APOE

Distribution by Scientific Domains
Distribution within Medical Sciences

Terms modified by APOE

  • apoe gene
  • apoe genotype

  • Selected Abstracts


    Characterization and gene expression profiling in glioma cell lines with deletion of chromosome 19 before and after microcell-mediated restoration of normal human chromosome 19

    GENES, CHROMOSOMES AND CANCER, Issue 10 2009
    Kristen L. Drucker
    Nearly 10% of human gliomas are oligodendrogliomas. Deletion of chromosome arm 19q, often in conjunction with deletion of 1p, has been observed in 65,80% of these tumors. This has suggested the presence of a tumor suppressor gene located on the 19q arm. Chromosome 19 deletion is also of interest due to the better prognosis of patients with deletion, including longer survival and better response to chemotherapy, compared with patients without deletion. Two glioma cell lines with deletion of 19q were used for chromosome 19 microcell-mediated transfer, to assess the effect of replacing the deleted segment. Complementation with chromosome 19 significantly reduced the growth rate of the hybrid cells compared with the parental cell lines. Affymetrix U133 Plus 2.0 Gene Chip analysis was performed to measure and compare the expression of the chromosome 19 genes in the chromosome 19 hybrid cell lines to the parental cell line. Probes were considered significantly different when a P value <0.01 was seen in all of the cell line comparisons. Of 345 probes within the commonly deleted 19q region, seven genes (APOE, RCN3, FLJ10781, SAE1, STRN4, CCDC8, and BCL2L12) were identified as potential candidate genes. RT-PCR analysis of primary tumor specimens showed that several genes had significant differences when stratified by tumor morphology or deletion status. This suggests that one or more of these candidates may play a role in glioma formation or progression. © 2009 Wiley-Liss, Inc. [source]


    Informative-Transmission Disequilibrium Test (i-TDT): combined linkage and association mapping that includes unaffected offspring as well as affected offspring

    GENETIC EPIDEMIOLOGY, Issue 2 2007
    Chao-Yu Guo
    Abstract To date, there is no test valid for the composite null hypothesis of no linkage or no association that utilizes transmission information from heterozygous parents to their unaffected offspring as well as the affected offspring from ascertained nuclear families. Since the unaffected siblings also provide information about linkage and association, we introduce a new strategy called the informative-transmission disequilibrium test (i-TDT), which uses transmission information from heterozygous parents to all of the affected and unaffected offspring in ascertained nuclear families and provides a valid chi-square test for both linkage and association. The i-TDT can be used in various study designs and can accommodate all types of independent nuclear families with at least one affected offspring. We show that the transmission/disequilibrium test (TDT) (Spielman et al. [1993] Am. J. Hum. Genet. 52:506,516) is a special case of the i-TDT, if the study sample contains only case-parent trios. If the sample contains only affected and unaffected offspring without parental genotypes, the i-TDT is equivalent to the sibship disequilibrium test (SDT) (Horvath and Laird [1998] Am. J. Hum. Genet. 63:1886,1897. In addition, the test statistic of i-TDT is simple, explicit and can be implemented easily without intensive computing. Through computer simulations, we demonstrate that power of the i-TDT can be higher in many circumstances compared to a method that uses affected offspring only. Applying the i-TDT to the Framingham Heart Study data, we found that the apolipoprotein E (APOE) gene is significantly linked and associated with cross-sectional measures and longitudinal changes in total cholesterol. Genet. Epidemiol. © 2006 Wiley-Liss, Inc. [source]


    LPL polymorphism predicts stroke risk in men

    GENETIC EPIDEMIOLOGY, Issue 3 2002
    Alanna C. Morrison
    Abstract Variation in lipid levels has been associated with atherosclerotic vascular disease, including stroke. Genes contributing to interindividual variation in lipid levels may play a role in the etiology of stroke, either through their effects on lipid synthesis and metabolism or through separate pathways. For this reason, we sought to examine the association between polymorphisms in the lipoprotein lipase (LPL) and apolipoprotein E (APOE) genes and subclinical and clinical stroke in the Atherosclerosis Risk in Communities (ARIC) Study. Subclinical stroke was determined by cerebral magnetic resonance imaging (MRI). Subclinical cerebral infarct cases (n = 197) were compared to a stratified random sample identified from individuals participating in the MRI examination (n = 200). Incidence of clinical ischemic stroke was determined by following the ARIC cohort for an average of 7.5 years for potential cerebrovascular events; 218 validated clinical ischemic strokes were identified. A stratified random sample of the ARIC cohort (CRS, n = 964) was used as the comparison group for clinical cases. The LPL S291-carrying genotypes and APOE ,2- and ,4-carrying genotypes were not significantly associated with subclinical or clinical stroke. The LPL X447-containing genotypes were significantly associated with subclinical (odds ratio [OR], 4.32; 95% confidence interval [CI], 1.23,15.15; P = 0.020) and clinical stroke (hazard rate ratio [HRR], 2.57; 95% CI, 1.24,5.34; P = 0.01) in men, both by themselves and after adjustment for multiple stroke risk factors. The LPL S447X polymorphism is significantly associated with subclinical cerebral infarction and incident clinical ischemic stroke in men from a middle-aged American population. This association does not appear to be mediated by triglyceride, high-density lipoprotein (HDL)- and low-density lipoprotein (LDL)-cholesterol levels, or additional stroke risk factors. Genet. Epidemiol. 22:233,242, 2002. © 2002 Wiley-Liss, Inc. [source]


