Non-apolipoprotein E and apolipoprotein E genetics of sporadic Alzheimer's disease

The genetic epidemiology of sporadic Alzheimer's disease (SAD) remains a very active area of research, making it one of the most prolifically published areas in medicine and biology. Numerous putative candidate genes have been proposed. However, with the exception of apolipoprotein E (APOE), the only confirmed genetic risk factor for SAD, all the other data appear to be not consistent. Nevertheless, the genetic risk for SAD attributable to the APOE gene in the general population is 20–70%, providing a strong evidence for the existence of additional genetic risk factors. The first part of the present article was dedicated to non-APOE genetics of SAD, reviewing chromosomes-by-chromosomes the available data concerning the major candidate genes. The second part of this article focused on some recently discovered aspects of the APOE polymorphism and their implications for SAD. An attempt to identify the future directions for non-APOE genetic research in SAD was also discussed.     

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。     

乌鲁木齐地区老年人群三种与ApoE基因相关因子与Alzheimer''''s病的相关性研究

目的研究乌鲁木齐市老年人群的性别、年龄以及所受教育程度这三种与ApoE相关危险因子与AD发病风险之间的关系.方法应用PCR-RFLP等技术对60例AD患者和90例对照者的ApoE基因进行分型,分别计算两组ApoE各等住基因、基因型的频率,按照性别、年龄以及所受教育程度进行分组分析.结果(1)女性的ε4等位基因频率在AD和对照组间有显著性差异(ε4AD:ε4Cpmtrol=20.97:5.00,P＜0.01);(2)小于75岁的AD患者ε4等位基因频率大大高于同龄对照组(P＜0.01),而≥75的AD患者ε4等位基因频率明显低于75岁以下AD患者(P＜0.01);(3)文盲和小学文化程度的AD患者的ε4等位基因频率明显高于对照组,而高中文化程度的AD患者其ε4等位基因频率却低于对照,统计学处理说明这些差异都有显著性(P＜0.01).结论:(1)携带ε4等位基因的女性AD发病风险高于男性;(2)75岁以下ε4携带者具有高的AD发病风险;(3)受教育程度低且携带ε4等位基因者易患AD.     

The impact of apolipoprotein E on dementia in persons with Down's syndrome

Apolipoprotein E (APOE) is consistently associated with dementia in the general population. Findings on the role of this gene in persons with Down's syndrome (DS) are inconclusive. We studied the effects of APOE on mortality and dementia in a longitudinal prospective study of a large population-based sample of persons with DS (n = 425), demented and non-demented. There was evidence that APOE 4 is correlated with the rate of decline in the social competence rating scale (SRZ) (p = 0.04). In our population, we found overall a modest but not statistical significant effect on the prevalence of dementia (OR = 1.57, 95%CI: 0.87–2.82). We did observed a significant long-term effect on the incidence of dementia (HR = 4.66, 95%CI: 1.35–16.14), but for those with a follow-up less than 3 years the risk was not significantly increased: HR = 0.83 (95%CI 0.35–1.94). When pooling our data in a meta-analysis, the APOE 4 allele shows a 1.59-fold (95%CI: 1.19–2.12) increase in risk of dementia in persons with DS. We conclude that APOE is influencing the risk of dementia in persons with DS.     

EEG alterations in non-demented individuals related to apolipoprotein E genotype and to risk of Alzheimer disease

Identification of preclinical markers is required for early diagnosis of Alzheimer's disease (AD) and cognitive dysfunction in advancing age. Quantitative EEG was examined in 145 individuals with AD, their unaffected relatives and unrelated individuals. The AD patients and their relatives were stratified by ApoE genotype. The resting EEG parameters were severely changed in AD patients, and in patients carrying the ApoE 4 allele the decrease in alpha power was higher than in 4 non-carriers. The resting EEG parameters were indistinguishable in AD relatives with different ApoE genotypes and similar to EEG pattern in common population. Under hyperventilation the presence of the 4 allele in AD relatives was associated with the manifestation of synchronous high-voltage delta-, theta-activity and sharp-waves, pronounced decrease in alpha and increase in delta and theta relative powers. The data suggest that neurophysiological endophenotype of non-demented individuals at genetic risk for AD, characterized by increased excitability and dysfunction of deep brain and alpha rhythm-generating structures, may be revealed decades before the first clinical symptoms of presumable dementia.     

