Memory performance and the apolipoprotein E polymorphism in a community sample of middle‐aged adults

The apolipoprotein E genotype (APOE) is an established risk factor for Alzheimer disease, with the age‐at‐onset occurring earlier in individuals having at least one APOE ϵ4 allele, relative to the APOE ϵ3 or APOE ϵ2 isoforms. Moreover, nondemented older adults with the APOE ϵ4 allele also show diminished cognitive performance, particularly on tests of learning and memory, and an accelerated decline in memory performance with increasing age. The current investigation extends the study of the APOE ϵ4 allele and cognitive performance to healthy, middle‐aged adults. A community sample of 220 non‐Hispanic Caucasian men and women, aged 24–60 (average age = 46), were genotyped for the APOE polymorphism and completed a battery of neuropsychological tests. Multivariate analyses were conducted on measures of verbal learning and memory (e.g., learning a list of words and recalling them 30 min later), visual memory (e.g., reproducing a previously copied figure from memory), and attention span (e.g., repeating long lists of digits), after adjustments for age, and estimated IQ. Results indicated that performance on learning and memory tasks was significantly poorer in adults having any APOE ϵ4 allele, relative to adults with APOE ϵ2 and ϵ3 genotypes (P < .01). Attention span did not differ by genotype. These findings, the first in a sample of middle‐aged adults, suggest that the APOE polymorphism is a marker for age‐related decline in memory (detectable prior to overt, clinical manifestations of memory loss), and/or a marker for individual differences in memory ability across the life span. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:707–711, 2000. © 2000 Wiley‐Liss, Inc.     

The effect of apolipoprotein E polymorphism on lipid levels in Korean adults

The aim of this study was to determine the effects of polymorphisms in the apolipoprotein E gene (APOE) on lipid levels in Korean adults and to investigate the interactions between these polymorphisms and environmental factors in determining lipid levels. We performed a cross-sectional study of 1,900 subjects (668 men and 1,232 women; 45-74 yr old) in Namwon, Korea, in 2004. APOE polymorphisms were determined by polymerase chain reaction and restriction enzyme analysis. Carriers of the APOE*E2 (E2) allele had significantly lower total cholesterol and low-density lipoprotein cholesterol (LDL-C) concentrations than did carriers of the APOE*E3 (E3) or APOE*E4 (E4) alleles, regardless of gender. The APOE allele type had significant effect on high-density lipoprotein cholesterol (HDL-C) and triglyceride levels in women, but not in men. The effect of APOE allele type on HDL-C levels was modified by age in women. In addition, in men, the effect of APOE allele type on triglyceride levels was modified by smoking. These findings highlight the important effect of gene-environment interactions on lipid levels.     

载脂蛋白E基因多态性与疾病的相关性研究

载脂蛋白E（ApoE）是一种重要的血浆脂蛋白,由3种等位基因构成：E2、E3和E4。ApoE作为一种载脂蛋白,在脂质运输和代谢过程中发挥重要作用,而目前越来越多的研究表明：ApoE在免疫调节方面发挥重要作用,从而参与到多种疾病的发生发展中。近年来发现,ApoE及其基因多态性与高脂血症、动脉粥样硬化、Alzheimer病、神经系统病变及脓毒血症等人类疾患的发生发展有着密切关系。     

Memory performance in a sample of very low birth weight adolescents

Prematurely born participants with very low birth weight (VLBW) are at high risk of brain injury in the perinatal period and of later cognitive impairment. Studies of long-term memory sequelae in VLBW participants are scarce and focus on verbal and visual memory assessed by standard clinical memory tests. There is even less research into everyday memory, and the results obtained are contradictory. This study explores long-term memory deficits in VLBW adolescents using 2 standard clinical memory tests and 1 everyday memory test. Results show impairment only in everyday memory. These memory deficits are not specific; they are related to an impaired general cognitive performance. Unlike birth weight, gestational age is a good predictor of intelligence.     

