Repeat expansions in the C9ORF72 gene contribute to Alzheimer's disease in Caucasians

Martin A. Kohli, Krista John-Williams, Ruchita Rajbhandary, Adam Naj, Patrice Whitehead, Kara Hamilton, Regina M. Carney, Clinton Wright, Elizabeth Crocco, Harry E. Gwirtzman, Rosalyn Lang, Gary Beecham, Eden R. Martin, John Gilbert, Michael Benatar, Gary W. Small, Deborah Mash, Goldie Byrd, Jonathan L. Haines, Margaret A. Pericak-VanceStephan Züchner

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


Recently, a hexanucleotide repeat expansion in the C9ORF72 gene has been identified to account for a significant portion of Caucasian families affected by frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Given the clinical overlap of FTD with Alzheimer's disease (AD), we hypothesized that C9ORF72 expansions might contribute to AD. In Caucasians, we found C9ORF72 expansions in the pathogenic range of FTD/ALS (>30 repeats) at a proportion of 0.76% in AD cases versus 0 in control subjects (p = 3.3E-03; 1182 cases, 1039 controls). In contrast, no large expansions were detected in individuals of African American ethnicity (291 cases, 620 controls). However, in the range of normal variation of C9ORF72 expansions (0-23 repeat copies), we detected significant differences in distribution and mean repeat counts between Caucasians and African Americans. Clinical and pathological re-evaluation of identified C9ORF72 expansion carriers revealed 9 clinical and/or autopsy confirmed AD and 2 FTD final diagnoses. Thus, our results support the notion that large C9ORF72 expansions lead to a phenotypic spectrum of neurodegenerative disease including AD.

Original languageEnglish (US)
Pages (from-to)1519.e5-1519.e12
JournalNeurobiology of aging
Issue number5
StatePublished - May 2013


  • Alzheimer disease
  • C9ORF72
  • Genetic association
  • Repeat expansion
  • Repeat-primed PCR
  • Spectrum of neurodegenerative phenotypes

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Aging
  • Developmental Biology
  • Geriatrics and Gerontology


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