM , Ebmeier KP , Bulte DP , Filippini N (2015) Reduced cerebrovascular reactivity in young adults carrying the APOE E4 allele. Alzheimers Dement 11, 648–657.
Leon AS , Togashi K , Rankinen T , Després JP , Rao DC , Skinner JS , Wilmore JH , Bouchard C (2004) Association of apolipoprotein E polymorphism with blood lipids and maximal oxygen uptake in the sedentary state and after exercise training in the HERITAGE Family Study. Metabolism 53, 108–116.
Coto-Segura P , Coto E , Alvarez V , Morales B , Soto-Sánchez J , Corao AI , Santos-Juanes J (2010) Apolipoprotein E4 allele is associated with psoriasis severity. Arch Dermatol Res 302, 145–149.
Gozal D , Capdevila OS , Gozal LK , McLaughlin V (2007) APOE E4 allele, cognitive dysfunction, and obstructive sleep apnea in children. Neurology 69, 243–249.
Wozniak MA , Riley EM , Itzhaki RF (2004) Apolipoprotein E polymorphisms and risk of malaria. J Med Genet 41, 145–146.
Perkins M , Wolf AB , Chavira B , Shonebarger D , Meckel JP , Leung L , Ballina L , Ly S , Saini A , Jones TB , Vallejo J , Jentarra G , Valla J (2016) Altered energy metabolism pathways in the posterior cingulate in young adult apolipoprotein E ɛ4 carriers. J Alzheimers Dis 58, 95–106.
Pomara N , Belzer KD , Silva R , Cooper TB , Sidtis JJ (2008) The apolipoprotein E E4 allele and memory performance in HIV-1 seropositive subjects: Differences at baseline but not after acute oral lorazepam challenge. Psychopharmacology 201, 125–135.
Wishart HA , Saykin AJ , Rabin LA , Santulli RB , Flashman LA , Guerin SJ , Mamourian AC , Belloni DR , Rhodes CH , McAllister TW (2006) Increased brain activation during working memory in cognitively intact adults with the APOE E4 allele. Am J Psychiatry 163, 1603–1610.
Nijenhuis JT , Choi KY , Choi YY , Lee JJ , Seo EH , Kim H , Lee KH (2018) Differences between APOE carriers and non-APOE carriers on neurocognitive tests: Jensen Effects? Dis Other Demen 33, 353–361.
Evans S , Gray MA , Dowell NG , Tabet N , Tofts PS , King SL , Rusted JM (2013) APOE E4 carriers show prospective memory enhancement under nicotine, and evidence for specialization within medial BA10. Neuropsychopharmacology 38, 655–663.