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Phosphorylated Tau-Aβ42 Ratio as a Continuous Trait for Biomarker Discovery for Early-Stage Alzheimer’s Disease in Multiplex Immunoassay Panels of Cerebrospinal Fluid

  • Oscar Harari
    Affiliations
    Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
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  • Carlos Cruchaga
    Affiliations
    Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri

    Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri
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  • John S.K. Kauwe
    Affiliations
    Department of Biology, Brigham Young University, Provo, Utah
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  • Benjamin J. Ainscough
    Affiliations
    Division of Biology & Biomedical Sciences, Washington University School of Medicine, St. Louis, Missouri
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  • Kelly Bales
    Affiliations
    Neuroscience Research Unit, Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut
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  • Eve H. Pickering
    Affiliations
    Neuroscience Research Unit, Worldwide Research and Development, Pfizer, Inc., Groton, Connecticut
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  • Sarah Bertelsen
    Affiliations
    Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
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  • Anne M. Fagan
    Affiliations
    Department of Neurology, Washington University School of Medicine, St. Louis, Missouri

    Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, Missouri

    Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri
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  • David M. Holtzman
    Affiliations
    Department of Neurology, Washington University School of Medicine, St. Louis, Missouri

    Developmental Biology, Washington University School of Medicine, St. Louis, Missouri

    Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, Missouri

    Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri
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  • John C. Morris
    Affiliations
    Department of Neurology, Washington University School of Medicine, St. Louis, Missouri

    Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri

    Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, Missouri

    Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri
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  • Alison M. Goate
    Correspondence
    Address correspondence to Alison M. Goate, D.Phil., Department of Psychiatry, Washington University School of Medicine, 425 S. Euclid Avenue, St. Louis, MO 63110
    Affiliations
    Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri

    Department of Neurology, Washington University School of Medicine, St. Louis, Missouri

    Department of Genetics, Washington University School of Medicine, St. Louis, Missouri

    Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, Missouri

    Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri
    Search for articles by this author
  • Alzheimer’s Disease Neuroimaging Initiative

      Background

      Identification of the physiologic changes that occur during the early stages of Alzheimer’s disease (AD) may provide critical insights for the diagnosis, prognosis, and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome.

      Methods

      A novel approach was applied to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay, and common associations were detected in the Knight Alzheimer’s Disease Research Center (N = 311) and the Alzheimer’s Disease Neuroimaging Initiative (N = 293) cohorts. Rather than case-control status, the ratio of CSF levels of tau phosphorylated at threonine 181 (ptau181) and Aβ42 was used as a continuous trait in these analyses.

      Results

      The ptau181-Aβ42 ratio has more statistical power than traditional modeling approaches, and the levels of CSF heart-type fatty acid binding protein (FABP) and 12 other correlated analytes increase as AD progresses. These results were validated using the traditional case-control status model. Stratification of the dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in nondemented individuals with AD pathology (low ptau181, low Aβ42) compared with elderly control subjects with no pathology (low ptau181, high Aβ42). The FABP-Aβ42 ratio demonstrates a similar hazard ratio for disease conversion to ptau181-Aβ42 even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor of AD.

      Conclusions

      Our results indicate that the approach presented here can be used to identify novel biomarkers for AD correctly and that CSF heart FABP levels start to increase at very early stages of AD.

      Key Words

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