Association between apolipoprotein E polymorphism and serum lipid and apolipoprotein levels with Alzheimer's disease

We have recently demonstrated that apolipoprotein E (APOE)-varepsilon4 allele is a risk factor for Alzheimer disease (AD) in Tehran, Iran. The current study specifically aimed to examine whether APOE polymorphism in association with serum lipids-apolipoprotein level is a risk factor for AD in a population from Tehran, Iran. APOE polymorphism and plasma lipids, apoA1, apoB and lipoprotein (a) (Lp(a)) levels were determined in 94 AD patients and 111matched controls. Our study demonstrated a significant association between APOE polymorphism and the level of plasma lipids and apolipoprotein with AD in this population. The AD subjects had significantly lower apoA1 (p<0.001) and HDL-C (p<0.01) and higher apoB (p=0.01) and LDL-C (p=0.02) levels than that of the control group. The AD subjects carrying APOE-varepsilon4 allele had lower plasma apoA1 (t=5.2, p<0.002) and HDL-C level (t=2.7, p=0.01) but had higher plasma apoB (t=-5.4, p<0.002), LDL-C (t=-4.6, p=0.005) and total cholesterol (TC) (t=-2.7, p=0.01) than that of the non APOE-varepsilon4 carriers. These results indicated that AD patients with APOE-varepsilon4 allele has a distinct plasma lipid profile and carrier of this allele with low levels of apoA1 and HDL-C may be more susceptible to AD.     

载脂蛋白E基因多态性与术后谵妄的关系

目的 探讨载脂蛋白E(APOE)基因多态性与老年非心脏手术患者术后谵妄是否具有相关性。方法 212例65岁以上的择期非心脏手术患者纳入研究,于手术后1~3d密切随访,根据CAM的标准判断患者有无发生谵妄。用突变特异性多重扩增系统 (multi-ARMS PCR)方法测定患者APOE基因型。结果 212例患者中有45例发生术后谵妄,共检出APOEε4等位基因携带者18例(8.5%)。谵妄组有3例APOEε4携带者（6.7%）,非谵妄组有15例APOEε4携带者（9.0%）,两组比较无显著差异。ε4/4纯合子型共有4例,其中1例术前3d发生过一过性谵妄,还有1例发生术后严重谵妄,症状持续17d。结论APOEε4等位基因与术后谵妄发病率无显著的相关性,但ε4/4纯合子型可能更容易发生谵妄。     

载脂蛋白E基因多态性与散发性老年性痴呆病的关系

目的:探讨载脂蛋白E(apoE)外显子4和增强子元件基因多态性与散发性Alzheimer病(AD)的关系。方法:应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术分别检测apoE外显子4和内含子1内增强子元件(IE1)基因型。结果:(1)ApoE外显子4基因多态性:AD组ε3/4基因型频率(0.381)和ε4等位基因频率(0.226)显著高于对照组(P＜0.05)。(2)ApoEIE1基因多态性AD组G/G基因型频率(0.595)显著高于对照组(P＜0.05)。(3)有apoEε4个体患AD风险为无ε4个体的3倍,比值比为2.932,95%可信区间1.379~6.226;G/G基因型个体患AD风险为G/C、C/C个体的2倍,比值比为2.223,95%可信区间1.075~4.599;经统计分析发现apoEε4与IE1G/G呈非常显著性正相关(P＜0.01);排除apoEε4后发现IE1G/G与AD发病风险无关。结论:ApoEε4等位基因是个体发生AD的危险因素,IE1G/G增加AD发病风险是因其与ε4相关所致。     

纳米磁珠法与试剂盒法分析载脂蛋白E基因的多态性

背景：相对于血液标本,口腔拭子标本更利于大规模载脂蛋白E基因多态性分析的研究,但目前对口腔拭子标本基因组DNA的提取尚无统一方法。 目的：探索合适的口腔拭子标本基因组提取方法以分析载脂蛋白E基因的多态性。 方法：收集50例散发性阿尔茨海默病患者口腔拭子标本,每份标本分别应用纳米磁珠法与PicoDNA微量核酸提取试剂盒法提取基因组DNA,对比分析两种方法获得的基因组DNA纯度和浓度,后续进行PCR反应,应用DNA电泳确认有无成功扩增出目的条带,通过DNA测序方法分析载脂蛋白E基因的多态性。 结果与结论：两种方法提取的基因组DNA纯度均较好,纳米磁珠法提取的基因组DNA浓度要高于PcioDNA微量核酸提取试剂盒法所得浓度(P < 0.05)。两组获取的基因组DNA均可成功进行PCR扩增,但电泳结果示纳米磁珠法扩增的目的条带更清楚。两组PCR产物DNA测序结果一致,载脂蛋白E基因ε2、ε3、ε4基因型的比例分别是6%,71%,23%。表明纳米磁珠法相对于PcioDNA微量核酸提取试剂盒法提取口腔拭子标本基因组DNA更适合用于大样本载脂蛋白E基因多态性的研究。     

