The effects of apolipoprotein E on non-impaired cognitive functioning: A meta-analysis

Nearly twice as many participants are represented in the current literature than were available at the time of the last major meta-analytic neurocognitive examination of apolipoprotein E (ApoE) epsilon allele combinations [Small, B.J., Rosnick, C.B., Fratiglioni, L., Backman, L., 2004. Apolipoprotein E and cognitive performance: a meta-analysis. Psychol. Aging 19, 592-600]. The meta-analysis in the current study sought to specifically examine (1) small effects and (2) possible moderating variables associated with ApoE allele combinations that may have been undiscoverable in previous examinations of smaller data sets. A total of 77 studies, representing 40,942 cognitively healthy adults were identified for inclusion in the current meta-analysis (random effects design). Results were congruent with the previous meta-analytic findings indicating that carriers of ApoE allele 4 (?4) perform significantly worse on measures of episodic memory, executive functioning, and overall global cognitive ability. In addition, the current analysis revealed a small effect suggesting that ApoE allele 4 adversely impacts perceptual speed. In contrast to earlier studies, the results also indicate that increases in age result in significantly larger differences between ApoE ?4 carriers and ApoE non-?4 carriers on measures of episodic memory and global cognitive ability. ApoE ?4 exerts broad, but specific, adverse small effects on a range of neurocognitive functions in cognitively healthy adults.     

Mortality and Apolipoprotein E in Hispanic,African‐American,and Caucasian elders

To investigate whether mortality risk is influenced by apolipoprotein E (APOE) genotype and whether the risk differs by ethnicity, we compared the mortality risk in 2,112 individuals ≥ 65 years of age residing in northern Manhattan in New York. Mortality risks associated with the APOE genotype, adjusted for sex, high‐density lipoprotein (HDL), low‐density lipoprotein (LDL), and triglycerides, differed significantly by ethnic group. Among Caucasian and Hispanics, the E2/E3 genotype was associated with the lowest mortality risk in the multivariate Cox proportional hazards modeling, adjusted for lipid levels, whereas mortality risk did not differ substantially between the E4/E3 and E3/E3 genotypes. Among African‐Americans, the E2/E3 genotype was not associated with the lowest mortality risk, but the E4/E3 genotype was. Adjustment for heart disease, diabetes, and stroke reduced mortality risk associated with each genotype by about 50% for all ethnic groups, but the patterns remained the same. Although we cannot rule out the possibility of a healthy survival bias, our analyses designed to examine healthy survival by comparing risk of mortality in groups who were younger or older at entry do not support this possibility. Our findings suggest that the APOE genotype is associated with mortality and that the genotypic risks differ by ethnic group. Nearly 50% of the mortality risk associated with the APOE genotype appears to act through major chronic diseases, but those diseases only partially explain the mechanism by which the genotypic risk acts. To better understand the observed ethnic differences in mortality risk by genotype, a detailed prospective study is needed to examine the relationships among APOE, other candidate genes, health conditions, and eventual death. © 2001 Wiley‐Liss, Inc.     

Apolipoprotein E polymorphism, age and coronary heart disease

Plasma concentrations of lipids, lipoproteins, and apolipoproteins (apo) are established risk factors for coronary heart disease (CHD). The knowledge of lipid profile may predict the potential victims of cardiovascular disease before its initiation and progression and offer the opportunity for primary prevention. The most common apo E polymorphism has been found to influence blood lipid concentrations and its correlation with CHD has been extensively investigated in the last decade. At younger ages, death from CHD is influenced by genetic factors, while the genetic effect decreases at older ages where environmental factors may play a more prominent role. If apo E polymorphism is an important genetic factor in the pathogenesis of atherosclerosis, it could affect the age of CHD onset. This review analyses the influence of apo E polymorphism on blood lipids and CHD in respect to age.     

