Characterization of two APP gene promoter polymorphisms that appear to influence risk of late-onset Alzheimer's disease

Debomoy K. Lahiri, Yuan Wen Ge, Bryan Maloney, Fabienne Wavrant-De Vrièze, John Hardy

Research output: Contribution to journalArticle

29 Scopus citations


Alzheimer's disease (AD) is characterized by formation of plaques of amyloid β peptide (Aβ). Autosomally-inherited or "familial" AD had been demonstrated only in connection with coding sequence mutations. We characterized DNA-protein interaction and expression influence of two polymorphisms that occur in the promoter (C ↔ T at -3829 and T ↔ C at -1023, +1 transcription start site) of the Aβ precursor protein (APP) gene. We report distinct functional differences in reporter expression and in DNA-protein interaction for variant sequences in both -3829 and -1023 polymorphic regions. The -3829T variant has reduced DNA-protein interaction and reporter expression compared to -3829C, while -1023C has greater DNA-protein interaction and reporter expression than -1023T. Our predictions for likely transcription factors for loss of function (-3829T) are ADR1, MIG1, and PuF, and for gain of function (-1023C) are E12/E47, ITF-2, and RFX2. Characterization of the activity of a regulatory polymorphism of the APP gene points towards understanding mechanisms that likely underlie the majority of AD cases and may contribute to promoter-based drug design.

Original languageEnglish (US)
Pages (from-to)1329-1341
Number of pages13
JournalNeurobiology of Aging
Issue number10
StatePublished - Nov 1 2005


  • Aging
  • Amyloid β protein
  • Brain
  • CAT reporter gene
  • DNA-protein interaction
  • E12/E47
  • E47
  • Gel shift assay
  • Polymorphism
  • PuF
  • Regulatory region
  • Transcription factor

ASJC Scopus subject areas

  • Clinical Neurology
  • Biological Psychiatry
  • Developmental Neuroscience
  • Neurology
  • Psychology(all)

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