Relationship of homocysteine, folic acid and vitamin B12 with depression in a middle-aged community sample

BACKGROUND: Case control studies have supported a relationship between low folic acid and vitamin B112 and high homocysteine levels as possible predictors of depression. The results from epidemiological studies are mixed and largely from elderly populations. METHOD: A random subsample of 412 persons aged 60-64 years from a larger community sample underwent psychiatric and physical assessments, and brain MRI scans. Subjects were assessed using the PRIME-MD Patient Health Questionnaire for syndromal depression and severity of depressive symptoms. Blood measures included serum folic acid, vitamin B12, homocysteine and creatinine levels, and total antioxidant capacity. MRI scans were quantified for brain atrophy, subcortical atrophy, and periventricular and deep white-matter hyperintensity on T2-weighted imaging. RESULTS: Being in the lowest quartile of homocysteine was associated with fewer depressive symptoms, after adjusting for sex, physical health, smoking, creatinine, folic acid and B12 levels. Being in the lowest quartile of folic acid was associated with increased depressive symptoms, after adjusting for confounding factors, but adjustment for homocysteine reduced the incidence rate ratio for folic acid to a marginal level. Vitamin B12 levels did not have a significant association with depressive symptoms. While white-matter hyperintensities had significant correlations with both homocysteine and depressive symptoms, the brain measures and total antioxidant capacity did not emerge as significant mediating variables. CONCLUSIONS: Low folic acid and high homocysteine, but not low vitamin B12 levels, are correlates of depressive symptoms in community-dwelling middle-aged individuals. The effects of folic acid and homocysteine are overlapping but distinct.     

Relevance of apolipoprotein E polymorphism for coronary artery disease in the Saudi population

BACKGROUND: The apolipoprotein E alleles epsilon2 and epsilon4 have been reported as independent risk factors for coronary artery disease (CAD) and as predictors for the development of atherosclerosis. METHODS AND RESULTS: We determined by polymerase chain reaction the distribution of apolipoprotein E polymorphism in 320 Saudi blood donors (BD), 96 CAD patients, and 40 control subjects who had undergone angiography. Compared to controls, only epsilon4 was elevated in CAD patients. More than 61% (P <.0001) of the patients had angina, and 52.1% (P <.05) were diabetic; both of these factors were strongly associated with the presence of allele epsilon2. The epsilon2 allele was also associated with hypertension, elevated serum triglycerides, and total cholesterol. On the other hand, the allele epsilon4 appeared to be associated with increased risk of CAD and was also associated with hypertension, 3-vessel disease, and restenosis. CONCLUSIONS: Accordingly, epsilon4 may be associated with increased risk of CAD, whereas epsilon2 appears to be a predictor of several risk factors for atherosclerosis.     

Association between apolipoprotein E polymorphism and Alzheimer disease in Tehran, Iran

Epsilon 4 allele of apolipoprotein E (APOE-epsilon4) is a major risk factor for Alzheimer's disease (AD). The association of APOE allele frequencies with AD remains unknown in developing countries. We examined the frequency of APOE alleles in 105 patients with AD and 129 cognitively normal subjects of similar age and sex (control group), in Tehran, Iran. The APOE-epsilon4 allele frequency was significantly higher in the AD subjects than in the control group (21% versus 6.2%, p < 0.001). In addition, the OR for APOE-epsilon4 heterozygous and homozygous subjects were 3.2 (p = 0.001) and 12.75 (p = 0.01), respectively. The OR was not uniform across age groups. The AD subjects carrying one or two APOE-epsilon4 allele showed earlier age-at-onset (p < 0.001). These data suggest that the APOE-epsilon4 allele increase the risk for AD in Tehran population in a dose and age-dependent manner. Although the APOE-epsilon2 allele frequency was lower in the AD subjects than in the control group (0.95% versus 2.7%, p = 0.15), APOE-epsilon2 was not associated with the onset of AD in Tehran's population. The OR for epsilon2 allele in AD subjects was 0.34 (p = 0.21). The genotype frequencies for epsilon3, epsilon4, and epsilon2 alleles in control subjects were 91.2, 6.1, and 2.7%, respectively. These values were similar to that reported for Turkish, Greece, Japanese, Spanish, and Moroccan populations, but they were significantly different from the reported values for the other ethnic populations. This observation emphasizes the importance of geographical location and ethnical background of the subjects in the study of APOE genotypes and their association with AD.     

