Role of common and rare APP DNA sequence variants in Alzheimer disease
Open accessAbstract
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.
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APOE and APP are among the most significant genetic risk factors for AD.
“In addition, we found the APOE and APP subnetwork within the vesicle mediated transport pathway which are among the most significant genetic risk factors for AD (Figure 5F).46,47,48”
From SCING: Inference of robust, interpretable gene regulatory networks from single cell and spatial transcriptomics (2023) · cites this paper as [47]
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- Authors
- Hooli, B. V., Mohapatra, G., Mattheisen, M., Parrado, A. R., Roehr, J. T., Shen, Y., Gusella, J. F., Moir, R., Saunders, A. J., Lange, C., Tanzi, R. E., & Bertram, L.
- Affiliations
- Harvard University (US)
- ORCID
- Venue
- Neurology
- Published
- 2012-04-17
- Volume
- 78
- Issue
- 16
- Pages
- 1250-1257
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC3324321
- OpenAlex
- W2080882681
- Cited by
- 87
- References
- 35
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 10 · 2022: 10 · 2021: 6 · 2020: 5 · 2019: 5 · 2018: 4 · 2017: 4 · 2016: 10 · 2015: 5 · 2014: 4 · 2013: 10 · 2012: 3
- FWCI
- 4.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neurology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Autism Speaks
- Simons Foundation
- Pfizer
- Massachusetts General Hospital
- CHDI Foundation
- Leona M. and Harry B. Helmsley Charitable Trust
- Cure Alzheimer's Fund
- Johns Hopkins University
- Simons Foundation Autism Research Initiative
- Eisai
- National Institutes of Health
- National Institute on Aging (5R01-AG23667, R01AG023667, U24AG021886)
- National Institute of Mental Health (U01MH046373, 5R37MH60009, R01MH060009, U01MH046290, R37MH060009, U01MH046281)
- National Institute of General Medical Sciences
- National Institute of Neurological Disorders and Stroke (R01NS057295)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, amyloid precursor protein gene, APP, copy number variation, missense mutations, single nucleotide polymorphisms, promoter polymorphism, genetic susceptibility, penetrance
- MeSH terms
- Aged, Alzheimer Disease, Female, Humans, Male, Middle Aged, Pedigree, Amyloid beta-Protein Precursor, Genetic Predisposition to Disease, Mutation, Missense, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Loci, DNA Copy Number Variations
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