Influence of Apolipoprotein E polymorphism on susceptibility of Wilson disease

Wilson disease (WD) is an autosomal‐recessive disorder caused by mutations in the ATP7B gene leading to abnormal copper deposition in liver and brain. WD manifests diverse neurological and hepatic phenotypes and different age of onset, even among the siblings, with same mutational background suggesting complex nature of the disease and involvement of other candidate genes. In that context, Apolipoprotein E (APOE) and Prion Protein (PRNP) have been proposed to be potential candidates for modifying the WD phenotype and age of onset. This study aims to identify the contribution of APOE and PRNP polymorphisms on the variable phenotypic expression of Indian WD patients. A total of 171 WD patients and 291 controls from Indian population were included in this study. Two APOE cSNPs (rs429358 and rs7412) resulting in three isoforms and M129V (rs1799990) polymorphism of PRNP were examined for their association with WD and its clinical phenotypes. The APOE ?4 allele was found to be significantly overrepresented in WD patients compared to controls. However, the frequency of the APOE ?3 allele and ?3/?3 genotype was significantly higher in WD patients without cognitive behavior impairment compared to the ones with the impairment. On the contrary, the PRNP allele representing Val129 was found to be present in higher proportion in WD patients with cognitive behavioral decline. Our data suggest that the APOE ?4 allele could act as a potential risk for the pathogenesis of WD. Also, APOE and PRNP might contribute toward the cognitive behavioral decline in a section of WD patients.     

Apolipoprotein E genotypes and the risk of Parkinson disease

We examined apolipoprotein E (ApoE) genotypes in relation to Parkinson's disease (PD) among 786 cases and 1537 controls, all non-Hispanic Caucasians. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived from multivariate logistic regression models, adjusting for year of birth, sex, smoking status, daily caffeine intake, and family history of PD. Compared with participants with ApoE ε33, ε4 carriers (ε34/ε44) had significantly lower odds for having PD (OR, 0.75; 95% CI, 0.59-0.94; p = 0.01), whereas ε2 carriers (ε23/ε22) did not (OR, 0.95; 95% CI, 0.73-1.24; p = 0.71). Subgroup analyses showed similar results. In addition, we conducted a meta-analysis which confirmed our primary findings (ε34/ε44 vs. ε33: OR, 0.90; 95% CI, 0.81-0.99; p = 0.024 and ε23/ε22 vs. ε33: OR, 1.10; 95% CI, 0.97-1.23; p = 0.13). In PD patients, the prevalence of dementia appeared to be higher among ε4 carriers (compared with ε33: OR, 1.59; 95% CI, 0.98-2.58; p = 0.06), but lower among ε2 carriers (OR, 0.75; 95% CI, 0.40-1.42; p = 0.38), although neither test was statistically significant. Our study suggested that the ApoE ε4 allele may be associated with a lower PD risk among non-Hispanic Caucasians.     

载脂蛋白E基因多态性与2型糖尿病的关系

目的:探讨载脂蛋白E基因型与2型糖尿病的易感性。方法:应用multi-ARMS快速分型法对316例T2DM患者、512例健康对照人群的ApoE基因第4外显子112位Cys/Arg和158位Arg/Cys进行检测;随机抽取分型标本进行DNA测序法验证。结果:ε2/2、ε2/3、ε3/3、ε4/2、ε4/3、ε4/4基因型在二组中的频率分布为:0.6%,5.7%,72.8%,1.9%,14.9%,4.1%(T2DM组);0.6%,9.4%,70.1%,1.8%,17.0%,1.2%(对照组)。二组间差异有显著性统计学意义(χ2=11.45,P<0.05),T2DM组ε4/4基因型频率明显高于对照组(4.11%VS1.17%)。结论:ApoEε4/4基因型可能与T2DM的易感性有关。     

Rare and common variants in the Apolipoprotein E gene in healthy oldest old

Apolipoprotein E (APOE) alleles are associated with longevity in genome-wide scans, with ε4 correlated with shorter life, and ε2 with longer life, than ε3. We hypothesized that rare APOE variants with large individual effects might also contribute to long-term good health. The APOE exons and promoter were resequenced in DNA samples from 376 healthy oldest old aged ≥85yrs with no self-reported history of cancer, cardiovascular disease, diabetes, major pulmonary disease or Alzheimer disease (“Super-Seniors”) and 376 population-based controls aged 41–54. Forty variants were observed: 32 were rare (minor allele frequency <2%); 9 were nonsynonymous. Controls were more likely to have an ε4 allele (Pearson χ² = 6.61, p = 0.04). Among the Super-Seniors, APOE allele status was not associated with body mass index or Mini Mental State Examination score. There was no excess of rare APOE variants in healthy oldest old compared with midlife controls, or vice-versa; however, this does not rule out an effect of some variants on ApoE function. Our findings were consistent with ε4 being a risk factor for early mortality.     

The effects of patient education on patient cognition and dis-related anxiety.