    Mortality differences by APOE genotype estimated from demographic synthesis

    GENETIC EPIDEMIOLOGY, Issue 2 2002
    Douglas C. EwbankArticle first published online: 10 JAN 200
    Abstract The 4 allele of apolipoprotein E (APOE) is associated with increased risk of two major causes of death in low-mortality populations: ischemic heart disease and Alzheimer's disease. It is less common among centenarians than at younger ages. Therefore, it is likely that it is associated with excess risk of death. This article extends demographic models that estimate relative mortality risks from changes in gene frequencies with age. The resulting demographic synthesis combines gene frequencies with data on mortality by genotype from cohort studies. The model was applied to data from Denmark, Finland, France, Italy, Sweden, and the United States. Near age 50, the 3/4 genotype is associated with a risk of death of 1.34 times that of the 3/3 (95% CI 1.18,1.67). The relative risk for 4/4 is the square of the relative risk for 3/4, 1.81. The 2/3 genotype is protective with a relative risk of 0.84 (0.68,0.93) near age 50. These relative risks move toward 1.0 at the oldest ages and APOE genotype is associated with little variation in mortality over age 100. There are no significant differences in the relative risks by sex. There is little evidence of differences within Europe in the effects of APOE. This approach can be generalized to combine data on genetic risk factors for disease from a wide variety of study designs and sample characteristics. Genet. Epidemiol. 22:146,155, 2002. © 2002 Wiley-Liss, Inc. [source]


    APOE epsilon-4 allele and cytokine production in Alzheimer's disease

    INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 4 2010
    Paolo Olgiati
    Abstract Objective The APOE epsilon-4 allele has consistently emerged as a susceptibility factor for Alzheimer's disease (AD). Pro-inflammatory cytokines are detectable at abnormal levels in AD, and are thought to play a pathophysiological role. Animal studies have shown dose-dependent correlations between the number of APOE epsilon-4 alleles and the levels of pro-inflammatory cytokines. The aims of this study were to investigate the influence of APOE genotypes on TNF- ,, IL-6, and IL-1, secreted by peripheral blood mononuclear cells (PBMC) from human patients with AD and to analyze the correlation between cytokine production and AD clinical features. Methods Outpatients with AD (n,=,40) were clinically evaluated for cognitive decline (MMSE) and psychiatric symptoms (Cornell Scale for Depression in Dementia; Neuropsychiatric Inventory) and genotyped for APOE variants. PBMCs were isolated from the donors and used to assess spontaneous and PMA-stimulated secretion of TNF- ,, IL-6, and IL-1,. Cytokine production was determined by immuno-enzymatic assays (ELISA). Results In comparison with their counterparts without APOE4, patients with at least one copy of the APOE epsilon-4 allele showed higher spontaneous (p,=,0.037) and PMA-induced (p,=,0.039) production of IL-1, after controlling for clinical variables. Significant correlations were reported between NPI scores (psychotic symptoms) and IL-6 production. Conclusion These preliminary findings suggest the involvement of inflammatory response in the pathogenic effect of the APOE epsilon-4 allele in AD, although their replication in larger samples is mandatory. The modest correlations between pro-inflammatory cytokines released at peripheral level and AD features emphasizes the need for further research to elucidate the role of neuroinflammation in pathophysiology of AD. Copyright © 2009 John Wiley & Sons, Ltd. [source]


    Methylenetetrahydrofolate reductase gene and risk of Alzheimer's disease in Koreans

    INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 5 2008
    Jae-Min Kim
    Abstract Background The association between methylenetetrahydrofolate reductase (MTHFR) c.677C,>,T (A222V) polymorphism and Alzheimer's disease (AD) is controversial. The objectives of the study were to investigate the association between MTHFR c.677C,>,T polymorphism and AD in Korean elders and to the extent to which it is modified by the major components of one-carbon metabolism and apolipoprotein E (APOE) genotype. Methods Seven hundred and thirty-two community residents aged 65 or over were clinically assessed for AD. Genotyping was performed for MTHFR c.677C,>,T and APOE; serum levels of folate, vitamin B12, and homocysteine were assayed. Age, gender and education were included as covariates. Results A trend of association between TT genotype of MTHFR c.677C,>,T and AD was found [adjusted OR (95% CI): 1.73 (0.80,3.74)]. The association was significant in the presence of below-median vitamin B12 level [3.66 (1.14,11.71)] and in APOE e4 non-carriers [2.97 (1.00,8.55)] with significant interaction terms, and bordered on significance in the presence of above-median homocysteine level [2.73 (0.94,7.90)]. Conclusions These findings suggest gene-environment and gene-gene interactions on the risk of AD in Koreans. Copyright © 2007 John Wiley & Sons, Ltd. [source]


    Risk factors for neuropsychiatric symptoms in dementia: the Cache County Study

    INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 9 2006
    M. Steinberg
    Abstract Objective To investigate the probability of individual neuropsychiatric symptoms in dementia patients as a function of eight risk factors. Methods In the Cache County Study, we administered the Neuropsychiatric Inventory (NPI) to 328 dementia patients at baseline. Approximately 18 months later, we re-administered the NPI to 184 participants available for follow-up. Generalized estimating equation methods were used to model the probability of individual neuropsychiatric symptoms as a function of: gender, age, education, dementia type and severity, APOE status, time of observation, and general medical health. Results Women showed increased tendency toward anxiety, [odds ratio (OR) 2.22, 95% confidence interval (CI) 1.31,3.76] and delusions (OR 2.15, CI 1.22,3.78), but older persons of both sexes showed less tendency toward anxiety. Dementia severity increased the tendency toward hallucinations and agitation (OR 2.42, CI 1.81,3.23) and decreased risk of depression. Positive APOE ,4 status increased the tendency toward aberrant motor behavior (OR 1.84, CI 1.05,3.22). Among dementia diagnoses, those with Alzheimer's disease showed decreased tendency toward agitation (OR 0.58, CI 0.35,0.95), depression (OR 0.56, CI 0.33,0.96) and disinhibition (OR 0.46, CI 0.24,0.88). Later time of observation increased risk of aberrant motor behavior and delusions, and more serious medical comorbidity increased risk of, agitation, irritability, disinhibition, and aberrant motor behavior. Conclusions Gender, age, dementia severity, APOE ,4, dementia diagnosis, time of observation, and general medical health appear to influence the occurrence of individual neuropsychiatric symptoms. Copyright © 2006 John Wiley & Sons, Ltd. [source]


