Association between apolipoprotein CI HpaI polymorphism and sporadic Alzheimer's disease in Chinese

OBJECTIVE: To investigate into the relationship of apolipoprotein CI (ApoCI) polymorphism with sporadic Alzheimer's disease (AD) in Chinese. SUBJECTS AND METHODS: A total of 257 AD patients and 242 age-matched elderly individuals were genotyped for the ApoCI HpaI and apolipoprotein E (ApoE) HhaI polymorphisms. RESULTS: The ApoCI A allele was associated with AD of moderate to severe dementia when patients were divided into two subgroups according to Clinical Dementia Rating scale, and the AA genotype was strongly associated with moderate to severe AD in ApoE epsilon4 allele carriers [odds ratio (OR) = 8.19, 95% confidential interval: 1.28-52.30, after adjusting for age and gender by logistic regression analysis], although in total no significant differences of allele or genotype frequency between patients and controls were found. CONCLUSION: The present study partially confirmed the previous findings, suggesting that the ApoCI A allele might contribute to the susceptibility to moderate to severe sporadic AD in Chinese.     

The butyrylcholinesterase K variant is a protective factor for sporadic Alzheimer's disease in women

INTRODUCTION: Recent reports indicate that the K variant of the butyrylcholinesterase (BCHE) gene may act in synergism with the epsilon4 allele of apolipoprotein E (APOE) to increase the risk of Alzheimer's disease (AD), but this is controversial. MATERIAL AND METHODS: We genotyped for the BCHE-K and APOE epsilon4 alleles in a sample of 249 AD patients and 250 controls derived from the same region in a Spanish population. RESULTS: A protective effect of the K variant of BCHE with an odds ratio of 0.41 (95% confidence interval 0.19-0.86, P=0.02) was observed among non-APOE epsilon4 carriers, but it was limited to women. CONCLUSION: Our study is the first to demonstrate that lower susceptibility to AD determined by the K variant of BCHE is dependent on gender.     

Relationship between apolipoprotein E and the amyloid deposits and dystrophic neurites of Alzheimer's disease

T. C. Dickson, H. L. Saunders and J. C. Vickers (1997) Neuropathology and Applied Neurobiology , 23, 483–491
Relationship between apolipoprotein E and the amyloid deposits and dystrophic neurites of Alzheimer's disease
Although the inheritance of certain apolipoprotein E (ApoE) alleles has been recognized as a genetic risk factor for Alzheimer's disease, the role of ApoE in the pathology underlying this disease is unclear. Several reports have emphasized the association of ApoE with either β-amyloid plaque formation or the development of neurofibrillary pathology. Utilization of multiple label immunohistochemical methods enabled us to examine directly the localization of ApoE immunoreactivity relative to β- amyloid plaques, dystrophic neurites and neurofibrillary tangles. In Alzheimer's disease cases, β-amyloid plaques showing high ApoE immunoreactivity were localized to layers II, III and V of the neocortex. In layer I, β-amyloid plaques were unlabelled for ApoE relative to β-amyloid. Dense core plaques labelled for β-amyloid often had only the central portions labelled for ApoE. Conversely, ApoE labelled spherical structures within some plaques were not immunoreactive for β-amyloid or dystrophic neurite markers. Unlike β-amyloid labelled plaques, all ApoE immunoreactive plaques were associated with dystrophic neurites. In preclinical Alzheimer's disease cases, most plaques were double labelled for β-amyloid and ApoE. ApoE did not label dystrophic neurites or the early stages of neurofibrillary tangle formation, indicating that ApoE may not be directly involved in neurofibrillary pathology. The specific presence of ApoE in plaques associated with dystrophic neurites in demented patients suggests that ApoE may contribute toward a higher degree of β- amyloid fibrillogenesis, enhancing the ability of certain plaques to cause damage to surrounding axons.     

Parkinson病与Alzheimer病载脂蛋白E基因型分布的研究

目的探讨载脂蛋RE（apoE）基因多态性与Parkinson病及Alzheimer病的关系。方法应用聚合酶链反应-限制性片段氏度多态性（PCR－RFLP）技术检测72名帕金森氏病（PD）、68名Alzheimer病（AD）患者和66名正常老年人的apoE基因型分布。结果PD组apoE2、apoE3、apoE4及AD组apoE4等位基因频率与对照组比较无统计学意义（P＞0.05）;AD组apoE2等位基因频率明显低于对照组（P＜0．01）。结论apoE基因型分布与PD发病无关;与AD发病相关,即apoE2基因可能具有防止AD发病的作用;不支持apoE4是中国人散发性AD发病病危因素的结论。     

