• Open Access

Cerebrospinal fluid tau and ptau181 increase with cortical amyloid deposition in cognitively normal individuals: Implications for future clinical trials of Alzheimer's disease

Authors

  • Anne M. Fagan,

    Corresponding author
    1. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
    2. Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
    3. Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
    • Tel: +1 341 362 3453; Fax: +1 341 362 2244
    Search for more papers by this author
  • Mark A. Mintun,

    1. Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
    2. Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA
    Search for more papers by this author
  • Aarti R. Shah,

    1. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
    2. Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
    Search for more papers by this author
  • Patricia Aldea,

    1. Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA
    Search for more papers by this author
  • Catherine M. Roe,

    1. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
    2. Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
    Search for more papers by this author
  • Robert H. Mach,

    1. Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
    2. Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA
    Search for more papers by this author
  • Daniel Marcus,

    1. Department of Radiology, Washington University School of Medicine, St. Louis, MO, USA
    Search for more papers by this author
  • John C. Morris,

    1. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
    2. Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
    3. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
    Search for more papers by this author
  • David M. Holtzman

    1. Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
    2. Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
    3. Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
    4. Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO, USA
    Search for more papers by this author

Abstract

Alzheimer's disease (AD) pathology is estimated to develop many years before detectable cognitive decline. Fluid and imaging biomarkers may identify people in early symptomatic and even preclinical stages, possibly when potential treatments can best preserve cognitive function. We previously reported that cerebrospinal fluid (CSF) levels of amyloid-β42 (Aβ42) serve as an excellent marker for brain amyloid as detected by the amyloid tracer, Pittsburgh compound B (PIB). Using data from 189 cognitively normal participants, we now report a positive linear relationship between CSF tau/ptau181 (primary constituents of neurofibrillary tangles) with the amount of cortical amyloid. We observe a strong inverse relationship of cortical PIB binding with CSF Aβ42 but not for plasma Aβ species. Some individuals have low CSF Aβ42 but no cortical PIB binding. Together, these data suggest that changes in brain Aβ42 metabolism and amyloid formation are early pathogenic events in AD, and that significant disruptions in CSF tau metabolism likely occur after Aβ42 initially aggregates and increases as amyloid accumulates. These findings have important implications for preclinical AD diagnosis and treatment.

Ancillary