    No association between subjective memory complaints and apolipoprotein E genotype in cognitively intact elderly

    INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 12 2004
    Dylan G. Harwood
    Abstract Objective This cross-sectional study examined the relationship between subjective memory complaints and the apolipoprotein epsilon 4 allele (,4), a genetic risk factor for Alzheimer's disease (AD), among cognitively normal subjects identified from a community memory screening. Design The sample comprised 232 consecutive white non-Hispanic older adults who presented to a free community-based memory-screening program at a University affiliated memory disorders center. Participants were classified as cognitively normal based on scores on the age and educated adjusted Folstein Mini-Mental Status Exam (MMSAdj) and a brief Delayed Verbal Recall Test (DRT). Subjects were assessed for APOE genotype, subjective memory complaints (Memory Questionnaire, MQ), depressive symptoms (Hamilton Depression Rating Scale, HDRS), and history of four major medical conditions that have been associated with memory loss (stroke/transient ischemic attack [TIA], atherosclerotic heart disease, hypertension, and diabetes). A hierarchical regression analysis was performed to examine the association between APOE genotype and memory complaints after controlling for a host of potential confounding factors. Results The APOE ,4 allele frequency for cognitively normal subjects was 0.13. Subjective memory complaints were predicted by depressive symptoms and a history of stroke/TIA. They were not associated with APOE genotype, MMSAdj score, DRT score, age, education, gender, and reported history of atherosclerotic heart disease, hypertension, or diabetes. Conclusion The results did not suggest an association between subjective memory complaints and the APOE ,4 allele in this sample of cognitively intact subjects. This indicates that memory complaints may confer risk for future dementia through pathways independent of APOE genotype. The results also show that older adults with memory complaints are at increased risk for underlying depression. Copyright © 2004 John Wiley & Sons, Ltd. [source]


    Depressive Symptoms and Cognitive Decline in Community-Dwelling Older Adults

    JOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 5 2010
    Sebastian Köhler PhD
    OBJECTIVES: To examine the temporal association between depressive symptoms and cognitive functioning and estimate the effect measure modification of the apolipoprotein E (APOE) ,4 allele on this relationship. DESIGN: Prospective cohort study. SETTING: General community. PARTICIPANTS: Population-based sample of 598 cognitively intact older adults aged 60 and older, with re-assessments after 3 (N=479) and 6 years (N=412). MEASUREMENTS: Depressive symptoms (Symptom Checklist) and neurocognitive functioning (memory, Visual Verbal Learning Test; attention, Stroop Color,Word Test; processing speed, Letter Digit Substitution Test; general cognition, Mini-Mental State Examination). Longitudinal associations were assessed using linear mixed models. The risk for cognitive impairment, no dementia (CIND) was examined using logistic regression. RESULTS: Adjusting for age, sex, education, and baseline cognition, the rate of change in memory z -scores was 0.00, ,0.11, ,0.20, and ,0.37 for those in the lowest (reference group), second, third, and highest depressive symptom quartiles at baseline, respectively (P<.001 for highest vs lowest quartile). The odds ratios for developing CIND with amnestic features were 1.00, 0.87, 0.69, and 2.98 for the four severity groups (P=.05 for highest vs lowest quartile). Associations were strongest for those with persistent depressive symptoms, defined as high depressive symptoms at baseline and at least one follow-up visit. Results were similar for processing speed and global cognitive function but were not as strong for attention. No APOE interaction was observed. CONCLUSION: Depression and APOE act independently to increase the risk for cognitive decline and may provide targets for prevention and early treatment. [source]


    HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging

    AGING CELL, Issue 5 2010
    S. Michal Jazwinski
    Summary The search for longevity-determining genes in human has largely neglected the operation of genetic interactions. We have identified a novel combination of common variants of three genes that has a marked association with human lifespan and healthy aging. Subjects were recruited and stratified according to their genetically inferred ethnic affiliation to account for population structure. Haplotype analysis was performed in three candidate genes, and the haplotype combinations were tested for association with exceptional longevity. An HRAS1 haplotype enhanced the effect of an APOE haplotype on exceptional survival, and a LASS1 haplotype further augmented its magnitude. These results were replicated in a second population. A profile of healthy aging was developed using a deficit accumulation index, which showed that this combination of gene variants is associated with healthy aging. The variation in LASS1 is functional, causing enhanced expression of the gene, and it contributes to healthy aging and greater survival in the tenth decade of life. Thus, rare gene variants need not be invoked to explain complex traits such as aging; instead rare congruence of common gene variants readily fulfills this role. The interaction between the three genes described here suggests new models for cellular and molecular mechanisms underlying exceptional survival and healthy aging that involve lipotoxicity. [source]


    Association of the ,2 Allele of Apoe Gene to Hypertriglyceridemia and to Early-Onset Alcoholic Cirrhosis

    ALCOHOLISM, Issue 4 2008
    Zamira H. Hernández-Nazará
    Background:, The diverse incidence of alcoholic cirrhosis around the world and the fact that not all alcoholic drinkers develop liver disease indicates that genetic and environmental factors play an important role in the development of liver cirrhosis. Lipids participate in early stages of alcoholic cirrhosis. Therefore variations in the plasma lipid profile due to primary (genetic) or secondary (environmental) dyslipidemia could affect the development of liver disease. The aim of this study was to analyze the lipid profile and apolipoprotein E (APOE) polymorphism in patients with alcoholic liver cirrhosis (AC) and determine the risk associated with genotype polymorphism with the onset of alcoholic cirrhosis. Methods:, In a case and control study, 86 patients with AC divided into hyperlipidemic (H) and non-hyperlipidemic (non-H) groups, and 133 healthy individuals (C) matched by age and sex were studied. Lipid profile and liver function tests were measured by enzymatic methods. The APOE genotypes were identified by PCR-RFLP,s. Results:, A statistically significant increase of the APOE*2 allele and genotypes 2/2, 2/3, and 2/4 was present in AC patients compared to C group. A hyperlipidemic state characterized by increased levels of triglycerides and apolipoprotein B (APOB) and a decrease of high density lipoprotein-cholesterol (HDL-c) was detected in young-aged patients (31.2 ± 6.2 years old vs. 46.3 ± 12.5 years old). In this group, hypertriglyceridemia was closely associated to APOE*2 allele and to an early onset of liver cirrhosis. By contrast, APOE*4 allele was associated with a longer duration of alcohol intake (>20 years) in the non-H group. Conclusions:, This study shows the association of hypertriglyceridemia and APOE allele with the early onset of alcoholic liver cirrhosis, and the interaction between environmental factors, such as duration of alcohol abuse and amount of alcohol intake, and genetic factors (APOE*2 allele) on the hypertriglyceridemic process. [source]