A rheumatoid arthritis patient education program was developed with objectives of increasing patient knowledge base and improving health status. Forty-six rheumatoid arthritis outpatients entered a three-session multidisciplinary education program. Each client was given a cognitive test and the Arthritis Impact Measurement Scale (AIMS) before, immediately after, and at remote follow-up. Data were analyzed to determine the effect of age and disease duration on clients' ability to benefit from group education. The effect of the program on physical and psychosocial parameters was also assessed. There was a significant increase in average cognitive scores between pre- and post-tests which remained at one month follow-up testing. Pre-test cognitive scores correlated positively with disease duration. At immediate post-test a correlation between anxiety scores and physical parameters was seen, which was not present on pre- or follow-up testing. No correlation was found between increase in cognitive scores and overall health status. Multivariate analysis of the AIMS test showed significant improvement in total health score at remote testing. Depression scores significantly improved from post to remote follow-up testing. This study suggests that one 'side effect' of patient education may be a transient worsening of psychological status in patients with greatest disease involvement.     

Apolipoprotein E isoform-specific effects on cytokine and nitric oxide production from mouse Schwann cells after inflammatory stimulation

Previously, we reported that apolipoprotein E (apoE) deficiency increased the susceptibility to experimental autoimmune neuritis (EAN), an inflammatory autoimmune disorder of the peripheral nervous system (PNS) and an animal model for human Guillain-Barré syndrome (GBS) by affecting the antigen-presenting function of Schwann cells (SCs) via influence upon IL-6 production. To further elucidate the role of apoE in inflammation of the PNS, here we studied the effect of different isoforms of apoE on SCs in response to inflammatory stimulation. SCs from apoE2, E3 and E4 transgenic (Tg) and wild type (WT) mice were cultured, and their responses to stimulation by lipopolysaccharide (LPS) plus interferon (IFN)-γ were compared. Upon stimulation, the morphology of cultured SCs changed. Pronounced production of interleukin (IL)-6 and IL-10 within SCs, and of IL-6 and nitric oxide (NO) in the supernatants were found in an isoform-dependent manner (apoE3>apoE2≈apoE4). Further results indicated that both nuclear factor (NF) κB and Akt signaling pathways were involved in the process by the same isoform-dependent pattern. However, the expression of co-stimulatory molecules as showing the antigen-presenting capacity of SCs was not significantly different among these groups. In conclusion, SCs respond to inflammatory insults accompanied by increased productions of IL-6, IL-10 and NO in an apoE-isoform-dependent manner. SCs from apoE2 and apoE4 Tg mice seem to bear some dysfunction in producing cytokines (IL-6 and IL-10) and NO as compared with their apoE3 counterparts, probably resulting from their insufficiency to suppress the activation of NFκB and Akt pathways. Our findings may help to understand the role of different isoforms of apoE in inflammatory disorders of the PNS.     

Apolipoprotein E genotypes and neuropsychiatric symptoms and syndromes in late-onset Alzheimer's disease

Neuropsychiatric symptoms (NPS) in dementia, previously denominated as behavioural and psychological symptoms of dementia, are often more distressing, impairing, and costly than cognitive symptoms, representing a major health burden for older adults. These symptoms are common features of Alzheimer's disease (AD), and are one of the major risk factors for institutionalization. There is a high prevalence of neuropsychiatric disturbances in patients with AD, including depression, anxiety, apathy, psychosis, aggression, and agitation. At present, the role of the apolipoprotein E (APOE) genotypes in the development of NPS or neuropsychiatric syndromes/endophenotypes in AD patients is unclear. In this article, we summarized the findings of the studies of NPS and neuropsychiatric syndromes in AD in relation to APOE genotypes, with special attention to the possible underlying mechanisms. While some studies failed to find a significant association between the APOE polymorphism and NPS in late-onset AD, other studies reported a significant association between the APOE ?4 allele and an increase in agitation/aggression, hallucinations, delusions, and late-life depression or anxiety. However, current cumulative evidence coming from the few existing longitudinal studies shows no association of APOE genotypes with NPS as a whole in AD. Some negative studies that focused on the distribution of APOE genotypes between AD patients with or without NPS further emphasized the importance of sub-grouping NPS in distinct neuropsychiatric syndromes. Explanations for the variable findings in the existing studies included differences in patient populations, differences in the assessment of neuropsychiatric symptomatology, possible lack of statistical power to detect associations in the negative studies, and small sample sizes generating false positives that cannot be consistently replicated. Finally, many reviewed studies were cross-sectional, whereas it would be of paramount importance to evaluate the risk for incident NPS in relation to the APOE genotype in prospectively followed cohorts of AD patients. In fact, identifying predisposing genetic risk factors may allow us to understand the pathophysiological features of neuropsychiatric syndromes or symptoms in AD, so optimizing possible therapeutic options.     

