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

Keith Anthony Josephs, Jennifer Lynn Whitwell, Stephen D. Weigand, Melissa E Murray, Nirubol Tosakulwong, Amanda M. Liesinger, Leonard Petrucelli, Matthew L. Senjem, David S Knopman, Bradley F Boeve, Robert J. Ivnik, Glenn E. Smith, Clifford R Jr. Jack, Joseph E Parisi, Ronald Carl Petersen, Dennis W Dickson

Research output: Contribution to journalArticle

131 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)811-824
Number of pages14
JournalActa Neuropathologica
Volume127
Issue number6
DOIs
StatePublished - 2014

Fingerprint

Alzheimer Disease
Atrophy
Cognition
Pathology
Apolipoproteins
Sclerosis
Atlases
Memory Disorders
DNA-Binding Proteins
Brain
Neuroimaging
Therapeutics

Keywords

  • Alzheimer disease
  • APOE ε4
  • Braak stage
  • MRI
  • Resilience
  • TDP-43

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

Cite this

TDP-43 is a key player in the clinical features associated with Alzheimer's disease. / Josephs, Keith Anthony; Whitwell, Jennifer Lynn; Weigand, Stephen D.; Murray, Melissa E; Tosakulwong, Nirubol; Liesinger, Amanda M.; Petrucelli, Leonard; Senjem, Matthew L.; Knopman, David S; Boeve, Bradley F; Ivnik, Robert J.; Smith, Glenn E.; Jack, Clifford R Jr.; Parisi, Joseph E; Petersen, Ronald Carl; Dickson, Dennis W.

In: Acta Neuropathologica, Vol. 127, No. 6, 2014, p. 811-824.

Research output: Contribution to journalArticle

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AU - Liesinger, Amanda M.

AU - Petrucelli, Leonard

AU - Senjem, Matthew L.

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