    Clinical correlates of depressive symptoms in familial Parkinson's disease,,

    MOVEMENT DISORDERS, Issue 15 2008
    Nathan Pankratz PhD
    Abstract Depression is one of the most common nonmotor complications of Parkinson's disease (PD) and has a major impact on quality of life. Although several clinical factors have been associated with depression in PD, the relationship between depression and stage of illness as well as between depression and degree of disability remains controversial. We have collected clinical data on 1,378 PD cases from 632 families, using the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II (activities of daily living) & III (motor), the Mini-Mental State Exam, the Geriatric Depression Scale (GDS), and the Blessed Functional Activity Scale (Blessed). Analyses were performed using the 840 individuals with verified PD and without evidence of cognitive decline. Logistic regression was used to identify study variables that individually and collectively best predicted the presence of depressive symptoms (GDS , 10). After correcting for multiple tests, depressive symptoms were significantly associated with Hoehn and Yahr stage and other clinical measures but not with any genetic variant (parkin, LRRK2, APOE). The Blessed score, education, presence of a first degree relative with signs of depression, and UPDRS Part II were found to best predict depressive symptomatology (R2 = 0.33; P = 4 × 10,48). Contrary to several reports, the results from this large study indicate that stage of illness, motor impairment, and functional disability are strongly correlated with depressive symptoms. © 2008 Movement Disorder Society [source]


    Genetic,morphologic association study: association between the low density lipoprotein-receptor related protein (LRP) and cerebral amyloid angiopathy

    NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 1 2005
    M. Christoforidis
    Accumulating evidence suggests that genetic factors such as apolipoprotein E (APOE), can act in different ways in the pathogenesis of cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). The role of the low-density lipoprotein-receptor related protein (LRP), the major cerebral APOE receptor, in AD has been discussed controversially depending on data from different populations and methodological approaches. We examined the influence of LRP polymorphisms on CAA in 125 post-mortem cases genotyped for APOE and classified according to the neurofibrillary Braak and Braak staging of AD (indicating neurodegeneration grade). CAA was assessed separately for leptomeningeal (CAAlep.), noncapillary cortical (CAAcort.) and capillary cortical (CAAcap.) vessels in ,-amyloid stained sections. Our results suggest: (i) the 87 bp allele of LRP5, polymorphism (LRP5,) is an independent predictive factor for CAAcort. and CAAlep.; (ii) the C/C genotype (C allele) of the LRP exon 3 polymorphism is positively associated with, the, severity, of, CAAlep., and, CAAcort.,, implicating a younger age of CAA onset and/or faster CAA progression; (iii) as CAAcort. and CAAlep. showed different genetic associations in contrast to CAAcap., we can underscore the hypothesis that different molecular mechanisms are involved in CAA pathogenesis of noncapillary and capillary cerebral vessels. Our results lead us to postulate that the LRP5,87 bp and the LRP exon 3 C alleles of the LRP gene (or another locus that might be in linkage disequilibrium with these LRP polymorphic sites) could modify cerebrovascular LRP function or expression in noncapillary cerebral vessels, leading to an increased cerebrovascular amyloid deposition. [source]


    There is no evidence of an association in children and teenagers between the apolipoprotein E ,4 allele and post-traumatic brain swelling

    NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 6 2004
    T. J. Quinn
    Traumatic brain injury (TBI) is an important cause of mortality and disability in children and teenagers. A particular feature of the neuropathology at post-mortem is brain swelling. The cause of the swelling in some cases is not known, while in others it is associated with traumatic axonal injury or hypoxia. Apolipoprotein E (APOE) ,4 allele is known to be an important genetic determinant of outcome in children after TBI. We hypothesized a relationship between possession of APOE,4 and diffuse traumatic brain swelling. A total of 165 cases aged between 2 and 19 years were identified from the department's tissue archive. APOE genotype was determined by polymerase chain reaction (PCR) in 106 cases. Bilateral swelling was present in 44 cases (11 with APOE,4), unilateral swelling in 25 cases (7 with APOE,4) and in 36 cases (9 with APOE,4) there was no evidence of brain swelling. There was no significant relationship between possession of APOE,4 and the presence of cerebral swelling (,2 = 0.09, df = 2, P = 0.96). The 95% confidence interval for difference in proportions with swelling, in, those, with, and, without, the,APOE,,4, is,,19%, to 22%. Thus, a significant relationship was not found between diffuse brain swelling and possession of APOE,4, and in this cohort of patients there was an identifying cause of the brain swelling in all cases. [source]


