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TDP-43 is a key player in the clinical features associated with Alzheimer’s disease

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Abstract

The aim of this study was to determine whether the TAR DNA-binding protein of 43 kDa (TDP-43) has any independent effect on the clinical and neuroimaging features typically ascribed to Alzheimer’s disease (AD) pathology, and whether TDP-43 pathology could help shed light on the phenomenon of resilient cognition in AD. Three-hundred and forty-two subjects pathologically diagnosed with AD were screened for the presence, burden and distribution of TDP-43. All had been classified as cognitively impaired or normal, prior to death. Atlas-based parcellation and voxel-based morphometry were used to assess regional atrophy on MRI. Regression models controlling for age at death, apolipoprotein ε4 and other AD-related pathologies were utilized to explore associations between TDP-43 and cognition or brain atrophy, stratified by Braak stage. In addition, we determined whether the effects of TDP-43 were mediated by hippocampal sclerosis. One-hundred and ninety-five (57 %) cases were TDP-positive. After accounting for age, apolipoprotein ε4 and other pathologies, TDP-43 had a strong effect on cognition, memory loss and medial temporal atrophy in AD. These effects were not mediated by hippocampal sclerosis. TDP-positive subjects were 10× more likely to be cognitively impaired at death compared to TDP-negative subjects. Greater cognitive impairment and medial temporal atrophy were associated with greater TDP-43 burden and more extensive TDP-43 distribution. TDP-43 is an important factor in the manifestation of the clinico-imaging features of AD. TDP-43 also appears to be able to overpower what has been termed resilient brain aging. TDP-43 therefore should be considered a potential therapeutic target for the treatment of AD.

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Acknowledgments

This study was funded by the US National Institute of Heath (NIA) Grants R01-AG037491 (to KAJ), R21-AG038736 (to JLW), P50-AG016574 (to RCP) and R01-AG011378 (to CRJ). We wish to thank the families of the patients who donated their brains to science allowing completion of this study. We further wish to thank Kris Johnson, Linda Rousseau, Virginia Phillips and Monica Casey-Castanedes for pathological support.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Department of Neurology (Behavioral Neurology), Mayo Clinic, Rochester, MN, 55905, USA

    Keith A. Josephs, David S. Knopman, Bradley F. Boeve & Ronald C. Petersen

  2. Department of Radiology (Radiology Research), Mayo Clinic, Rochester, MN, USA

    Jennifer L. Whitwell & Clifford R. Jack Jr.

  3. Department of Health Science Research (Biostatistics), Mayo Clinic, Rochester, MN, USA

    Stephen D. Weigand & Nirubol Tosakulwong

  4. Department of Information Technology, Mayo Clinic, Rochester, MN, USA

    Matthew L. Senjem

  5. Department of Laboratory Medicine and Neuropathology, Mayo Clinic, Rochester, MN, USA

    Joseph E. Parisi

  6. Department of Neuropsychiatry (Neuropsychology), Mayo Clinic, Rochester, MN, USA

    Robert J. Ivnik & Glenn E. Smith

  7. Department of Neuroscience (Neuropathology), Mayo Clinic, Jacksonville, FL, USA

    Melissa E. Murray, Amanda M. Liesinger & Dennis W. Dickson

  8. Molecular Neuroscience, Mayo Clinic, Jacksonville, FL, USA

    Leonard Petrucelli

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  1. Keith A. Josephs
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Correspondence to Keith A. Josephs.

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Josephs, K.A., Whitwell, J.L., Weigand, S.D. et al. TDP-43 is a key player in the clinical features associated with Alzheimer’s disease. Acta Neuropathol 127, 811–824 (2014). https://doi.org/10.1007/s00401-014-1269-z

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  • DOI: https://doi.org/10.1007/s00401-014-1269-z

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