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PLoS One. 2016 Jun 1;11(6):e0150079. doi: 10.1371/journal.pone.0150079. eCollection 2016.

Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer's Disease.

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Reta Lila, Weston Research Laboratories, Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom.
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States of America.
Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charite' Universitätmedizin, Berlin, Germany.
German Center for Neurodegenerative Diseases (DZNE), Berlin site, Germany.
Departments of Biology, Neuroscience, Brigham Young University, Provo, UT, United States of America.
King's College London Institute of Psychiatry, London, United Kingdom.
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, United Kingdom.
Washington University, Division of Biology and Biomedical Sciences St. Louis, MO, United States of America.
Icahn School of Medicine at Mount Sinai, Icahn Medical Institute, New York, NY, United States of America.


The cerebral deposition of Aβ42, a neurotoxic proteolytic derivate of amyloid precursor protein (APP), is a central event in Alzheimer's disease (AD)(Amyloid hypothesis). Given the key role of APP-Aβ metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, Aβ degradation and clearance. We then used exome and genome sequencing to investigate the single independent (single-variant association test) and cumulative (gene-based association test) effect of coding variants in these genes as potential susceptibility factors for AD, in a cohort composed of 332 sporadic and mainly late-onset AD cases and 676 elderly controls from North America and the UK. Our study shows that common coding variability in these genes does not play a major role for the disease development. In the single-variant association analysis, the main hits, none of which statistically significant after multiple testing correction (1.9e-4<p-value<0.05), were found to be rare coding variants (0.009%<MAF<1.4%) with moderate to strong effect size (1.84<OR<Inf) that map to genes mainly involved in Aβ extracellular degradation (TTR, ACE), clearance (LRP1) and APP trafficking and recycling (SORL1). These results were partially replicated in the gene-based analysis (c-alpha and SKAT tests), that reports ECE1, LYZ and TTR as nominally associated to AD (1.7e-3 <p-value <0.05). In concert with previous studies, we suggest that 1) common coding variability in APP-Aβ genes is not a critical factor for AD development and 2) Aβ degradation and clearance, rather than Aβ production, may play a key role in the etiology of sporadic AD.

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