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Abstract
Objectives: More than 30 different rare mutations, including copy number variants (CNVs), in the amyloid precursor protein gene (APP) cause early-onset familial Alzheimer disease (EOFAD), whereas the contribution of common APP variants to disease risk remains controversial. In this study we systematically assessed the role of both rare and common APP DNA variants in Alzheimer disease (AD) families.
Methods: Families with EOFAD genetically linked to the APP region were screened for missense mutations and locus duplications of APP. Further, using genome-wide DNA microarray data, we examined the APP locus for CNVs in a total of 797 additional early- and late-onset AD pedigrees. Finally, 423 single nucleotide polymorphisms (SNPs) in the APP locus, including 2 promoter polymorphisms previously associated with AD risk, were tested in up to 4,200 individuals from multiplex AD families.
Results: Analyses of 8 21q21-linked families revealed one family carrying a nonsynonymous mutation in exon 17 (Val717Leu) and another family with a partially penetrant 3.5-Mb locus duplication encompassing APP. CNV analysis in the APP locus revealed an additional family carrying a fully penetrant 380-kb duplication, merely spanning APP. Last, contrary to previous reports, association analyses of more than 400 different SNPs in or near APP failed to show significant effects on AD risk.
Conclusion: Our study shows that APP mutations and locus duplications are a very rare cause of EOFAD and that the contribution of common APP variants to AD susceptibility is insignificant. Furthermore, duplications of APP may not be fully penetrant, possibly indicating the existence of hitherto unknown protective genetic factors.
GLOSSARY
- Aβ=
- amyloid-β;
- AD=
- Alzheimer disease;
- APP=
- amyloid precursor protein;
- CNV=
- copy number variant;
- EOFAD=
- early-onset familial Alzheimer disease;
- FISH=
- fluorescent in situ hybridization;
- GWAS=
- genome-wide association study;
- LOAD=
- late-onset Alzheimer disease;
- NCRAD=
- National Cell Repository for Alzheimer's Disease;
- NIA=
- National Institute on Aging;
- NIMH=
- National Institute of Mental Health;
- SNP=
- single nucleotide polymorphism
Footnotes
Study funding: Funded by the Cure Alzheimer Fund (to L.B. and R.E.T.) as part of the “Alzheimer Genome ProjectTM” and by grants from the NIA (5R01-AG23667 to L.B.) and the NIMH (5R37-MH60009 to R.E.T.).
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Supplemental data at www.neurology.org
- Received October 5, 2011.
- Accepted November 28, 2011.
- Copyright © 2012 by AAN Enterprises, Inc.
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