高脂血症患者载脂蛋白E基因多态性与血脂水平分析

目的:分析载脂蛋白E基因多态性和高脂血症患者的血脂水平。方法:应用等位基因特异性多重PCR技术对高脂血症患者和健康对照者载脂蛋白E基因多态性进行分析,并测定所有样本血清载脂蛋白E等血脂指标水平。结果:高脂血症患者总胆固醇、甘油三脂、低密度脂蛋白胆固醇、载脂蛋白E水平明显高于健康对照组(P<0.05),而高密度脂蛋白胆固醇,载脂蛋白AI明显低于正常对照组(P<0.05);血浆中载脂蛋白E含量顺序是E2/3>E3/3>E3/4,两两比较具有统计学差异(P<0.05);在载脂蛋白E的基因型中以载脂蛋白E3/3型多见;高脂血症患者中载脂蛋白Eε4等位基因频率明显高于健康对照组(P<0.05)。结论:载脂蛋白Eε4等位基因与高脂血症有关,载脂蛋白E基因多态性可能是高脂血症患者的遗传因素。     

Describing the interplay between anxiety and cognition: from impaired performance under low cognitive load to reduced anxiety under high load

Anxiety impairs the ability to think and concentrate, suggesting that the interaction between emotion and cognition may elucidate the debilitating nature of pathological anxiety. Using a verbal n-back task that parametrically modulated cognitive load, we explored the effect of experimentally induced anxiety on task performance and the startle reflex. Findings suggest there is a crucial inflection point between moderate and high cognitive load, where resources shift from anxious apprehension to focus on task demands. Specifically, we demonstrate that anxiety impairs performance under low load, but is reduced when subjects engage in a difficult task that occupies executive resources. We propose a two-component model of anxiety that describes a cognitive mechanism behind performance impairment and an automatic response that supports sustained anxiety-potentiated startle. Implications for therapeutic interventions and emotional pathology are discussed.     

新疆维汉两民族冠心病患者载脂蛋白E基因多态性研究

目的探讨新疆乌鲁木齐地区维汉两民族冠心病患者载脂蛋白E(Apo E)基因多态性与冠心病的关系.方法用酚氯仿抽提核酸法从凝血块中分离DNA,用多聚酶链式反应-限制性片段长度多态性(PCR-RFLP)方法对新疆乌鲁木齐地区维汉两民族103例冠心病患者和54例对照组人群进行Apo E基因多态性(由ε2、ε3和ε4决定的E2/2、E3/3、E4/4、E4/2、E4/3和E3/2)HhaI酶切研究.结果(1)维族中Apo E之ε2,ε3和ε4等位基因频率分别为0.221±0.373,0.647±0.380和0.132±0.224,与汉族(0.081±0.196,0.772±0.315和0.146±0.237)比较,ε2明显增高(P＜0.05),ε3和ε4虽有减低但无显著差别(P＞0.05).(2)Apo E之ε2,ε3和ε4等位基因频率在冠心病组分别为0.073±0.215,0.777±0.311和0.151±0.241,与对照组(0.185±0.296,0.685±0.367和0.130±0.221)比较,ε2明显减低(P＜0.05),维族中更明显(0.105±0.315对0.367±0.296,P＜0.05),ε3和ε4虽有升高但无显著差别(P＞0.05).(3)由ε2到ε4低密度脂蛋白胆固醇(LDL)、总胆固醇(TC)和甘油三酯逐渐升高.ε2缺失与冠心病其它危险因子一起作Logistic回归分析,ε2缺失(危险比RR=3.45,P＜0.05)为冠心病的危险因子之一.结论新疆乌鲁木齐地区维汉两民族人群中(1)维族和汉族人群中Apo E基因型分布有非常显著性差异(P＜0.01);维族人群中ε2等位基因频率明显高于汉族.(2)CAD患者Apo E基因之ε2等位基因频率明显降低,其中维族更明显,ε3和ε4有所升高;从ε2到ε4,LDL、TG和TC有升高趋势.(3)Apo E基因多态性(ε2等位基因缺失)为冠心病的危险因子之一,亦即ε2与冠心病负相关.     

Characterization of a Monoclonal Antibody that Binds to Apolipoprotein E and to Lipoprotein of Human Plasma Containing APO E. Applications to ELISA Quantification of Plasma APO E

Abstract

This study describes the development of an enzyme-linked immunosorbent assay for human apolipoprotein E (apo E).