Relation of apolipoprotein E polymorphism to clinically diagnosed Alzheimer's disease in the Korean population

The gene for human apolipoprotein E (APOE) is found on the long arm of chromosome 19 (19q13.2) and exists in three common allelic forms, epsilon2, epsilon3, and epsilon4. The APOE epsilon4 allele is overrepresented in Alzheimer's disease (AD) and is accepted as a genetic risk factor. Some studies reported a protective effect of the APOE epsilon2 allele for AD. However, there are some ethnic variations in the proportion of different APOE alleles and their relationship to AD. We examine the distribution of APOE alleles from 30 AD patients and 158 controls in Korea. The control subjects were all cognitively intact unrelated Koreans. The frequencies of APOE alleles in AD patients were 18.3% (epsilon2), 58.3% (epsilon3), and 23.3% (epsilon4). The corresponding frequencies in controls were 13.3% (epsilon2), 72.5% (epsilon3), and 14.2% (epsilon4). The frequency of the APOE epsilon2 allele in AD patients was not significantly different from that in controls. When statistical analysis was conducted after the exclusion of the APOE epsilon2 allele, the frequency of the APOE epsilon4 allele in AD patients was significantly higher than that in controls (P < 0.05). These results support that the APOE epsilon4 allele plays a role as a risk factor for AD in Koreans and suggest that the APOE epsilon2 allele may not play a protective role in the development of AD in Koreans.     

Does apolipoprotein E (Apo-E) genotype influence nicotinic receptor binding in Alzheimer's disease

Summary. We wished to determine the influence of the apolipoprotein E (Apo-E) genotype on the loss of high affinity nicotinic acetylcholine receptor (nAChR) binding in Alzheimer's disease (AD). The interaction between ε4 allele gene dose and cholinergic loss in AD remains controversial. We have demonstrated that nicotinic binding is significantly lost in AD. Tissue from the midfrontal (MF) cortex of 7 subjects with no ε4 allele copies (ε−/ε−) (mean death age 75.1 ± 10.4 years) was compared to MF cortex of 14 subjects heterozygous for the ε4 allele (ε4/ε−) (mean death age 81.4 ± 7.3 years) and MF cortex of 10 subjects homozygous for the ε4 allele (ε4/ε4) (mean death age 79.6 ± 5.0 years). All subjects were autopsy confirmed AD (using NIA and CERAD criteria) and met NINCDS-ADRDA clinical criteria for probable or possible AD. Nicotine AChR binding was assayed using the high affinity nicotinic agonist ³H-epibatidine ([³H]-Epi). Apo-E genotype was determined in blood samples or in post-mortem tissue. The mean age at death was not significantly different among the groups (p = 0.19). There was no difference in mean [³H]-Epi total binding among the three groups (6.7 ± 4.6, 6.1 ± 2.4, and 6.0 ± 1.0 fmol/mg protein for ε−/ε−, ε4/ε−, and ε4/ε4 respectively. We conclude that the presence or absence of the Apo-E4 genotype does not influence the loss of high affinity nAChR in AD. Received January 16, 2001; accepted April 16, 2001     

Estrogen receptor α and APOEɛ4 polymorphisms interact to increase risk for sporadic AD in Italian females

Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects both sexes, with a higher prevalence in women. Declining estrogen levels after menopause may render estrogen target neurons in the brain more susceptible to age or disease-related processes such as AD. To investigate the role of two single nucleotide polymorphisms in the first intron of the ER-alpha gene, denominated PvuII and XbaI, and their interaction with the known AD susceptibility gene APOE, we examined 131 patients with sporadic AD and 109 healthy control subjects. In multinomial logistic regression analysis, a significantly increased risk of sporadic AD because of interaction between the ER-alpha p allele and APOE epsilon4 allele was observed in women, taking subjects who had neither the p allele nor epsilon4 as reference [odds ratio (OR) 7.24; 95% CI, 2.22-23.60]. For women carrying the ER-alpha x allele together with APOE epsilon4, the risk of sporadic AD was similarly elevated (OR 8.33; 95% CI, 1.73-40.06). The data suggest that the p and x alleles of polymorphic ER-alpha gene interact synergistically with the APOE epsilon4 allele to increase the risk of AD in women but not in men in this Italian cohort.     

