title: 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.
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.affiliation: AstraZeneca Translational Science Centre, Personalised Healthcare & Biomarkers, Innovative Medicines, AstraZeneca R&D, Sweden Department Clinical Neuroscience, Science for Life Laboratory, Karolinska Institutet, Solna, Sweden.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Clinical Informatics, CNS/Pain Clinical Development, AstraZeneca R&D Södertälje, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Bresell
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Rantalainen
authors.affiliation: 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.
authors.forename: Kina
authors.initials: K
authors.lastname: Höglund
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Sweden.
authors.forename: Thibaud
authors.initials: T
authors.lastname: Lebouvier
authors.affiliation: AstraZeneca Translational Science Centre, Personalised Healthcare & Biomarkers, Innovative Medicines, AstraZeneca R&D, Sweden Department Clinical Neuroscience, Science for Life Laboratory, Karolinska Institutet, Solna, Sweden.
authors.forename: Hugh
authors.initials: H
authors.lastname: Salter
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D053327:Apolipoprotein E4 / Q000235:genetics; D015415:Biomarkers / Q000134:cerebrospinal fluid; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid* / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D016875:tau Proteins / Q000134:cerebrospinal fluid* / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D015415:Biomarkers; D005819:Genetic Markers; C054369:MAPT protein, human; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
keywords: Alzheimer's disease; cerebrospinal fluid; genome-wide association study; mild cognitive impairment; multivariate analysis; pathway analysis; predictive model