    APOE,4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of A, protein

    NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 3 2003
    K. Chalmers
    The relative amounts of amyloid ,-protein (A,) in cerebral blood vessels and parenchyma vary considerably amongst patients with Alzheimer's disease (AD). Although several mechanisms have been proposed to explain this variability, the underlying genetic and environmental determinants are still unclear, as are the functional consequences. Polymorphisms in APOE, the gene for apolipoprotein E (ApoE), influence the risk of developing AD and of deposition of A, within the brain. We examined the relationship between the APOE genotype and the relative extent of accumulation of A, as plaques within the cerebral parenchyma and in cortical blood vessels in the form of cerebral amyloid angiopathy (CAA), in autopsy brain tissue from 125 AD cases and from 53 elderly, neurologically normal controls of which 19 had CAA without other neuropathological features of AD. In the AD cases, we also assessed whether the severity of CAA was related to the age of onset and duration of dementia, risk factors for atherosclerotic vascular disease, and histologically demonstrable cerebral in-farcts or foci of haemorrhage. The APOE genotype was determined by a standard polymerase chain reaction-based method. Paraffin sections of frontal, temporal and parietal lobes were immunolabelled for A, and the parenchymal A, load (total A, minus vessel-associated A,) was quantified by computer-assisted image analysis. CAA severity was scored for cortical and leptomeningeal vessels. The relevant clinical data were obtained from the database of the South West Brain Bank. In AD, we found the severity of CAA to be strongly associated with the number of ,4 alleles (P < 0.0001) but the parenchymal A, load to be independent of APOE genotype. Cases with severe CAA had a lower parenchymal A, load than had those with moderate CAA (P = 0.003). Neither the severity of CAA nor the parenchymal A, load correlated with age of onset, duration of disease or age at death, and the severity of CAA also did not correlate with the presence of cerebral infarcts or foci of haemorrhage. These findings indicate that possession of the APOE,4 allele favours vascular over parenchymal accumulation of A, in AD. This may influence the pathogenesis of neurodegeneration in ,4-associated AD. [source]


    Alterations of chaperone protein expression in presenilin mutant neurons in response to glutamate excitotoxicity

    PATHOLOGY INTERNATIONAL, Issue 9 2002
    Izumi Maezawa
    Mutations in the presenilin-1 (PS1) gene underlie the most common form of familial dementia of the Alzheimer type (DAT). We demonstrated previously that the expression of PS1 with a M146V mutation in transgenic mice potentiates glutamate toxicity to neurons, due to an altered calcium homeostasis. Here, using a subtractive cDNA library approach, we report the identification of several genes, the altered expression of which may be associated with this unique PS1 -related vulnerability to glutamate. The identified genes, including chaperonin subunit 2 and nucleophosmin 1/B23, are involved in the intracellular trafficking of proteins and ions. Northern blot analysis revealed that the effect of glutamate on calcium-binding proteins was augmented in neurons from PS1 mutation mice, compared with neurons from mice lacking other genes relevant to the pathogenesis of DAT (FE65 and APOE) or neurons from control wild-type mice. Interestingly, mRNA for two chaperone proteins were expressed at lower levels specifically in neurons from PS1 mutant mice. These findings suggest that PS1 mutations may, in part, contribute to the development of DAT via altered expression of chaperone proteins. [source]


    Application of proteomics for the identification of differentially expressed protein markers for Down syndrome in maternal plasma

    PRENATAL DIAGNOSIS, Issue 8 2008
    Aggeliki Kolialexi
    Abstract Background Despite the large impact of ultrasonographic and biochemical markers on prenatal screening, the ability to accurately diagnose Down syndrome (DS) is still limited and better diagnostic testing is needed. Methods Plasma from 8 women carrying a DS foetus and 12 with non-DS foetuses matched for gestational age, maternal age and ethnicity, in the second trimester of pregnancy, was analysed by two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) in order to identify biomarkers for DS. Results Gel comparison revealed nine proteins differentially expressed in maternal plasma in women with DS foetuses. Eight proteins, transthyretin (TTHY), ceruloplasmin (CERU), afamin (AFAM), alpha-1-microglobulin (AMBP), apolipoprotein E (APOE), serum amyloid P-component (SAMP), histidine-rich glycoprotein (HRG) and alpha-1-antitrypsin (A1AT) were up-regulated and one, clusterin (CLUS), down-regulated. All nine proteins are known to be involved in foetal growth and development. APOE, SAMP, AFAM and CLUS are associated with the DS phenotype. Western blot and densitometric analysis of APOE and SAMP confirmed the increase of both proteins by 19 and 48% respectively. Conclusions All differentially expressed proteins are candidate biomarkers for DS, providing opportunities for the development of non-invasive prenatal diagnosis. As these are preliminary findings, follow-up experiments are needed for their evaluation. Copyright © 2008 John Wiley & Sons, Ltd. [source]


    Effect of the APOE-491A/T promoter polymorphism on apolipoprotein E levels and risk of Alzheimer disease: The Rotterdam Study

    AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 5 2002
    G. Roks
    Abstract The apolipoprotein E (APOE) gene is involved in lipid transport. A common polymorphism in this gene with the APOE*2, APOE*3, and APOE*4 alleles influences plasma levels of apolipoprotein E and cholesterol. Besides its role in lipid transport, the APOE*4 allele is a genetic risk factor for Alzheimer disease (AD). Recently, a polymorphism in the APOE promoter region was found to be involved in plasma apolipoprotein E levels and was found associated with AD. We studied the effect of this ,491A/T promoter polymorphism on plasma apolipoprotein E levels and risk for AD in a population-based case-control study. We found that there was a modest but statistically significant effect of the ,491A/T polymorphism on plasma apolipoprotein E levels independent of the APOE genotype. The lowest plasma levels were measured for the AA genotype, highest levels for the TT genotype, and intermediate levels for the heterozygotes. There was a small effect of the ,491 AA genotype on AD risk that disappeared after adjusting for APOE genotypes. Our data suggest that the ,491A/T polymorphism has an APOE genotype-independent effect on plasma apolipoprotein E levels but no APOE-independent effect on AD risk. © 2002 Wiley-Liss, Inc. [source]


    Worldwide allele frequencies of the human apolipoprotein E gene: Climate, local adaptations, and evolutionary history

    AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY, Issue 1 2010
    Dan T.A. Eisenberg
    Abstract The ,4 allele of the apolipoprotein E (APOE) gene is associated with increased cholesterol levels and heart disease. Population allele frequencies of APOE have previously been shown to vary, with ,4 frequencies generally increasing with latitude. We hypothesize that this trend resulted from natural selection protecting against low-cholesterol levels. In high-latitude cold environments and low-latitude hot environments, metabolic rate is elevated, which could require higher cholesterol levels. To explore this hypothesis, we compiled APOE allele frequencies, latitude, temperature, and elevation from populations around the world. ,4 allele frequencies show a curvilinear relationship with absolute latitude, with lowest frequencies found in the mid-latitudes where temperatures generally require less expenditure on cooling/thermogenesis. Controlling for population structure in a subset of populations did not appreciably change this pattern of association, consistent with selection pressures that vary by latitude shaping ,4 allele frequencies. Temperature records also predict APOE frequency in a curvilinear fashion, with lowest ,4 frequencies at moderate temperatures. The model fit between historical temperatures and ,4 is less than between latitude and ,4, but strengthened after correcting for estimated temperature differences during the Paleolithic. Contrary to our hypothesis, we find that elevation did not improve predictive power, and an integrated measure of the cholesterol effect of multiple APOE alleles was less related to latitude than was ,4 alone. Our results lend mixed support for a link between past temperature and human APOE allele distribution and point to the need to develop better models of past climate in future analyses. Am J Phys Anthropol 143:13,20, 2010. © 2010 Wiley-Liss, Inc. [source]


    C677T polymorphism of methylenetetrahydrofolate reductase gene affects plasma homocysteine level and is a genetic factor of late-onset Alzheimer's disease

    PSYCHOGERIATRICS, Issue 1 2004
    Tomoyuki KIDA
    Abstract Background:, Elevated plasma homocysteine levels are known as a risk for atherosclerotic vascular disease and venous thrombosis and have been shown as a risk for late-onset Alzheimer's disease (LOAD). Method:, To examine the effect of genetic factors predisposing to elevated plasma homocysteine levels on the occurrence of LOAD, we determined the genotype of a C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene and a variable number tandem repeat (VNTR) spanning exon 13,intron 13 boundary of cystathionine ,-synthase (CBS) gene in patients with LOAD and community-based control subjects. Results:, Logistic regression indicated that the MTHFR-T allele was a risk for LOAD (P < 0.05), independently from apolipoprotein E-,4 (APOE-,4) allele. Kaplan,Meier tests showed that in APOE-,4 non-carriers, individuals with the MTHFR-TT genotype have occurences of LOAD earlier than those with the MTHFR-CC genotype (P < 0.05). Multiple regression analysis indicates that MTHFR-T allele increases plasma homocysteine levels (P = 0.0002), while the number of X chromosomes decreases (P = 0.01). Plasma homocysteine level was not correlated with age, plasma albumin reflecting nutritional condition, and the dose of APOE-,4 allele. The CBS-20 VNTR allele showed the same trend to increase plasma homocysteine level as the MTHFR-T allele, but a risk effect for LOAD was not evident. Conclusion:, A genetic propensity for elevated plasma homocysteine levels, explained by the MTHFR-T allele encoding defective enzymatic function, is involved in the development of LOAD, particularly in APOE-,4 non-carriers, and that homocysteine metabolism could be a preventive target to LOAD in the elderly. [source]


    Apolipoproteins and , Amyloid Transport Pathway

    PSYCHOGERIATRICS, Issue 3 2002
    Kouzin Kamino
    Abstract: Cholesterol metabolism has been viewed as an important step in the development of Alzheimer's disease, since it was shown that the ,4 allele of apolipoprotein E (APOE) gene is a genetic risk and modifies age-at-onset of Alzheimer's disease. Although the knowledge of the effect of cholesterol in the neuronal cell has been recently accumulated, the link between systemic and brain cholesterol metabolism remains to be elucidated. Lipoproteins in cerebrospinal fluid (CSF) are fractionated only to high-density lipoprotein (HDL), and contain apolipoprotein (apo) A-I, E, A-II, and J. Whereas apoE is produced in the brain, apoA-I and apoA-II in cerebrospinal fluid, the major components of plasma HDL cholesterol, originate from plasma. Plasma HDL is thought to act in reverse cholesterol transport, and in vitro experiments indicated that these apolipoproteins and albumin show a high affinity binding to , amyloid. In patients with Alzheimer's disease, plasma apoA-I and apoA-II levels are significantly decreased, which is possibly related to the deposition of , amyloid in the brain, and to the , amyloid transport pathway. [source]


    Identification of genetic markers associated with fatness and leg weakness traits in the pig

    ANIMAL GENETICS, Issue 6 2009
    B. Fan
    Summary Pigs have undergone long-term selection in commercial conditions for improved rate and efficiency of lean gain. Interestingly, it has been observed in both experimental and field conditions that leg weakness has increased over time, concurrent with the selection for improved rate of lean gain, while fatter animals tend to have better leg action, and foot and leg (FL) structure. The exact molecular mechanisms or individual genes responsible for this apparent genetic correlation between fatness and leg weakness and other physical adaptability traits have been less well reported. Based on our recent studies involving candidate genes and leg weakness traits, the present investigation has identified 30 SNPs from 26 genes that were found to be associated with 10th rib backfat in a sow population consisting of 2066 animals. The specific alleles associated with increased backfat tended to be associated with better overall leg action, as shown for the genes including MTHFR, WNT2, APOE, BMP8, GNRHR and OXTR, while inconsistent associations with the single FL structure trait and backfat were observed for other genes. This study suggests that in some cases there may be a common genetic mechanism or linked genes regulating fatness and leg weakness. Such relationships are clearly complex, and the utilization of genetic markers associated with both traits should be treated cautiously. [source]


    APOE is not Associated with Alzheimer Disease: a Cautionary tale of Genotype Imputation

    ANNALS OF HUMAN GENETICS, Issue 3 2010
    Gary W. Beecham
    Summary With the advent of publicly available genome-wide genotyping data, the use of genotype imputation methods is becoming increasingly common. These methods are of particular use in joint analyses, where data from different genotyping platforms are imputed to a reference set and combined in a single analysis. We show here that such an analysis can miss strong genetic association signals, such as that of the apolipoprotein-e gene in late-onset Alzheimer disease. This can occur in regions of weak to moderate LD; unobserved SNPs are not imputed with confidence so there is no consensus SNP set on which to perform association tests. Both IMPUTE and Mach software are tested, with similar results. Additionally, we show that a meta-analysis that properly accounts for the genotype uncertainty can recover association signals that were lost under a joint analysis. This shows that joint analyses of imputed genotypes, particularly failure to replicate strong signals, should be considered critically and examined on a case-by-case basis. [source]