A mouse monoclonal IgG₁ antibody named E01 against apolipoprotein E was selected from five antibodies secreted by hybridomas. This antibody had a high affinity for apo E ((K a 1.2 × 10⁷ L.M^?1 for purified apo E and K = 1.05 × 10⁷ L.M^?1 for native apo E in very low density lipoproteins) in liquid phase and recognized every isoform of apo E but not other proteins in VLDL. Competition experiments with ¹²⁵I apo E showed that its binding affinity for the E in every density class (VLDL, HDL, LDL) and in serum was the same.

This antibody was used for the quantification of human apo E in serum by enzyme linked immunoassay. E01 was coated on microtiter plates and a polyclonal peroxidase-conjugate was used as second antibody. A good correlation was observed between the values obtained for apo E using both monoclonal and polyclonal antibodies.     

The effects of metabolic syndrome and apolipoprotein E4 on cognitive event-related potentials

To reduce the care burden of dementia, identifying whether the combined effect of metabolic syndrome and ?4 increases the risk of cognitive decline needs to be determined. Using the Cognitive Abilities Screening Instrument (CASI), 145 mentally healthy middle-aged and older adults were recruited to investigate the influence of metabolic syndrome and ?4 on cognitive event-related potentials (ERPs). The results showed no difference in CASI scores, N100 and P300 measurements and ?4 carrier percentage between participants with and without metabolic syndrome. The ?4 carriers displayed a significant decrease in P300 amplitude, although the CASI scores and N100 component showed no difference. We conclude that metabolic syndrome exerts little effect on N100 and P300 measurements, and that ?4 carrier is an independent predictor of low P300 amplitude.     

Apolipoprotein E polymorphism is not associated with lipid levels and coronary artery disease in Greek patients with familial hypercholesterolaemia

Abstract Familial hypercholesterolaemia is a genetic disorder characterised by high low-density lipoprotein (LDL) cholesterol concentrations, which frequently gives rise to premature coronary artery disease (CAD). The clinical expression of familial hypercholesterolaemia is highly variable even in patients carrying the same LDL receptor gene mutation. This variability may be due to environmental and other genetic factors. Apolipoprotein E (Apo-E) has been extensively studied for its effects on the phenotype of familial hypercholesterolaemia. In this study we examined the influence of Apo-E genotype on lipid parameters and the incidence of CAD in 93 Greek patients with familial hypercholesterolaemia. Apo-E E2, E3 and E4 allele frequencies were 0.06, 0.86 and 0.09 respectively. The levels of total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, apolipoproteins A and B and lipoprotein α did not differ significantly among carriers and non-carriers of the E4 allele. The prevalence of CAD and hypertension did not differ either. Our results suggest that the E4 allele is not associated with lipid levels or with the prevalence of CAD among familial hypercholesterolaemia patients of the Greek population. *The two authors were equally involved in the work     

The contribution of apolipoprotein E alleles on cognitive performance and dynamic neural activity over six decades

Neuroimaging shows brain-functional differences due to apolipoprotein E (APOE) polymorphisms may exist decades before the increased risk period for Alzheimer's disease, but little is known about their effect on cognition and brain function in children and young adults. This study assessed 415 healthy epsilon2 and epsilon4 carriers and matched epsilon3/epsilon3 controls, spanning ages 6-65, on a range of cognitive tests. Subjects were also compared on a new dynamical measure of EEG activity during a visual working memory task using alphabetical stimuli. epsilon4 subjects had better verbal fluency compared to epsilon3, an effect that was strongest in 51-65 year-olds. No epsilon4 deficits in cognition were found. In 6-15 year-olds, there were differences in total spatio-temporal wave activity between epsilon3 and epsilon4 subjects in the theta band, approximately 200ms post-stimulus. Differences in brain function in younger epsilon4 subjects and superior verbal fluency across the entire age range suggest that the APOE epsilon4 allele is an example of antagonistic pleiotropy.     

Apolipoprotein E allele frequencies in a South African Indian female population

Coronary heart disease is common amongst South Africans of Indian (Asian) ancestry. As part of an investigation into risk factors in premenopausal and post-menopausal Indian nurses, we determined the apolipoprotein E genotype by means of restriction isotyping on 173 healthy nurses between the ages of 25–55 years. The apolipoprotein E allele frequencies on 346 chromosomes were: ε2, 1.2% (95% confidence interval 0.06-2.66); ε3, 87.6% (95% confidence interval 84.1–91.1 and ε4, 11.3% (95% confidence interval 7.94-14.60). No ε2/2 homozygotes were encountered. Our results demonstrate an extremely low frequency of the ε2 allele, a low-normal apo ε4 and a high ε3 allele frequency. It is unlikely that apolipoprotein E polymorphism contributes to the high incidence of coronary heart disease in this population.