Lack of variation in the nucleotide sequence corresponding to the transmembrane domain of the β‐amyloid precursor protein in Alzheimer's disease

Zubenko, George S.; Stiffler, Scott; Farr, Joan E.; Kopp, Ursula; Hughes, Hugh B.; Kaplan, Barry B.; Moossy, John

doi:10.1002/ajmg.1320480304

Cited by 10 publications

(6 citation statements)

References 41 publications

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“…Genomic DNA was isolated from lymphocytes or lymphoblasts using minor modifications of standard methods. 34,35 Genotyping of the D10S1423 polymorphism was performed as previously described, 21 using polymerase chain reaction (PCR) methodology employing the oligonucleotide primer pair included in the CHLC Human Screening Set/Weber Version 6 (Research Genetics, Huntsville, AL, USA). Following amplification, the resulting PCR products were resolved by electrophoresis under denaturing conditions, visualized by autoradiography, and sized by comparison to individuals of known genotypes from the CEPH panel, 1331-01 and 1331-02 (Coriell Institute, Camden, NJ, USA).…”

Section: Longitudinal Surveillance Protocolmentioning

confidence: 99%

D10S1423 identifies a susceptibility locus for Alzheimer's disease in a prospective, longitudinal, double-blind study of asymptomatic individuals

2001

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Typical, later-onset forms of Alzheimer's disease (AD) appear to be influenced by multiple susceptibility loci, combinations of which contribute to the development of this disorder. We previously reported the results of a systematic survey of the human genome for the identification of highly informative DNA polymorphisms (SSTRPs) that target new AD risk genes. In addition to the APOE locus, our survey detected five new candidate susceptibility loci for AD, including D10S1423. An association of the D10S1423 234-bp allele with AD has been reported in three independent samples of AD cases and controls (Boston, Pittsburgh, Bonn). Data from our case-control studies suggest a strong synergistic interaction between the D10S1423 234-bp and APOE E4 risk alleles (234-bp carrier: OR = 2.5, 95% CI = 1.4-4.5; E4 carrier: OR = 8.3, 95% CI = 4.3-15.8; both alleles: OR = 23.1, 95% CI = 5.3-99.5). This report describes the prospective, longitudinal, double-blind assessment of the age-specific risk of AD encountered by 325 asymptomatic first-degree relatives of AD probands who carried the D10S1423 234-bp allele, the APOE E4 allele, or both, after 11.5 years of systematic follow-up. A total of 18 incident cases of AD were detected during the first 3379 subject-years of this longitudinal study. The effects of carrying either or both of the D10S1423 234-bp and APOE E4 alleles on the age-specific risk of developing AD were determined using Kaplan-Meier survival analysis. The age-specific risk of developing AD was the greatest for individuals who carried both alleles (Mantel-Cox statistic = 20.12, df = 3, P = 0.0002; Breslow statistic = 13.36, df = 3, P = 0.004). Cox proportional hazards models were developed to estimate the risk ratios for each genotype, controlling for the potential effects of age at recruitment, sex, and years of education. In the resulting best fitting model, only individuals who carried both risk alleles exhibited a risk ratio that differed significantly from 1 (risk ratio = 16.2, P = 0.008, 95% CI = 2.1-128.3). After controlling for these genotypes, female gender was also significantly associated with increased risk of developing AD (risk ratio = 5.1, P = 0.02, 95% CI = 1.2-21.1). Neither age at recruitment nor years of education made significant contributions to the model. Molecular Psychiatry (2001) 6, 413-419.

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Section: Longitudinal Surveillance Protocolmentioning

confidence: 99%

D10S1423 identifies a susceptibility locus for Alzheimer's disease in a prospective, longitudinal, double-blind study of asymptomatic individuals

2001

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“…Genomic DNA was isolated from blood cells or brain tissue using minor modifications of standard methods [Zubenko et al, 1993;Miller et al, 19881. Lymphocytes or lymphoblasts were resuspended in 3 ml of lysis buffer (10 mM Tris-HC1, 400mM NaC1, 1mM EDTA, pH 7.5) and the resulting lysates were digested overnight at 37°C with 0.1 ml of 20% sodium dodecyl sulfate (SDS) and 0.5 ml of a 1% SDS solution containing 2.5 mg of proteinase K and 2 mM EDTA.…”

Section: Isolation Of Genomic Dnamentioning

confidence: 99%

“…This association arose from an interaction of the €4 allele INTRODUCTION Considerable progress has been made in identifying genetic factors that influence the development of Alzheimer's Disease (AD). In a small fraction of cases, missense mutations have been identified in the amyloid precursor protein (APP) gene on chromosome 21 that cosegregate with early-onset AD in extended families [see Zubenko et al, 1993 for review]. It is unclear whether this gene is identical to an unidentified locus on chromosome 21 previously reported t o cosegregate with early-onset, familial AD [St. George-Hyslop et al, 1987, 19901.…”

mentioning

confidence: 99%

Association of the apolipoprotein E ϵ4 allele with clinical subtypes of autopsy‐confirmed Alzheimer's disease

Zubenko¹,

Stiffler²,

Stabler³

et al. 1994

Am. J. Med. Genet.

