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Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease
  1. K Kasuga1,2,
  2. T Shimohata2,
  3. A Nishimura3,
  4. A Shiga1,2,
  5. T Mizuguchi3,
  6. J Tokunaga2,
  7. T Ohno4,
  8. A Miyashita5,
  9. R Kuwano5,
  10. N Matsumoto3,
  11. O Onodera1,
  12. M Nishizawa2,
  13. T Ikeuchi1
  1. 1
    Department of Molecular Neuroscience, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan
  2. 2
    Department of Neurology, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan
  3. 3
    Department of Human Genetics, Yokohama City University, Graduate School of Medicine, Yokohama, Japan
  4. 4
    Department of Neurology, Nagaoka Chuo General Hospital, Nagaoka, Japan
  5. 5
    Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan
  1. Correspondence to Dr T Ikeuchi, Department of Molecular Neuroscience, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951-8585, Japan; ikeuchi{at}bri.niigata-u.ac.jp

Abstract

Background: The occurrence of duplications of the amyloid precursor protein gene (APP) has been described in European families with early-onset familial Alzheimer disease (EO-FAD) and cerebral amyloid angiopathy. However, the contribution of APP duplication to the development of AD in other ethnic populations remains undetermined.

Methods: The occurrence of APP duplication in probands from 25 families with FAD and 11 sporadic EO-AD cases in the Japanese population was examined by quantitative PCR and microarray-based comparative genomic hybridisation analyses. APP expression level was determined by real-time quantitative reverse-transcription (RT) PCR analysis using mRNA extracted from the peripheral blood of the patients.

Results: We identified APP locus duplications in two unrelated EO-FAD families. The duplicated genomic regions in two patients of these families differed from each other. No APP duplication was found in the late-onset FAD families or sporadic EO-AD patients. The patients with APP duplication developed insidious memory disturbance in their fifties without intracerebral haemorrhage and epilepsy. Quantitative RT-PCR analysis showed the increased APP mRNA expression levels in these patients compared with those in age- and sex-matched controls.

Conclusions: Our results suggest that APP duplication should be considered in patients with EO-FAD in various ethnic groups, and that increased APP mRNA expression level owing to APP duplication contributes to AD development.

https://doi.org/10.1136/jnnp.2008.161703

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    Footnotes

    • Funding This study was supported in part by Grant-in-Aid for Scientific Research (20590990) from the MEXT, Japan.

    • Competing interests None.

    • Ethics approval Provided by Niigata University School of Medicine.

    • ▸ Additional figures are published online only at http://jnnp.bmj.com/content/vol80/issue9

    • Patient consent Obtained.