Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease.
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.
Kasuga
K
K
Department of Molecular Neuroscience, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
Shimohata
T
T
Nishimura
A
A
Shiga
A
A
Mizuguchi
T
T
Tokunaga
J
J
Ohno
T
T
Miyashita
A
A
Kuwano
R
R
Matsumoto
N
N
Onodera
O
O
Nishizawa
M
M
Ikeuchi
T
T
D017668:Age of Onset; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D001284:Atrophy; D001921:Brain / Q000473:pathology; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D020440:Gene Duplication; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010375:Pedigree; D012333:RNA, Messenger / Q000097:blood; D016875:tau Proteins / Q000134:cerebrospinal fluid
D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D012333:RNA, Messenger; D016875:tau Proteins; D004247:DNA