细胞钙离子转运蛋白兰尼碱受体3与ApoE基因敲除小鼠动脉粥样硬化斑块形成的关系

目的:观察细胞钙离子转运蛋白兰尼碱受体3(ryanodine receptor 3, RYR3)在动脉粥样硬化斑块形成过程中的改变,探讨两者的相关性。方法:选取6周龄雄性载脂蛋白E基因敲除(ApoE^-/-)小鼠及野生型C57BL/6J小鼠,高脂饲喂20、27和33周后,在各个时点处死动物取主动脉根部制作连续切片。(1)HE染色,观察组织形态学的变化,计算机图像分析仪测量斑块面积和血管管腔面积,计算校正斑块面积(斑块面积/血管管腔面积)。(2)免疫组织化学染色,计算机图像分析仪测定不同周龄小鼠细胞钙离子转运蛋白RYR3表达变化。结果:与同周龄对照组小鼠相比,ApoE^-/-小鼠体内RYR3表达显著减少(P<0.05),随着ApoE^-/-小鼠周龄的增加,RYR3的表达明显减少,且与斑块面积/血管管腔面积呈负相关(r＝-0.652,P<0.01)。结论:细胞钙离子转运蛋白RYR3参与动脉粥样硬化的病理过程,且与动脉粥样硬化斑块的形成密切相关。     

The apolipoprotein E gene in Binswanger's disease and vascular dementia

We investigated the polymorphism of the apolipoprotein E (ApoE) gene using a PCR-RFLP method in patients with Binswanger's disease (BD), non-BD vascular dementia, or Alzheimer's disease (AD). The frequency of the e4 allele of the ApoE (ApoE4) in BD patients and non-BD vascular dementia patients did not differ from that observed in the non-demented elderly controls, but it was significantly lower than the frequency in AD patients. These results and other recent observations suggest that one or more factors other than the ApoE gene contribute to the pathogenesis of dementia in BD and non-BD vascular dementia.     

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     

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。     

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.     

新疆维吾尔族阿尔茨海默病患者脑啡肽酶基因与载脂蛋白E基因多态性的关联分析

目的 探讨脑啡肽酶(neprilysin,NEP)基因rs3736187位点突变及其与载脂蛋白E(apolipoprotein E,ApoE)基因相互作用在新疆维吾尔族人群散发性阿尔茨海默病(sporadic Alzheimer disease,SAD)发病机制中的作用.方法 应用聚合酶链反应-限制性片段长度多态性方法 检测了111例维吾尔族SAD患者和117名维吾尔族正常老年人NEP基因和ApoE基因多态性分布特征.结果 (1)NEP基因T等位基因频率在AD组高于对照组(x2=5.005,P＜0.05),携带T等位基因个体出现AD的危险性高于携带C等位基因的个体.(2)ApoE基因ε4等位基因频率AD组高于对照组(x2=4.218,P＜0.05),携带ε4等位基因个体出现AD的危险性高于未携带ε4等位基因的个体.(3)NEP基因的T等位基因与SAD发病相关且不受ApoE基因型影响.结论 NEP基因和ApoE基因的基因多态性与新疆维吾尔族SAD发病有关联.NEP基因可能是新疆维吾尔族SAD发病独立的易感基因.     

