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An Integrated Bioinformatics Approach for Identifying Genetic Markers that Predict Cerebrospinal Fluid Biomarker p-tau181/Aβ1-42 Ratio in ApoE4-Negative Mild Cognitive Impairment Patients.
J Alzheimers Dis 2015; 45(4):1061-76JA

Abstract

Alzheimer's disease (AD) is the most common form of dementia, with no disease-modifying treatment yet available. Early detection of patients at risk of developing AD is of central importance. Blood-based genetic signatures can serve as early detection and as population-based screening tools. In this study, we aimed to identify genetic markers and gene signatures associated with cerebrospinal fluid (CSF) biomarkers levels of t-tau, p-tau181, and with the two ratios t-tau/Aβ1-42 and p-tau181/Aβ1-42 in the context of progression from mild cognitive impairment (MCI) to AD, and to identify a panel of genetic markers that can predict CSF biomarker p-tau181/Aβ1-42 ratio with consideration of APOE ε4 stratification. We analyzed genome-wide the Alzheimer's Disease Neuroimaging Initiative dataset with up to 48 months follow-up. In the first part of the analysis, the main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed for each of the four CSF biomarkers. In the second part of the analysis, we performed an integrated analysis of genome-wide association study results with pathway enrichment analysis, predictive modeling and network analysis in the subgroup of ApoE4-negative subjects. We identified a panel of five SNPs, rs6766238, rs1143960, rs1249963, rs11975968, and rs4836493, that are predictive for p-tau181/Aβ1-42 ratio (high/low) with a sensitivity of 66% and a specificity of 70% (AUC 0.74). These results suggest that a panel of SNPs is a potential prognostic biomarker in ApoE4-negative MCI patients.

Authors+Show Affiliations

AstraZeneca Translational Science Centre, Personalised Healthcare & Biomarkers, Innovative Medicines, AstraZeneca R&D, Sweden Department Clinical Neuroscience, Science for Life Laboratory, Karolinska Institutet, Solna, Sweden.Clinical Informatics, CNS/Pain Clinical Development, AstraZeneca R&D Södertälje, Sweden.Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.AstraZeneca Translational Science Centre, Personalised Healthcare & Biomarkers, Innovative Medicines, AstraZeneca R&D, Sweden Institute of Neuroscience & Physiology, Department of Psychiatry & Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Sweden.Department of Immunology, Genetics and Pathology, Uppsala University, Sweden.AstraZeneca Translational Science Centre, Personalised Healthcare & Biomarkers, Innovative Medicines, AstraZeneca R&D, Sweden Department Clinical Neuroscience, Science for Life Laboratory, Karolinska Institutet, Solna, Sweden.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

25720397

Citation

Sun, Ying, et al. "An Integrated Bioinformatics Approach for Identifying Genetic Markers That Predict Cerebrospinal Fluid Biomarker p-tau181/Aβ1-42 Ratio in ApoE4-Negative Mild Cognitive Impairment Patients." Journal of Alzheimer's Disease : JAD, vol. 45, no. 4, 2015, pp. 1061-76.
Sun Y, Bresell A, Rantalainen M, et al. An Integrated Bioinformatics Approach for Identifying Genetic Markers that Predict Cerebrospinal Fluid Biomarker p-tau181/Aβ1-42 Ratio in ApoE4-Negative Mild Cognitive Impairment Patients. J Alzheimers Dis. 2015;45(4):1061-76.
Sun, Y., Bresell, A., Rantalainen, M., Höglund, K., Lebouvier, T., & Salter, H. (2015). An Integrated Bioinformatics Approach for Identifying Genetic Markers that Predict Cerebrospinal Fluid Biomarker p-tau181/Aβ1-42 Ratio in ApoE4-Negative Mild Cognitive Impairment Patients. Journal of Alzheimer's Disease : JAD, 45(4), pp. 1061-76. doi:10.3233/JAD-142118.
Sun Y, et al. An Integrated Bioinformatics Approach for Identifying Genetic Markers That Predict Cerebrospinal Fluid Biomarker p-tau181/Aβ1-42 Ratio in ApoE4-Negative Mild Cognitive Impairment Patients. J Alzheimers Dis. 2015;45(4):1061-76. PubMed PMID: 25720397.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - An Integrated Bioinformatics Approach for Identifying Genetic Markers that Predict Cerebrospinal Fluid Biomarker p-tau181/Aβ1-42 Ratio in ApoE4-Negative Mild Cognitive Impairment Patients. AU - Sun,Ying, AU - Bresell,Anders, AU - Rantalainen,Mattias, AU - Höglund,Kina, AU - Lebouvier,Thibaud, AU - Salter,Hugh, AU - ,, PY - 2015/2/28/entrez PY - 2015/2/28/pubmed PY - 2016/3/10/medline KW - Alzheimer's disease KW - cerebrospinal fluid KW - genome-wide association study KW - mild cognitive impairment KW - multivariate analysis KW - pathway analysis KW - predictive model SP - 1061 EP - 76 JF - Journal of Alzheimer's disease : JAD JO - J. Alzheimers Dis. VL - 45 IS - 4 N2 - Alzheimer's disease (AD) is the most common form of dementia, with no disease-modifying treatment yet available. Early detection of patients at risk of developing AD is of central importance. Blood-based genetic signatures can serve as early detection and as population-based screening tools. In this study, we aimed to identify genetic markers and gene signatures associated with cerebrospinal fluid (CSF) biomarkers levels of t-tau, p-tau181, and with the two ratios t-tau/Aβ1-42 and p-tau181/Aβ1-42 in the context of progression from mild cognitive impairment (MCI) to AD, and to identify a panel of genetic markers that can predict CSF biomarker p-tau181/Aβ1-42 ratio with consideration of APOE ε4 stratification. We analyzed genome-wide the Alzheimer's Disease Neuroimaging Initiative dataset with up to 48 months follow-up. In the first part of the analysis, the main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed for each of the four CSF biomarkers. In the second part of the analysis, we performed an integrated analysis of genome-wide association study results with pathway enrichment analysis, predictive modeling and network analysis in the subgroup of ApoE4-negative subjects. We identified a panel of five SNPs, rs6766238, rs1143960, rs1249963, rs11975968, and rs4836493, that are predictive for p-tau181/Aβ1-42 ratio (high/low) with a sensitivity of 66% and a specificity of 70% (AUC 0.74). These results suggest that a panel of SNPs is a potential prognostic biomarker in ApoE4-negative MCI patients. SN - 1875-8908 UR - https://www.unboundmedicine.com/medline/citation/25720397/An_Integrated_Bioinformatics_Approach_for_Identifying_Genetic_Markers_that_Predict_Cerebrospinal_Fluid_Biomarker_p_tau181/Aβ1_42_Ratio_in_ApoE4_Negative_Mild_Cognitive_Impairment_Patients_ L2 - https://content.iospress.com/openurl?genre=article&id=doi:10.3233/JAD-142118 DB - PRIME DP - Unbound Medicine ER -