The effect of the apolipoprotein E polymorphism on lipid levels in patients with familial defective apolipoprotein B-100

Summary Serum lipid concentrations of patients with familial defective apolipoprotein B-100 (FDB) show a high interindividual variability although the underlying defect is caused by a single point mutation. On the other hand, several genetic factors modulating serum cholesterol levels are known, such as DNA polymorphisms of the apopolipoprotein B or the apolipoprotein E (apo E) gene. To assess the effect of the apo E polymorphism on serum cholesterol, lipid levels of FDB patients (n=36) were compared with those of a normolipidemic control group (n=272) according to their apo E genotype. For the FDB group mean values of low-density lipoprotein (LDL) cholesterol (mg/dl) were 225.7 ± 53.7 for E3/2 genotype (n = 3), 234.2±48.3 for E3/3 genotype (n=20), and 252.4±73.8 for E4/3 genotype (n=13). Means of triglycerides (mg/dl) were 121.0±21.2, 114.8± 60.7, and 110.0 ± 62.8 for the respective apo E genotypes. The calculated average effect of the apo E alleles on LDL cholesterol levels was –6.0% for allele e2 and +3.7% for e4 relative to the whole FDB group. The effect on triglyceride levels was +7.5% for e2 and –3.6% for e4. The control group showed a similar variation in LDL cholesterol depending on the different apo E genotypes. About 6% of the total variation in LDL cholesterol can be accounted for by the apo E locus in normolipidemic and hypercholesterolemic individuals alike.Abbreviations FDB familial defective apolipoprotein B-100 - apo apolipoprotein - LDL low-density lipoprotein - VLDL very low density lipoprotein - HDL high-density lipoprotein - PCR polymerase chain reaction Dedicated to Prof. Dr. N. Zöllner on the occasion of his 70th birthday     

Lack of association of apolipoprotein E polymorphism with plasma Lp(a) levels in the Chinese

Apolipoprotein E (apoE) polymorphism and its influence on plasma lipids, lipoproteins, lipoprotein (a) [Lp(a)] and apolipoproteins was studied in 536 (270 males and 266 females) healthy Chinese in Singapore. From analysis of variance with age and BMI as covariates, apoE genotype was found to exert a significant influence on plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apoB in females. Its effect in males was marginally significant only on LDL-C. In both sexes, plasma TC, LDL-C and apoB were lower in those who were E2-3 than in those who were E3-3. There was no significant difference in log-transformed Lp(a) level between the apoE genotypes after adjusting for the confounding effect of LDL-C in addition to age and BMI. The percentage variance (R2times100) of the lipid traits explained by apoE polymorphism in the females was 4.94% for plasma TC, 5.85% for LDL-C and 4.25% for apoB. We conclude that: 1) ε2 allele had a lowering effect on plasma TC, LDL-C and apoB; 2) apoE polymorphism did not have any significant influence on Lp(a) concentration; and 3) the effect of apoE polymorphism on plasma TC, LDL-C and apoB was gender-specific, with a stronger influence in females than in males.     