Development of atherosclerosis in Balb/c apolipoprotein E-deficient mice

BACKGROUND: Since its creation in 1992 by gene inactivation via gene targeting, the apolipoprotein E "knockout" mouse has become the most widely used rodent model for the study of atherosclerosis. Commercially available apolipoprotein E(-/-) mice are bred on a C57BL/6J background. The goal of the present study was to investigate the development of atherosclerosis in apolipoprotein E-deficient mice generated on a Balb/c background. METHODS: We compared serum cholesterol concentrations and the development of atherosclerotic lesions in heterozygous Balb/c [apolipoprotein E(+/-)] mice fed regular rodent chow, Balb/c apolipoprotein E-deficient mice fed regular chow, and Balb/c apolipoprotein E-deficient mice fed a high-fat diet for up to 30 weeks. Expression of the chemokine JE (murine homologue of MCP-1), as well as the adhesion molecules E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, in the aortas of knockout mice fed a high-fat diet was measured by enzyme-linked immunosorbent assay. RESULTS: Balb/c apolipoprotein E-deficient mice develop atherosclerotic lesions in a reproducible temporal and morphological pattern. Total serum cholesterol concentrations in Balb/c apolipoprotein E-deficient mice fed regular chow or a high-fat diet, respectively, closely parallel those reported for C57BL/6J apolipoprotein E-deficient mice. The expression of all three adhesion molecules in the aorta follows a similar temporal pattern, peaking in the first 15 weeks, whereas JE concentrations peak around 23 weeks. CONCLUSION: The availability of Balb/c apolipoprotein E-deficient mice will facilitate the study of atherosclerosis in a mouse strain that can concomitantly develop other pathological states that are not readily inducible in mice with the C57BL/6J background.     

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.     

PCR结合银染法检测载脂蛋白E等位基因

目的介绍一种高效、灵敏、安全的载脂蛋白Ｅ等位基因检测法。方法采用非酚法快速提取人全血基因组ＤＮＡ，ＰＣＲ扩增包含两个等位基因决定位点的ＤＮＡ片段，扩增产物经限制性酶切后进行聚丙烯酰胺凝胶电泳，用简易银染法显示酶切片段。结果银染显示出清晰易辨的ＤＮＡ酶切小片段，整个检测过程２４小时完成。将此法初步用于１９例散发性阿尔茨海默病患者和４１名无精神神经疾患老年人载脂蛋白Ｅ等位基因的检测，测得ε４等位基因频率分别为０．２９和０．０２，两者之间差异非常显著（Ｐ＜０．００１）。结论ＰＣＲ结合银染法检测载脂蛋白Ｅ等位基因，在尽量避免使用有害试剂的同时，提高了检测灵敏度和效率，因此适用于临床及流行病学调查时对大批标本的检测     

Detection of behavioral alterations and learning deficits in mice lacking synaptophysin

The integral membrane protein synaptophysin is one of the most abundant polypeptide components of synaptic vesicles. It is not essential for neurotransmission despite its abundance but is believed to modulate the efficiency of the synaptic vesicle cycle. Detailed behavioral analyses were therefore performed on synaptophysin knockout mice to test whether synaptophysin affects higher brain functions. We find that these animals are more exploratory than their wild type counterparts examining novel objects more closely and intensely in an enriched open field arena. We also detect impairments in learning and memory, most notably reduced object novelty recognition and reduced spatial learning. These deficits are unlikely caused by impaired vision, since all electroretinographic parameters measured were indistinguishable from those in wild type controls although an inverse optomotor reaction was observed. Taken together, our observations demonstrate functional consequences of synaptophysin depletion in a living organism.     

Association between apolipoprotein E gene polymorphism and the risk of vascular dementia: A meta-analysis

It remains controversial regarding the association between Apolipoprotein E (ApoE) gene polymorphism and the risk of vascular dementia (VaD). The present meta-analysis was performed to derive a more precise estimation of the relationship. The meta-analysis was performed by searching PubMed, Embase and Web of Science databases. A total of 29 studies included 1763 VaD cases and 4534 controls were identified. The results showed evidence for significant association between ApoE ?4 mutation and VaD risk (for ?3/?4 vs. ?3/?3: OR = 1.65, 95% CI = 1.40–1.94, p-value < 0.00001; for ?4/?4 vs. ?3/?3: OR = 3.17, 95% CI = 2.09–4.80, p-value < 0.00001; for ?4 allele vs. ?3 allele: OR = 1.72, 95% CI = 1.40–2.12, p-value < 0.00001). The similar results were obtained in the subgroup analysis based on ethnicity. In summary, the present meta-analysis suggests an association between ApoE ?4 mutation and increased risk of VaD. However, due to the small sample size in most of the included studies and the selection bias existed in some studies, the results should be interpreted with caution.     