Codon 129 polymorphism of prion protein gene in sporadic Alzheimer's disease

Codon 129 polymorphism of the prion protein gene represents a major genetic risk factor for Creutzfeldt-Jakob disease (CJD). Both CJD and Alzheimer's disease (AD) are brain amyloidoses and it would be possible that codon 129 polymorphism plays a role in the susceptibility to AD. In order to investigate this polymorphism in AD the distribution of polymorphic codon 129 of the PRNP gene in 194 probable AD and 124 controls selected in Italy and 109 neuropathologically verified AD and 58 matched controls recruited in the USA was studied. No significant association was found for the PRNP polymorphism in AD compared to controls either in Probable or in Definite AD series even after stratification for APOE polymorphism. This study does not support a role of PRNP polymorphism as a susceptibility factor for AD.     

Increased apolipoprotein B serum concentration in Alzheimer's disease

OBJECTIVE: To investigate the lipoprotein profile in a group of Alzheimer's disease (AD) patients. PATIENTS AND METHODS: Twenty-four patients with AD and 32 elderly controls were evaluated. Fasting blood samples were obtained for determination of total VLDL, HDL and LDL cholesterol, lipoprotein (a), triglycerides, apolipoprotein A1 and apolipoprotein B. RESULTS: Significantly higher levels of apolipoprotein B were found in AD patients (P = 0.004), whereas the concentration of lipoprotein (a) and plasma lipids was not statistically different. Apo B levels were similar between AD patients with or without leukoaraiosis on CT scan. CONCLUSION: AD patients had high serum concentration of apolipoprotein B. This finding suggests that apolipoprotein E may not be the single factor in lipid metabolism to play a role in AD pathogenesis.     

Possible increased risk for Alzheimer's disease associated with neprilysin gene

Summary. Neprilysin has recently been reported to be the major physiological Aβ-degradating enzyme. In this study we describe a new biallelic polymorphism in the 3′UTR of the neprilysin gene in a representative population sample. The ^*159C/C genotype was found to be associated with an increased risk for Alzheimer's disease in an age-dependent manner. Adjusting for sex and APOE status, an odds ratio of 2.74 (p < 0.05) was observed among patients under 75 years old. Received October 2, 2002; accepted December 9, 2002 Published online February 19, 2003 Acknowledgements We would like to thank A. Andrés, F. Calafell (Universitat Pompeu Fabra), and B. Cormand (Universitat de Barcelona) for useful comments and fruitful discussion. We also thank M. Vallés for technical assistance and the ACE staff for their invaluable help. This study was supported by grants from DGICT (PB98-1064, and BOS2001-0794) and by the Generalitat de Catalunya, Grup de Recerca Consolidat 2001SGR00285. Authors' address: Dr. D. Comas, Unitat de Biologia Evolutiva, Universitat Pompeu Fabra, C/ Doctor Aiguader 80, Barcelona 08003, Catalonia, Spain, e-mail: david.comas@cexs.upf.es     

Decreasing hazards of Alzheimer's disease with the use of antidepressants: mitigating the risk of depression and apolipoprotein E

Objective

Alzheimer's disease (AD) is a neurodegenerative disease, manifesting in clinically observable deficits in memory, thinking, and behavior that disproportionately affects older adults. Susceptibility genes, such as apolipoprotein ε4, have long been associated with an increased risk of AD diagnosis. Studies have shown associations between depression and increased risk of AD development. Furthermore, findings from previous investigations suggest mixed effects in the use of psychotropic medication in older adults. The hypothesis for this study is that antidepressant use modifies the increased hazard of depression or such that a non‐significant hazard will result with respect to eventual AD development.

Methods

Utilizing data from the National Alzheimer's Coordinating Center, we examined evaluations of 11,443 cognitively intact participants. Survival analysis was used to explore relationships between depression, apolipoprotein E, AD diagnosis, and antidepressant use.

Results

An analytical sample of 8732 participants with normal cognition was examined. Among users of antidepressant medication, the hazard, in most cases, was no longer statistically significant. One generic medication showed protective benefits for users (p < 0.001). In addition, there was a statistically significant relationship between recent depression (n = 2083; p < 0.001), lifetime depression (n = 2068; p < 0.05), and ε4 carrier status (n = 2470; p < 0.001) and AD development.

Conclusions

The findings suggest that a mechanism related to antidepressant use may reduce the hazard of eventual AD. Furthermore, the findings reinforce the association between depression, apolipoprotein E (APOE) ε4, and AD diagnosis. This study contributes to the emerging literature exploring interventions aimed at decreasing the risk of AD by targeting potentially modifiable psychosocial risk factors such as depression. Copyright © 2017 John Wiley & Sons, Ltd.     

