title: Genetic risk and transcriptional variability of amyloid precursor protein in Alzheimer's disease.
abstract: It is well established that Alzheimer's disease causing mutations in APP, PSEN1 and PSEN2 lead to a relative increased production of Abeta42, thereby fostering its deposition in plaques. Recently others and we showed that amyloid precursor protein (APP) overproduction, either as a result of genomic locus duplication or altered regulatory sequences in the APP promoter region, leads to early-onset disease. Here, we have expanded our study of genetic variability in the APP promoter to a large group of well-documented Belgian patients (n = 750, mean onset age = 75.0 +/- 8.6, range = 37-96). We identified three different APP promoter mutations (-369C-->G, -534G-->A and -479C-->T) in seven patients. In patients with onset < or =70 years (n = 204), we identified one patient carrying the London APP V717I mutation while no patients carried an APP locus duplication, indicating that APP promoter mutations (n = 2) were more frequently associated with increased risk for early-onset Alzheimer's disease. The two mutations (-369C-->G and -534G-->A) increasing APP promoter activity by nearly 2-fold and mimicking an APP duplication, appeared in probands of families with multiple patients with dementia. The -479C-->T mutation that increased APP expression only mildly (1.2-fold), was observed in four patients with onset ages ranging from 62 to 79 years (mean 71.5 years), suggesting that its contribution to disease risk is more pronounced at later age due to modulating factors. In conclusion, we provided evidence that mutations in APP regulatory sequences are more frequent than APP coding mutations, and that increased APP transcriptional activity constitutes a risk factor for Alzheimer's disease with onset ages inversely correlated with levels of APP expression.
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics Flanders Interuniversity Institute for Biotechnology Antwerpen, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Brouwers
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.forename: Veerle
authors.initials: V
authors.lastname: Bogaerts
authors.forename: Sally
authors.initials: S
authors.lastname: Serneels
authors.forename: Kenan
authors.initials: K
authors.lastname: Kamali
authors.forename: Ellen
authors.initials: E
authors.lastname: Corsmit
authors.forename: Evelyn
authors.initials: E
authors.lastname: De Leenheir
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Martin
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: Jessie
authors.initials: J
authors.lastname: Theuns
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D014158:Transcription, Genetic
chemical_list: D016564:Amyloid beta-Protein Precursor