    Evaluating differences in linkage disequilibrium between populations

    ANNALS OF HUMAN GENETICS, Issue 3 2010
    Birgir Hrafnkelsson
    Summary We propose two methods to evaluate the statistical significance of differences in linkage disequilibrium (LD) between populations, where LD is measured by the standardised parameter D,. The first method is based on bootstrapping individuals within populations in order to test LD differences for each pair of loci. Using this approach we propose a solution to the problem of testing multiple locus-pairs by means of a single test for the number of pairs that exhibit significant LD differences among populations. The second method provides the Bayesian posterior probability that one population has greater LD than the other for each locus pair. Both methods can handle genotypes with unknown phase, and are demonstrated using two data sets. For the purpose of demonstration, we apply the methods to two different sets of data from humans. First, we explore the issue of LD differences between reproductively isolated populations using a new data set of twelve Xq25 microsatellites, typed in four European populations. Second, we examine evidence for LD differences between Alzheimer cases and controls from the Icelandic population using 19 single nucleotide polymorphisms (SNPs) from a 97 kb region flanking the Apolipoprotein E (APOE) gene on chromosome 19. [source]


    Effect of apolipoprotein E on biomarkers of amyloid load and neuronal pathology in Alzheimer disease

    ANNALS OF NEUROLOGY, Issue 3 2010
    Prashanthi Vemuri PhD
    Objective To study the effect of apolipoprotein E ,4 status on biomarkers of neurodegeneration (atrophy on magnetic resonance imaging [MRI]), neuronal injury (cerebrospinal fluid [CSF] t-tau), and brain A, amyloid load (CSF A,1,42) in cognitively normal subjects (CN), amnestic subjects with mild cognitive impairment (aMCI), and patients with Alzheimer disease (AD). Methods We included all 399 subjects (109 CN, 192 aMCI, 98 AD) from the Alzheimer's Disease Neuroimaging Initiative study with baseline CSF and MRI scans. Structural Abnormality Index (STAND) scores, which reflect the degree of AD-like anatomic features on MRI, were computed for each subject. Results A clear ,4 allele dose effect was seen on CSF A,1,42 levels within each clinical group. In addition, the proportion of the variability in A,1,42 levels explained by APOE ,4 dose was significantly greater than the proportion of the variability explained by clinical diagnosis. On the other hand, the proportion of the variability in CSF t-tau and MRI atrophy explained by clinical diagnosis was greater than the proportion of the variability explained by APOE ,4 dose; however, this effect was only significant for STAND scores. Interpretation Low CSF A,1,42 (surrogate for A, amyloid load) is more closely linked to the presence of APOE ,4 than to clinical status. In contrast, MRI atrophy (surrogate for neurodegeneration) is closely linked with cognitive impairment, whereas its association with APOE ,4 is weaker. The data in this paper support a model of AD in which CSF A,1,42 is the earliest of the 3 biomarkers examined to become abnormal in both APOE carriers and noncarriers. ANN NEUROL 2010;67:308,316 [source]


    APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging

    ANNALS OF NEUROLOGY, Issue 1 2010
    John C. Morris MD
    Objective To examine interactions of apolipoprotein E (APOE) genotype with age and with in vivo measures of preclinical Alzheimer disease (AD) in cognitively normal aging. Methods Two hundred forty-one cognitively normal individuals, aged 45,88 years, had cerebral amyloid imaging studies with Pittsburgh Compound-B (PIB). Of the 241 individuals, 168 (70%) also had cerebrospinal fluid (CSF) assays of amyloid-beta42 (A,42), tau, and phosphorylated tau (ptau181). All individuals were genotyped for APOE. Results The frequency of individuals with elevated mean cortical binding potential (MCBP) for PIB rose in an age-dependent manner from 0% at ages 45,49 years to 30.3% at 80,88 years. Reduced levels of CSF A,42 appeared to begin earlier (18.2% of those aged 45,49 years) and increase with age in higher frequencies (50% at age 80,88 years) than elevations of MCBP. There was a gene dose effect for the APOE4 genotype, with greater MCBP increases and greater reductions in CSF A,42 with increased numbers of APOE4 alleles. Individuals with an APOE2 allele had no increase in MCBP with age and had higher CSF A,42 levels than individuals without an APOE2 allele. There was no APOE4 or APOE2 effect on CSF tau or ptau181. Interpretation Increasing cerebral A, deposition with age is the pathobiological phenotype of APOE4. The biomarker sequence that detects A, deposition may first be lowered CSF A,42, followed by elevated MCBP for PIB. A substantial proportion of cognitively normal individuals have presumptive preclinical AD. ANN NEUROL 2010;67:122,131 [source]


    Apolipoprotein E,dependent accumulation of Alzheimer disease,related lesions begins in middle age,