Alzheimer病早期脑脊液tau蛋白与ApoE基因的关系

目的探讨Alzheimer病患者脑脊液tau蛋白与ApoE基因型的关系。方法对84例患者脑脊液微管相关蛋白(tau蛋白)应用ELISA法对进行定量,其中41例临床诊断为早期Alzheimer病(AD),23例伴其他类型的痴呆,6例为Down综合征患者;14例非痴呆患者为对照组。结果多变量ANOVA分析显示痴呆患者与ApoE等位基因者脑脊液tau蛋白升高,AD患者脑脊液tau蛋白浓度明显高于对照组。而非AD痴呆患者脑脊液tau蛋白浓度与AD患者和对照组无明显差异,伴ApoEε4等位基因的AD病人与不伴ε4等位基因的AD病人相比,tau蛋白浓度升高。结论脑脊液tau蛋白浓度升高提示携带ε4等位基因AD病人早期发生神经变性和神经纤维病理学改变,应用ELISA法检测脑脊液tau蛋白对诊断早期AD及与其他类型的痴呆相鉴别缺乏敏感性和特异性,应首先考虑ApoE基因类型。     

载脂蛋白E与阿尔茨海默病相关性研究进展

阿尔茨海默病(AD)是老年期痴呆的主要类型,目前发病机制不完全清楚,可能与基因和环境共同作用有关,载脂蛋白E(Apo E)基因是目前被公认的AD最常见的风险因子,Apo Eε4等位基因是目前散发性AD的最强遗传性危险因素。近年许多基因被证实与散发性AD具有相关性,研究Apo E在AD发病中的作用,对AD病理生理学机制的研究及AD的治疗具有重要意义。     

Apolipoprotein E allele frequencies in patients with late-onset sporadic Alzheimer's dementia in Hungary

Introduction – The presence of the apolipoprotein E4 allele (apoE4) has been recognized as a risk factor for the development of presenile and senile forms of Alzheimer's dementia (AD). Material and methods – The apoE alleles frequency of 71 normal controls (NC), 60 demented controls (DC) and 50 senile type AD subjects was determined by polymerase chain reaction in order to get data about the apoE polymorphism of the Hungarian AD population. Results – The apoE3/3 genotype was the most common in all groups. The apoE4 frequency was significantly higher (28%) in the AD group than that was (7% and 9%) in the NC and DC populations, respectively. No apoE4 homozygotes were found in the DC group and the number of heterozygotes was lower in the DC than in the AD group. Conclusion – The results are in good agreement with others in the literature and support the occurrence of an increased apoE4 allele frequency in Hungarian senile AD population.     

Association between apolipoprotein E gene polymorphism and Alzheimer's disease in Uighur and Han populations

Aim: Currently, there are almost 100 genes related to Alzheimer's disease (AD), and studies have indicated that apolipoprotein E (APO E) ε4 allele is a genetic risk factor of AD. However, there have been no reports of the distributions of APO E genotypes and allele frequencies in Uighur and Han AD patients. Methods: We analyzed APO E gene polymorphism in 209 AD cases diagnosed based on National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association and 220 non‐dementia controls. We used polymerase chain reaction‐restriction fragment length polymorphism methods as the basis of this epidemiological survey. Results: In the AD and control groups, there are no statistically significant differences in APO E genotypes and allele frequency between the Uighur and Han ethnicities (P < 0.05). In the AD group, the ε3/4 genotype (28.2%) and ε4 allele frequency (14.8%) occurred at a higher rate than in the control (13.2% and 8.0%, respectively; P < 0.05). This distinction remained true within each ethnicity; the ε3/4 genotype and ε4 allele frequency are higher in the AD groups (Uighur, 30.6% and 15.8%, respectively; Han, 25.5% and 13.8%, respectively) than in the control groups (Uighur, 14.5% and 9.4%, respectively; Han, 11.7% and 6.3%, respectively; P < 0.05). Conclusions: The distribution of APO E genotype and allele frequency does not differ between the Uighur and Han ethnicities. The APO E ε4 allele is a risk factor of AD for both populations.     

