C9orf72 mutations do not influence the tau signature of amyotrophic lateral sclerosis with cognitive impairment (ALSci)

Amyotroph Lateral Scler Frontotemporal Degener. 2017 Nov;18(7-8):549-554. doi: 10.1080/21678421.2017.1332075. Epub 2017 May 31.


Objective: C9orf72 mutations are associated with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and ALS-FTD. In addition to ALS-FTD, ALS patients may develop a spectrum of neuropsychological and neuropsychiatric deficits including ALS with cognitive impairment (ALSci). Here we examine the extent to which C9orf72 mutations are associated with ALSci and whether this alters the tau molecular signature.

Methods: We identified 16 ALSci cases within a post-mortem archive of 94 fully genotyped ALS cases, eight of which harboured a C9orf72 mutation, in addition to three cognitively-intact ALS cases with a C9orf72 mutation. Tau was fractionated into soluble and insoluble fractions, with or without dephosphorylation, and immunoblots for tau phospho-isoforms performed.

Results: Regardless of cognitive state or the presence of C9orf72 mutation, all ALS cases demonstrated six tau isoforms in both soluble and insoluble tau isolates. This pattern was unaffected by dephosphorylation. pThr175tau isoforms, a molecular signature of ALSci, were present regardless of C9orf72 genetic status. The pathognomic paired helical triplet in the insoluble tau fraction of Alzheimer's disease was not observed, regardless of cognitive or C9orf72 status.

Conclusions: These findings suggest that the presence of a C9orf72 mutation does not influence the tau signature of ALS or ALSci.

Keywords: Alzheimer’s disease; Amyotrophic lateral sclerosis; frontotemporal dementia; frontotemporal spectrum disorder; tauopathy.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / genetics*
  • Amyotrophic Lateral Sclerosis / genetics*
  • Cognition Disorders / genetics*
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease / genetics
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics
  • Polymorphism, Single Nucleotide / genetics*
  • RNA-Binding Proteins / genetics*
  • tau Proteins / genetics*


  • FAM120A protein, human
  • RNA-Binding Proteins
  • tau Proteins