Machine Learning to Detect Alzheimer's Disease from Circulating Non-coding RNAs.

Journal: Genomics, proteomics & bioinformatics
PMID: 31809862

Abstract

Blood-borne small non-coding (sncRNAs) are among the prominent candidates for blood-based diagnostic tests. Often, high-throughput approaches are applied to discover biomarker signatures. These have to be validated in larger cohorts and evaluated by adequate statistical learning approaches. Previously, we published high-throughput sequencing based microRNA (miRNA) signatures in Alzheimer's disease (AD) patients in the United States (US) and Germany. Here, we determined abundance levels of 21 known circulating miRNAs in 465 individuals encompassing AD patients and controls by RT-qPCR. We computed models to assess the relation between miRNA expression and phenotypes, gender, age, or disease severity (Mini-Mental State Examination; MMSE). Of the 21 miRNAs, expression levels of 20 miRNAs were consistently de-regulated in the US and German cohorts. 18 miRNAs were significantly correlated with neurodegeneration (Benjamini-Hochberg adjusted P < 0.05) with highest significance for miR-532-5p (Benjamini-Hochberg adjusted P = 4.8 × 10). Machine learning models reached an area under the curve (AUC) value of 87.6% in differentiating AD patients from controls. Further, ten miRNAs were significantly correlated with MMSE, in particular miR-26a/26b-5p (adjusted P = 0.0002). Interestingly, the miRNAs with lower abundance in AD were enriched in monocytes and T-helper cells, while those up-regulated in AD were enriched in serum, exosomes, cytotoxic t-cells, and B-cells. Our study represents the next important step in translational research for a miRNA-based AD test.

Authors

  • Nicole Ludwig
    Department of Human Genetics, Saarland University, 66421 Homburg/Saar, Germany.
  • Tobias Fehlmann
    Chair for Clinical Bioinformatics, Saarland University, 66123 Saarbrücken, Germany.
  • Fabian Kern
    Chair for Clinical Bioinformatics, Saarland University, 66123 Saarbrücken, Germany.
  • Manfred Gogol
    Institut für Gerontologie, Universität Heidelberg, 69047 Heidelberg, Germany.
  • Walter Maetzler
    Department of Neurology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany; Center for Neurology and Hertie Institute for Clinical Brain Research, Department of Neurodegeneration, University of Tuebingen, 72074 Tuebingen, Germany; German Center for Neurodegenerative Diseases (DZNE), 72076 Tuebingen, Germany.
  • Stephanie Deutscher
    Department of Human Genetics, Saarland University, 66421 Homburg/Saar, Germany.
  • Simone Gurlit
    Department of Anesthesiology and Intensive Care, St. Franziskus Hospital Muenster, 48145 Muenster, Germany.
  • Claudia Schulte
    Center for Neurology and Hertie Institute for Clinical Brain Research, Department of Neurodegeneration, University of Tuebingen, 72074 Tuebingen, Germany; German Center for Neurodegenerative Diseases (DZNE), 72076 Tuebingen, Germany.
  • Anna-Katharina von Thaler
    Center for Neurology and Hertie Institute for Clinical Brain Research, Department of Neurodegeneration, University of Tuebingen, 72074 Tuebingen, Germany; German Center for Neurodegenerative Diseases (DZNE), 72076 Tuebingen, Germany.
  • Christian Deuschle
    Center for Neurology and Hertie Institute for Clinical Brain Research, Department of Neurodegeneration, University of Tuebingen, 72074 Tuebingen, Germany; German Center for Neurodegenerative Diseases (DZNE), 72076 Tuebingen, Germany.
  • Florian Metzger
    Department of Psychiatry and Psychotherapy, University Hospital Tuebingen, 72016 Tuebingen, Germany.
  • Daniela Berg
    Department of Neurology, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany; Center for Neurology and Hertie Institute for Clinical Brain Research, Department of Neurodegeneration, University of Tuebingen, 72074 Tuebingen, Germany; German Center for Neurodegenerative Diseases (DZNE), 72076 Tuebingen, Germany.
  • Ulrike Suenkel
    Center for Neurology and Hertie Institute for Clinical Brain Research, Department of Neurodegeneration, University of Tuebingen, 72074 Tuebingen, Germany; German Center for Neurodegenerative Diseases (DZNE), 72076 Tuebingen, Germany.
  • Verena Keller
    Department of Medicine II, Saarland University Medical Center, 66421 Homburg/Saar, Germany.
  • Christina Backes
    Chair for Clinical Bioinformatics, Saarland University, 66123 Saarbrücken, Germany.
  • Hans-Peter Lenhof
    Center for Bioinformatics, Saarland Informatics Campus, 66123 Saarbrücken, Germany.
  • Eckart Meese
    Department of Human Genetics, Saarland University, 66421 Homburg/Saar, Germany.
  • Andreas Keller
    Chair for Clinical Bioinformatics, Saarland University, 66123 Saarbrücken, Germany; Center for Bioinformatics, Saarland Informatics Campus, 66123 Saarbrücken, Germany. Electronic address: andreas.keller@ccb.uni-saarland.de.

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