Apolipoprotein E distribution among different plaque types in Alzheimer's disease: implications for its role in plaque progression

We sought to determine the pattern of ApoE immunoreactivity in mesial temporal lobe tissue from 12 Alzheimer patients, age 66–88, and to determine the distribution of this immunoreactivity among different plaque types representing hypothesized stages of plaque evolution. In these patients, the cortical area of ApoE immunoreactivity was 30% that of β-amyloid. Only 6% of diffuse non-neuritic amyloid deposits were even weakly ApoE immunoreactive (ApoE+). This is in contrast to our previous demonstration that microglia overexpressing interleukin-1 (IL-1) are present in most diffuse non-neuritic deposits. Eighty-three per cent of diffuse neuritic plaques and 86% of dense-core neuritic plaques were highly ApoE+, consistent with IL-1–induced astrocyte activation and synthesis of ApoE, resulting in the appearance of ApoE immunoreactivity in neuritic plaques. Dense-core non-neuritic ('burned out') plaques were only rarely (6%) ApoE+. These results, together with the known trophic and toxic effects of ApoE on neurites, suggest that plaque-associated ApoE contributes to the formation of overgrown degenerating (dystrophic) neurites in plaques. However, the fact that some neuritic plaques are not ApoE+ suggests contributions by additional trophic and toxic factors. Our results are also consistent with a role for ApoE in the condensation of diffuse amyloid deposits into a β-pleated-sheet form that occurs concomitant with dystrophic neurite formation in the neuritic β-amyloid plaques of Alzheimer's disease.     

Analysis of the effect of aluminum in drinking water and transferrin C2 allele on Alzheimer's disease

Although highly controversial, the hypothesis of a link between aluminum (Al) in drinking water and Alzheimer's disease (AD) has been supported by several epidemiological studies. Transferrin (Tf) is a major transport protein for both iron and Al. Moreover, it has been demonstrated that defective binding of iron and Al to the Tf variant C2 could be present in AD. Individuals carrying the Tf C2 allele might therefore be at greater risk of developing AD. We investigated whether the Tf C2 allele might be responsible for susceptibility to AD in a sample of 292 subjects (with 55 AD) aged ≥75 years from south-west France, some exposed to high levels of Al in tap water ( n  = 181 subjects) and others to low levels of Al ( n  = 111 subjects). We also examined the combined genetic effects of Tf C2 and ɛ 4 allele of apolipoprotein E gene (ApoE). Logistic regression analysis showed that neither Tf C2 nor its interaction with Al or with the ɛ 4 allele of the ApoE were significantly associated with the risk of AD.     

No Association between Presenilin 1 Intron Gene or Butyrylcholinesterase K Variant and Alzheimer's Disease in Japanese Populations

Background : One of the purposes of this study was to examine whethe apolipoprotein E (ApoE) ɛ4 allele as a risk factor for Alzheimer's disease (AD) may be associated with the higher prevalence of AD in women compared with men. Recently, the polymorphic K variant of the butyrylcholinest erase (BChE-K) gene and presenilin 1 (PS1) intronic polymorphism have been reported to be associated with AD respectively. Thus we have reexamined the frequency of BChE-K, PS1 intronic polymorphism, and the ApoE ɛ4 allele in a large series of Japanese AD patients and controls.
Methods : We have genotyped a large series of Japanese AD and age-and sex-matched controls by the method of polymerase chain reaction and restriction fragment length polymorphism for ApoE, BChE-K, and PS1 intronic polymorphism.
Results : The frequency of ApoE ɛ4 allele was significantly higher in AD patients than in controls, confirming the previous reports. In comparison between men and women, the number of individuals carrying one ɛ4 allele was much greater in women with AD than in men with this illness. Kaplan-Meier analyses, plotting the ɛ4 gene doses against age of onset for men and women, revealed significant differences in age-of-onset curves between men and women.     

Apolipoprotein E type 4 allele and Alzheimer's disease: Effect on age at onset and relative risk in different age groups

The effect of the apolipoprotein E (apoE) genotype on the age at onset of Alzheimer's disease (AD) and the relative risk conferred by the apoE 4 allele were studied in 91 patients and 69 healthy age-matched controls. According to the age of presentation, which varied from 44 to 95 years, subjects were divided into four groups. The inheritance of at least one 4 allele was associated with a significant reduction of the age at onset by 7.7 years among patients who were 83 years or older when examined. A weaker inverse relationship between the 4 allele and the age at onset was also observed among patients who were aged 44–63 years at presentation. The effect of the c4 allele was minimal or absent in the two intermediate age categories. The relative risk of AD conferred by the inheritance of at least one £4 allele showed no consistent age-related pattern. The overall risk expressed as an odds ratio was 5.0 (95% CI 2.4–10.5). With respect to the limitations of the study, we tentatively conclude (1) that the effect of the apoE 4 allele on the age at onset is not restricted to AD patients of a particular age, in accordance with current hypotheses on the role of apoE gene products in the biology of AD; (2) that the relative risk of AD associated with the 4 allele is not significantly modulated by age. Although the apoE 4 allele is an important susceptibility factor for AD occurring in middle age as well as in later life, it is of limited value in routine clinical diagnosis and should not be used for predictive testing in asymptomatic individuals.