Daniel Felsky1, Jishu Xu2, Lori B Chibnik2, Julie A Schneider3, Jo Knight4, James L Kennedy5, David A Bennett3, Philip L De Jager2, Aristotle N Voineskos6. 1. Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA. 2. Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA. 3. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA. 4. Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Data Science Institute and the Medical School, Lancaster University, Bailrigg, Lancaster, UK. 5. Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. 6. Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. Electronic address: aristotle.voineskos@camh.ca.
Abstract
INTRODUCTION: The brain-derived neurotrophic factor (BDNF) interacts with important genetic Alzheimer's disease (AD) risk factors. Specifically, variants within the SORL1 gene determine BDNF's ability to reduce amyloid β (Aβ) in vitro. We sought to test whether functional BDNF variation interacts with SORL1 genotypes to influence expression and downstream AD-related processes in humans. METHODS: We analyzed postmortem brain RNA sequencing and neuropathological data for 441 subjects from the Religious Orders Study/Memory and Aging Project and molecular and structural neuroimaging data for 1285 subjects from the Alzheimer's Disease Neuroimaging Initiative. RESULTS: We found one SORL1 RNA transcript strongly regulated by SORL1-BDNF interactions in elderly without pathological AD and showing stronger associations with diffuse than neuritic Aβ plaques. The same SORL1-BDNF interactions also significantly influenced Aβ load as measured with [18F]Florbetapir positron emission tomography. DISCUSSION: Our results bridge the gap between risk and resilience factors for AD, demonstrating interdependent roles of established SORL1 and BDNF functional genotypes.
INTRODUCTION: The brain-derived neurotrophic factor (BDNF) interacts with important genetic Alzheimer's disease (AD) risk factors. Specifically, variants within the SORL1 gene determine BDNF's ability to reduce amyloid β (Aβ) in vitro. We sought to test whether functional BDNF variation interacts with SORL1 genotypes to influence expression and downstream AD-related processes in humans. METHODS: We analyzed postmortem brain RNA sequencing and neuropathological data for 441 subjects from the Religious Orders Study/Memory and Aging Project and molecular and structural neuroimaging data for 1285 subjects from the Alzheimer's Disease Neuroimaging Initiative. RESULTS: We found one SORL1 RNA transcript strongly regulated by SORL1-BDNF interactions in elderly without pathological AD and showing stronger associations with diffuse than neuritic Aβ plaques. The same SORL1-BDNF interactions also significantly influenced Aβ load as measured with [18F]Florbetapir positron emission tomography. DISCUSSION: Our results bridge the gap between risk and resilience factors for AD, demonstrating interdependent roles of established SORL1 and BDNF functional genotypes.
Authors: Susan M Landau; Christopher Breault; Abhinay D Joshi; Michael Pontecorvo; Chester A Mathis; William J Jagust; Mark A Mintun Journal: J Nucl Med Date: 2012-11-19 Impact factor: 10.057
Authors: Clemens R Scherzer; Katrin Offe; Marla Gearing; Howard D Rees; Guofu Fang; Craig J Heilman; Chica Schaller; Hideaki Bujo; Allan I Levey; James J Lah Journal: Arch Neurol Date: 2004-08
Authors: Michael F Egan; Masami Kojima; Joseph H Callicott; Terry E Goldberg; Bhaskar S Kolachana; Alessandro Bertolino; Eugene Zaitsev; Bert Gold; David Goldman; Michael Dean; Bai Lu; Daniel R Weinberger Journal: Cell Date: 2003-01-24 Impact factor: 41.582
Authors: Adaikalavan Ramasamy; Daniah Trabzuni; Sebastian Guelfi; Vibin Varghese; Colin Smith; Robert Walker; Tisham De; Lachlan Coin; Rohan de Silva; Mark R Cookson; Andrew B Singleton; John Hardy; Mina Ryten; Michael E Weale Journal: Nat Neurosci Date: 2014-08-31 Impact factor: 24.884
Authors: David A Bennett; Aron S Buchman; Patricia A Boyle; Lisa L Barnes; Robert S Wilson; Julie A Schneider Journal: J Alzheimers Dis Date: 2018 Impact factor: 4.472
Authors: Jiahui Hou; Jonathan L Hess; Nicola Armstrong; Joshua C Bis; Benjamin Grenier-Boley; Ida K Karlsson; Ganna Leonenko; Katya Numbers; Eleanor K O'Brien; Alexey Shadrin; Anbupalam Thalamuthu; Qiong Yang; Ole A Andreassen; Henry Brodaty; Margaret Gatz; Nicole A Kochan; Jean-Charles Lambert; Simon M Laws; Colin L Masters; Karen A Mather; Nancy L Pedersen; Danielle Posthuma; Perminder S Sachdev; Julie Williams; Chun Chieh Fan; Stephen V Faraone; Christine Fennema-Notestine; Shu-Ju Lin; Valentina Escott-Price; Peter Holmans; Sudha Seshadri; Ming T Tsuang; William S Kremen; Stephen J Glatt Journal: Transl Psychiatry Date: 2022-07-25 Impact factor: 7.989