Association of apolipoprotein E gene polymorphism with essential hypertension and its complications

The clinical significance of the apolipoprotein E genotype in patients with hypertension has been a subject of debate. We enrolled 94 patients with hypertension and 102 healthy controls in this study and determined their plasma levels of triglyceride, total cholesterol, high- and low-density lipoprotein-cholesterol, apolipoprotein AI, and apolipoprotein B. The apolipoprotein E genotypes were identified by polymerase chain reaction, restriction fragment length polymorphism, and polyacrylamide gel electrophoresis. Apolipoprotein E3/4 genotype and 4 allele frequencies in the hypertensive group were higher than in controls. In hypertensive patients with apolipoprotein E3/4 and E4/4 genotypes, systolic blood pressure was significantly higher than in those with apolipoprotein E2/3 or E3/3 genotypes. Meanwhile, the plasma levels of total cholesterol, low-density lipoprotein-cholesterol, and apolipoprotein B were higher in hypertensive patients with the .4 allele than the 2 or 3 allele. The echographic measurements of carotid artery intimal-medial thickness showed increasing values from 2 to 4 allele carriers in the hypertensive group. Analysis of variance showed that the carotid intimal-medial thickness was significantly greater in hypertensive patients with 4 alleles compared with 2 or 3 alleles. Our data show an association between apolipoprotein E genotype and hypertension and support the hypothesis that the apolipoprotein 4 allele is a susceptibility locus for systolic hypertension and carotid artery atherosclerosis. Received: 23 July 2002 / Accepted: 27 December 2002 Correspondence to Xiaotao Li     

Clinical implications of the apolipoprotein E polymorphism and genetic variants: current methods for apo E phenotyping

There is agreement about the influence of the genetic apolipoprotein (apo E) polymorphism on plasma lipid and apoprotein levels in man. Whereas the association of the apo E2 isoform with primary dysbetalipoproteinemia and hyperlipoproteinemia type III is well established, the plasma- and LDL-cholesterol lowering effects of apo E2 and the phenomenon of apo E4 raising these parameters on the development of coronary heart disease is still a matter of controversial discussion. Despite these uncertainties the knowledge of an individual's apo E phenotype may provide additional information in future to judge its risk to develop atherosclerosis. From a variety of methods meanwhile described to analyze the polymorphism and evaluate the apo E phenotype the author has modified three procedures to apply to different questions concerning apo E isoform analysis. They concern the visualization of the apo E pattern in diluted solutions and those containing high salt concentrations, the apo E phenotyping on a large scale basis from whole plasma avoiding a possible misinterpretation by a thrombin fragment of apo E and finally the search for new apo E variants with a high resolution system on immobilized pH gradient gels.     

载脂蛋白E多态性与脑梗死及脂类代谢关系的研究

目的:探讨载脂蛋白E(ApoE)多态性与脑梗死及脂类代谢的关系。方法:缺血性脑梗死组110例,健康对照组60例。ApoE表型采用等电聚焦(IEF)电泳及免疫印迹(Westernblotting)技术测定,血清总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)采用酶法测定,低密度脂蛋白胆固醇(LDL-C)按Fridwald公式计算,ApoAⅠ、ApoB用火箭电泳法测定,ApoE、脂蛋白(a)用ELISA法测定。结果:脑梗死组ApoEε4等位基因表达显著高于对照组(P＜0.05);脑梗死组TC、TG、LDL-C、ApoB、ApoE、Lp(a)水平显著高于对照组(P＜0.05或P＜0.01),ApoAⅠ、HDL-C显著低于对照组(P＜0.05);脑梗死组各等位基因(ε2、ε3、ε4)之间血脂水平比较;含ε4等位基因者,TC、LDL-C、ApoB、Lp(a)水平高于含ε3者(P＜0.05),HDL-C、ApoAⅠ较低(P＜0.05);含ε2等位基因者,TG、HDL-C、ApoAⅠ、ApoE高于含ε3者(P＜0.05),TC、LDL-C、ApoB较低(P＜0.05)。结论:ApoEε4等位基因与脑梗死发病有关,ε2、ε4等位基因与脑硬死患者的脂类代谢改变有关。     

Association of apolipoprotein E polymorphism to clinical heterogeneity of multiple sclerosis

In this study we investigated the distribution of apolipoprotein E (APO E) genotypes in sporadic multiple sclerosis (MS) cases and in normal controls. Later onset of chronic progressive MS was observed in patients carrying the epsilon2 allele, whereas APO E alleles were found at similar frequency in MS and in the control population. These findings indicate that clinical heterogeneity, but probably not susceptibility to the disease, is associated to APO E genotypes.