@article{7a3101a11e354137b73e7332c55b4cf5,
title = "Discovery and validation of autosomal dominant Alzheimer's disease mutations",
abstract = "Background: Alzheimer's disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. Mutations in amyloid-β precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the pathogenic cause of autosomal dominant AD (ADAD). However, polymorphisms also exist within these genes. Methods: In order to distinguish polymorphisms from pathogenic mutations, the DIAN Expanded Registry has implemented an algorithm for determining ADAD pathogenicity using available information from multiple domains, including genetic, bioinformatic, clinical, imaging, and biofluid measures and in vitro analyses. Results: We propose that PSEN1 M84V, PSEN1 A396T, PSEN2 R284G, and APP T719N are likely pathogenic mutations, whereas PSEN1 c.379-382delXXXXinsG and PSEN2 L238F have uncertain pathogenicity. Conclusions: In defining a subset of these variants as pathogenic, individuals from these families can now be enrolled in observational and clinical trials. This study outlines a critical approach for translating genetic data into meaningful clinical outcomes.",
keywords = "APP, Autosomal dominant Alzheimer's disease, Cell-based assays, PSEN1, PSEN2, Pathogenicity algorithm",
author = "Simon Hsu and Gordon, {Brian A.} and Russ Hornbeck and Norton, {Joanne B.} and Denise Levitch and Adia Louden and Ellen Ziegemeier and Robert Laforce and Jasmeer Chhatwal and Day, {Gregory S.} and Eric McDade and Morris, {John C.} and Fagan, {Anne M.} and Benzinger, {Tammie L.S.} and Goate, {Alison M.} and Carlos Cruchaga and Bateman, {Randall J.} and Karch, {Celeste M.}",
note = "Funding Information: Funding provided by the DIAN Expanded Registry (to RJB), National Institutes of Health grant K01 AG046374 (to CMK) and DIAN-TU Pharma Consortium (https://dian.wustl.edu/our-research/the-pharma-consortium/; to RJB, CC, AMG, CMK), Fidelity Biosciences Research Initiative (RJB, CC, and CMK), and the Gerald and Henrietta Rauenhorst Foundation (RJB, CC, and CMK). Data collection and sharing for this project were supported by The Dominantly Inherited Alzheimer{\textquoteright}s Network (DIAN; grant UF1AG032438) funded by the National Institute on Aging (NIA), the German Center for Neurodegenerative Diseases (DZNE), and the Institute for Neurological Research Dr. Raul Carrea (FLENI). Partial support was received through research and development grants for dementia from the Japan Agency for Medical Research and Development (AMED) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI). The funding bodies played no role in the design of the study; in the collection, analysis, and interpretation of data; or in the writing of the manuscript. Funding Information: We gratefully acknowledge the altruism of the participants and their families and contributions of the DIAN research and support staff at each of the participating sites for their contributions to this study. The DIAN Expanded Registry welcomes contact from any families or treating clinicians interested in research about autosomal dominant familial Alzheimer{\textquoteright}s disease. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders and the departments of neurology and psychiatry at Washington University School of Medicine. This article was reviewed by DIAN Study investigators for scientific content and consistency of data interpretation with previous DIAN study publications. We acknowledge the altruism of the participants and their families and the contributions of the DIAN research and support staff at each of the participating sites for their contributions to this study. We thank the DIAN Steering Committee: Ricardo Allegri, Tammie Benzinger, Sarah Berman, Virginia Buckles, Nigel Cairns, Helena Chui, Maritza Ciliberto, Anne Fagan, Howard Feldman, Bernardino Ghetti, Neill Graff-Radford, David Holtzman, Rachel Huber, Mathias Jucker, Jae-Hong Lee, Johannes Levin, Daniel Marcus, Ralph Martins, Colin Masters, Hiroshi Mori, James Noble, Nick Fox, Stephen Salloway, Peter Schofield, Michael Weiner, and Chengjie Xiong. Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = jul,
day = "18",
doi = "10.1186/s13195-018-0392-9",
language = "English",
volume = "10",
journal = "Alzheimer's Research and Therapy",
issn = "1758-9193",
publisher = "BioMed Central Ltd.",
number = "1",
}