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Consistent with previous reports, we observed a significant association of the APOE epsilon 4 allele with Alzheimer's Disease (AD) in a series of 91 autopsy-confirmed cases. The epsilon 4 allele frequency was higher in cases with a family history of AD-like dementia (0.54 +/- 0.07), although the epsilon 4 allele frequency in the AD cases with a negative family history (0.38 +/- 0.05) remained significantly greater than that for the non-AD control group (0.13 +/- 0.03). A similar increase in epsilon 4 allele frequency (0.54 +/- 0.07) was observed in the AD cases with amyloid angiopathy, compared to those who did not have amyloid angiopathy (0.36 +/- 0.04). Contrary to previous reports, no effect of the dosage of the epsilon 4 allele was found on the age of onset of dementia among the AD cases and, contrary to reports suggesting an association of epsilon 4 and atherosclerosis, the epsilon 4 allele frequency was similar in cases with or without concurrent brain infarcts. Modest but consistent correlations were observed between the dosage of epsilon 4 alleles and the cortical density of senile plaques, but not neurofibrillary tangles. The last finding suggests that the pathogenic events mediated by the epsilon 4 allele may be more directly involved in the formation of senile plaques, the identifying lesions in AD, than neurofibrillary tangles. A robust association of both the presence of an epsilon 4 allele and a family history of AD-like dementia with concurrent amyloid angiopathy occurred within our sample of AD cases. This association arose from an interaction of the epsilon 4 allele with a separate familial factor for which a family history of dementia served as a surrogate. These results suggest that amyloid angiopathy may be a common or central feature of a form of familial AD that is associated with the transmission of the APOE epsilon 4 allele.

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“…Brain tissue samples from an additional group of 50 autopsied cases with AD, acquired between 1986 and 1992 as previously described [Zubenko et al, 1993[Zubenko et al, , 1994, were provided by the Division of Neuropathology, Presbyterian University Hospital, and the Alzheimer's Disease Research Center (AG05133), University of Pittsburgh, Pittsburgh, PA. Autopsies were performed and neuropathologic diagnoses were established by boardcertified neuropathologists at each site. Brain tissue samples from an additional group of 50 autopsied cases with AD, acquired between 1986 and 1992 as previously described [Zubenko et al, 1993[Zubenko et al, , 1994, were provided by the Division of Neuropathology, Presbyterian University Hospital, and the Alzheimer's Disease Research Center (AG05133), University of Pittsburgh, Pittsburgh, PA. Autopsies were performed and neuropathologic diagnoses were established by boardcertified neuropathologists at each site.…”

Section: Materials and Methods Study Populationsmentioning

confidence: 99%

Initial results of a genome survey for novel alzheimer's disease risk genes: association with a locus on the X chromosome

et al. 1998

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As the initial step in a systematic genome survey, 16 simple sequence tandem repeat polymorphisms that span the X chromosome at an average spacing of 10 cM were examined for allelic associations with typical-onset Alzheimer's disease (AD). The efficiency of this survey was substantially enhanced by genotyping pools of genomic DNA from 50 autopsy-confirmed AD cases and 50 autopsied controls who were similar in sex ratio, race, and age at death. The frequency of the DXS1047 202-bp allele was twice as common among AD cases (0.45+/-S.E. 0.06) than controls (0.22+/-S.E. 0.05), a finding that was reproduced in an independent and geographically disparate sample. Consistent with Hardy-Weinberg equilibrium, the proportion of women with AD who carried the 202-bp allele, 73% was nearly double that observed for men with AD, 38%. However, the frequency of the 202-bp allele was similar for men and women and the presence of this allele did not affect the age at onset of dementia in either sex. Furthermore, the frequency of the DXS1047 202-bp allele in AD cases and controls was unaffected by the APOE genotype, indicating that these two loci modulate AD risk independently. Finally, the frequency of the 202-bp allele among 50 autopsy-confirmed cases of Parkinson's disease (0.29+/-S.E. 0.06) was indistinguishable from the control value, reflecting relative specificity for this allelic association with AD.

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Lack of variation in the nucleotide sequence corresponding to the transmembrane domain of the β‐amyloid precursor protein in Alzheimer's disease

Cited by 10 publications

References 41 publications

D10S1423 identifies a susceptibility locus for Alzheimer's disease in a prospective, longitudinal, double-blind study of asymptomatic individuals

D10S1423 identifies a susceptibility locus for Alzheimer's disease in a prospective, longitudinal, double-blind study of asymptomatic individuals

Association of the apolipoprotein E ϵ4 allele with clinical subtypes of autopsy‐confirmed Alzheimer's disease

Initial results of a genome survey for novel alzheimer's disease risk genes: association with a locus on the X chromosome

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