TAR DNA-binding protein 43 and pathological subtype of Alzheimer's disease impact clinical features

Keith A. Josephs, Jennifer L. Whitwell, Nirubol Tosakulwong, Stephen D. Weigand, Melissa E. Murray, Amanda M. Liesinger, Leonard Petrucelli, Matthew L. Senjem, Robert J. Ivnik, Joseph E. Parisi, Ronald C. Petersen, Dennis W. Dickson

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Objective The aim of this study was to determine whether the frequency of TAR DNA-binding protein 43 (TDP-43) deposition in Alzheimer's disease (AD) differs across pathologically defined AD subtypes (hippocampal sparing [HpSp]; typical and limbic) and further examine the relationship between TDP-43, pathological subtype, and clinical features in AD. Methods We identified all cases with pathologically confirmed AD (NIA-Reagan intermediate-high probability, Braak stage IV-VI) independent of cognitive status (n = 188). Neurofibrillary tangle counts were performed using thioflavin-S microscopy in hippocampus and three neocortical regions, and all cases were subtyped: HpSp AD pathology (n = 19); typical AD pathology (n = 136); and limbic AD pathology (n = 33). TDP-43 immunoreactivity was performed in multiple brain regions to assess for the presence of TDP-43 and TDP-43 stage. All cases were clinically subclassified at presentation as amnestic AD dementia versus atypical AD dementia. Statistical analysis was performed using linear and penalized logistic regression to assess associations with pathological subtype, and the effects of TDP-43, accounting for possible interactions between pathological subtype and TDP-43. Results TDP-43 deposition was frequent in typical (59%) and limbic AD pathologies (67%), but not HpSp AD pathology (21%; p = 0.003). The observed associations of TDP-43 with greater memory loss, naming and functional decline, and smaller hippocampal volumes, closest to death, did not differ across AD pathological subtype. Clinical presentation was associated with pathological subtype (p = 0.01), but not TDP-43 (p = 0.69). Interpretation Although the frequency of TDP-43 deposition in AD varies by pathological subtype, the observed effects of TDP-43 on clinical/magnetic resonance imaging features are consistent across pathological subtypes. Clinical presentation in AD is driven by pathological subtype, not by TDP-43.

Original languageEnglish (US)
Pages (from-to)697-709
Number of pages13
JournalAnnals of neurology
Issue number5
StatePublished - Nov 2015

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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