    ANNALS OF NEUROLOGY, Issue 6 2009
    Eloise Kok BScHons
    Objective To study the prevalence and age dependency of senile plaques (SP) and neurofibrillary tangles (NFT), the brain changes characteristic of Alzheimer disease (AD), and their association with apolipoprotein E (APOE) genotypes in a community-dwelling normal population. Methods This neuropathological study used both silver staining and A, immunohistochemistry in brain tissue microarrays, including SP coverage and NFT counts from frontal cortex and hippocampus, and APOE genotyping, and was performed on a consecutive prospective series of 603 subjects (aged between 0 and 97 years) of an unselected population living outside of institutions. Cases were subjected to autopsy following sudden or unexpected out-of-hospital death, covering 22.1% of the mortality of Tampere, Finland and its surroundings. None died of AD, although 22 (3.7%) were demented and 10 (1.7%) had memory problems. Results Of the series, 30.8% had SP, and 42.1% had NFT; these occurred more commonly among females and showed a strong relationship with age. Both changes had already appeared at around 30 years of age, reaching an occurrence of almost 100% in the oldest. SP were more frequent in APOE ,4-carriers compared with noncarriers in every age group except the oldest (>90 years). The difference was most evident during the ages 50 to 59 years, where 40.7% of ,4-carriers had SP, compared with 8.2% in noncarriers (odds ratio, 8.39; 95% confidence interval, 2.55,27.62). The difference in NFT prevalence between APOE genotypes was not statistically significant in any age group. Interpretation The brain changes associated with AD may already begin developing early in middle age, especially among APOE ,4 carriers. Ann Neurol 2009;65:650,657 [source]


    Shorter telomeres are associated with mortality in those with APOE ,4 and dementia

    ANNALS OF NEUROLOGY, Issue 2 2006
    Lawrence S. Honig MD
    Objective Reduced telomere length may be a marker of biological aging. We hypothesized that telomere length might thus relate to increased risk for dementia and mortality. Methods This nested case,control study used stored leukocyte DNA from 257 individuals (mean age, 81.4 ± 7.9 years; 64.6% female; 44.7% Hispanic, 33.5% non-Hispanic black, and 21.8% non-Hispanic white). Our assay used real-time polymerase chain reaction, with two separate reactions amplifying telomere sequence and reference single copy gene (ribosomal-protein-P0), providing a calculated telomere-to-single copy gene (T/S) ratio. Results Mean telomere length was shorter among subjects dying during follow-up than in those surviving (0.453 ± 0.211 vs 0.525 ± 0.226 [± standard deviation]; p < 0.009). It was also shorter in those with Alzheimer's disease compared with control subjects (0.458 ± 0.207 vs 0.516 ± 0.229; p < 0.03). For participants with Alzheimer's disease, compared with those with the longest telomeres, the mortality odds ratio (OR) was 4.8 (95% confidence interval [CI], 1.7,13.8) in those with intermediate-length telomeres and 7.3 (95% CI, 2.4,22.0) in those with the shortest telomeres. The presence of an ,4 allele also increased the mortality OR, with an OR of 5.8 (95% CI, 1.3,26.4) for intermediate-length telomeres and an OR of 9.0 (95% CI, 1.9,41) for the shortest telomeres. Interpretation Our findings suggest that leukocyte telomere length is related to both dementia and mortality and may be a marker of biological aging. Ann Neurol 2006; [source]


    Oligomeric A, in Alzheimer's Disease: Relationship to Plaque and Tangle Pathology, APOE Genotype and Cerebral Amyloid Angiopathy

    BRAIN PATHOLOGY, Issue 2 2010
    Zoë Van Helmond
    Abstract Despite accumulating evidence of a central role for oligomeric amyloid , (A,) in the pathogenesis of Alzheimer's Disease (AD), there is scant information on the relationship between the levels and distribution of oligomeric A, and those of other neurodegenerative abnormalities in AD. In the present study, we have found oligomeric A, to be associated with both diffuse and neuritic plaques (mostly co-localized with A,1,42) and with cerebrovascular deposits of A, in paraffin sections of formalin-fixed human brain tissue. The amount of oligomeric A, that was labeled in the sections correlated with total A, plaque load, but not phospho-tau load, cerebral amyloid angiopathy (CAA) severity or APOE genotype. Although soluble, oligomeric and insoluble A, levels were all significantly increased in AD brain homogenates, case-to-case variation and overlap between AD and controls were considerable. Over the age-range studied (43,98 years), the levels of soluble A,, oligomeric A,42, oligomeric A,40 and insoluble A, did not vary significantly with age. Oligomeric A,1,42 and insoluble A, levels were significantly higher in women. Overall, the level of insoluble A,, but neither oligomeric nor soluble A,, was associated with Braak stage, CAA severity and APOE,4 frequency, raising questions as to the role of soluble and oligomeric A, in the progression of AD. [source]


    SYMPOSIUM: Clearance of A, from the Brain in Alzheimer's Disease: A,-Degrading Enzymes in Alzheimer's Disease

    BRAIN PATHOLOGY, Issue 2 2008
    James Scott Miners
    Abstract In Alzheimer's disease (AD) A, accumulates because of imbalance between the production of A, and its removal from the brain. There is increasing evidence that in most sporadic forms of AD, the accumulation of A, is partly, if not in some cases solely, because of defects in its removal,mediated through a combination of diffusion along perivascular extracellular matrix, transport across vessel walls into the blood stream and enzymatic degradation. Multiple enzymes within the central nervous system (CNS) are capable of degrading A,. Most are produced by neurons or glia, but some are expressed in the cerebral vasculature, where reduced A,-degrading activity may contribute to the development of cerebral amyloid angiopathy (CAA). Neprilysin and insulin-degrading enzyme (IDE), which have been most extensively studied, are expressed both neuronally and within the vasculature. The levels of both of these enzymes are reduced in AD although the correlation with enzyme activity is still not entirely clear. Other enzymes shown capable of degrading A,in vitro or in animal studies include plasmin; endothelin-converting enzymes ECE-1 and -2; matrix metalloproteinases MMP-2, -3 and -9; and angiotensin-converting enzyme (ACE). The levels of plasmin and plasminogen activators (uPA and tPA) and ECE-2 are reported to be reduced in AD. Reductions in neprilysin, IDE and plasmin in AD have been associated with possession of APOE,4. We found no change in the level or activity of MMP-2, -3 or -9 in AD. The level and activity of ACE are increased, the level being directly related to A, plaque load. Up-regulation of some A,-degrading enzymes may initially compensate for declining activity of others, but as age, genetic factors and diseases such as hypertension and diabetes diminish the effectiveness of other A,-clearance pathways, reductions in the activity of particular A,-degrading enzymes may become critical, leading to the development of AD and CAA. [source]