Polymorphism of apolipoprotein E

Two methods for phenotyping apolipoprotein E are compared. One is based on preparation of VLDL by conventional ultracentrifugation, whereas the other uses heparin/Mg precipitation of VLDG. In principle, the same results were obtained by both methods. However, the group limits for the three different phenotypes Apo E-N, Apo E-ND and Apo E-D were slightly different by the two methods. Phenotype Apo E-D - the phenotype characterizing type III dyslipoproteinemia - is clearly definable by both methods. Hence the precipitation-I.E.F. method for Apo E phenotyping provides a simple tool for genetic and population genetic studies and also for the routine diagnosis of hyperlipoproteinemia type III, based on the only specific marker known for this disease.     

Reduced plasticity and mild cognitive impairment-like deficits after entorhinal lesions in hAPP/APOE4 mice

Mild cognitive impairment (MCI) is a clinical condition that often precedes Alzheimer disease (AD). Compared with apolipoprotein E-ε3 (APOE3), the apolipoprotein E-ε4 (APOE4) allele is associated with an increased risk of developing MCI and spatial navigation impairments. In MCI, the entorhinal cortex (EC), which is the main innervation source of the dentate gyrus, displays partial neuronal loss. We show that bilateral partial EC lesions lead to marked spatial memory deficits and reduced synaptic density in the dentate gyrus of APOE4 mice compared with APOE3 mice. Genotype and lesion status did not affect the performance in non-navigational tasks. Thus, partial EC lesions in APOE4 mice were sufficient to induce severe spatial memory impairments and synaptic loss in the dentate gyrus. In addition, lesioned APOE4 mice showed no evidence of reactional increase in cholinergic terminals density as opposed to APOE3 mice, suggesting that APOE4 interferes with the ability of the cholinergic system to respond to EC input loss. These findings provide a possible mechanism underlying the aggravating effect of APOE4 on the cognitive outcome of MCI patients.     

F-fluorodeoxyglucose positron emission tomography,aging, and apolipoprotein E genotype in cognitively normal persons

Our objective was to examine associations between glucose metabolism, as measured by ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG PET), and age and to evaluate the impact of carriage of an apolipoprotein E (APOE) ε4 allele on glucose metabolism and on the associations between glucose metabolism and age. We studied 806 cognitively normal (CN) and 70 amyloid-imaging-positive cognitively impaired participants (35 with mild cognitive impairment and 35 with Alzheimer's disease [AD] dementia) from the Mayo Clinic Study of Aging, Mayo Alzheimer's Disease Research Center and an ancillary study who had undergone structural MRI, FDG PET, and ¹¹C-Pittsburgh compound B (PiB) PET. Using partial volume corrected and uncorrected FDG PET glucose uptake ratios, we evaluated associations of regional FDG ratios with age and carriage of an APOE ε4 allele in CN participants between the ages of 30 and 95 years, and compared those findings with the cognitively impaired participants. In region-of-interest (ROI) analyses, we found modest but statistically significant declines in FDG ratio in most cortical and subcortical regions as a function of age. We also found a main effect of APOE ε4 genotype on FDG ratio, with greater uptake in ε4 noncarriers compared with carriers but only in the posterior cingulate and/or precuneus, lateral parietal, and AD-signature meta-ROI. The latter consisted of voxels from posterior cingulate and/or precuneus, lateral parietal, and inferior temporal. In age- and sex-matched CN participants the magnitude of the difference in partial volume corrected FDG ratio in the AD-signature meta-ROI for APOE ε4 carriers compared with noncarriers was about 4 times smaller than the magnitude of the difference between age- and sex-matched elderly APOE ε4 carrier CN compared with AD dementia participants. In an analysis in participants older than 70 years (31.3% of whom had elevated PiB), there was no interaction between PiB status and APOE ε4 genotype with respect to glucose metabolism. Glucose metabolism declines with age in many brain regions. Carriage of an APOE ε4 allele was associated with reductions in FDG ratio in the posterior cingulate and/or precuneus, lateral parietal, and AD-signature ROIs, and there was no interaction between age and APOE ε4 status. The posterior cingulate and/or precuneus and lateral parietal regions have a unique vulnerability to reductions in glucose metabolic rate as a function both of age and carriage of an APOE ε4 allele.