Abstract
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. 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. 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. 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.
References
Feb 1, 1996·Nature Medicine·D M KovacsW Wasco
Nov 21, 2000·The Journal of Biological Chemistry·H SteinerC Haass
Jun 19, 2001·Neuroscience Letters·J Hardy, R Crook
Apr 2, 2004·Neurobiology of Disease·Jun WangAlison Goate
Jan 25, 2005·Journal of Neurochemistry·Emily S WalkerAlison Goate
May 4, 2005·Molecular and Cellular Neurosciences·Anne L BrunkanAlison M Goate
Feb 28, 2008·Journal of Magnetic Resonance Imaging : JMRI·Clifford R JackMichael W Weiner
Aug 1, 2008·Neurobiology of Aging·Rita Joao GuerreiroJordi Clarimón
Apr 1, 2010·Nature Methods·Ivan A AdzhubeiShamil R Sunyaev
May 11, 2010·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Clifford R JackUNKNOWN Alzheimer's Disease Neuroimaging Initiative
May 15, 2012·Human Mutation·Marc CrutsChristine Van Broeckhoven
Jul 13, 2012·The New England Journal of Medicine·Randall J BatemanUNKNOWN Dominantly Inherited Alzheimer Network
Feb 6, 2013·Journal of Alzheimer's Disease : JAD·Rachael I ScahillNick C Fox
Jun 12, 2013·Molecular Psychiatry·B V HooliR E Tanzi
Nov 14, 2013·PloS One·Yi SuTammie L S Benzinger
Mar 7, 2014·Science Translational Medicine·Anne M FaganUNKNOWN Dominantly Inherited Alzheimer Network
Jul 6, 2014·Neuron·Celeste M KarchAlison M Goate
May 6, 2015·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Carlo Sala FrigerioBart De Strooper
Mar 25, 2016·PloS One·Yi SuUNKNOWN Dominantly Inherited Alzheimer Network
Citations
Feb 13, 2019·International Journal of Molecular Sciences·Maria CondelloStefania Meschini
Jul 27, 2018·Alzheimer's Research & Therapy·Celeste M KarchAlison M Goate
Feb 14, 2020·Antioxidants & Redox Signaling·Yunhua PengJiangang Long
Oct 17, 2019·JAMA Network Open·Gregory S DayJohn C Morris
Sep 29, 2019·International Journal of Molecular Sciences·Vo Van GiauSangYun Kim
Feb 23, 2020·Neurobiology of Disease·Simon HsuCeleste M Karch
Mar 3, 2021·Neurobiology of Aging·Antoinette O'ConnorNick C Fox
Sep 4, 2020·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Longfei JiaJianping Jia
Jul 6, 2021·Frontiers in Aging Neuroscience·Xuewen XiaoBin Jiao
Aug 13, 2021·Science Translational Medicine·María Pagnon de la VegaMartin Ingelsson