Genetic epistasis regulates amyloid deposition in resilient aging

Daniel Felsky; Jishu Xu; Lori B Chibnik; Julie A Schneider; Jo Knight; James L Kennedy; Alzheimer's Disease Neuroimaging Initiative; David A Bennett; Philip L De Jager; Aristotle N Voineskos

doi:10.1016/j.jalz.2017.01.027

Genetic epistasis regulates amyloid deposition in resilient aging

Alzheimers Dement. 2017 Oct;13(10):1107-1116. doi: 10.1016/j.jalz.2017.01.027. Epub 2017 Mar 17.

Authors

Daniel Felsky¹, Jishu Xu², Lori B Chibnik², Julie A Schneider³, Jo Knight⁴, James L Kennedy⁵; Alzheimer's Disease Neuroimaging Initiative; David A Bennett³, Philip L De Jager², Aristotle N Voineskos⁶

Affiliations

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.

Keywords: Alzheimer's disease; Amyloid; BDNF; Epistasis; PET imaging; RNA sequencing; SORL1.

MeSH terms

Aged
Aged, 80 and over
Aging*
Alzheimer Disease / diagnostic imaging
Alzheimer Disease / genetics*
Alzheimer Disease / pathology
Amyloid beta-Peptides / metabolism*
Aniline Compounds / pharmacokinetics
Anisotropy
Autopsy
Brain / diagnostic imaging
Brain / drug effects
Brain / metabolism
Brain / pathology
Brain-Derived Neurotrophic Factor / genetics*
Brain-Derived Neurotrophic Factor / metabolism
Cohort Studies
Epistasis, Genetic / genetics*
Ethylene Glycols / pharmacokinetics
Female
Genetic Predisposition to Disease
Genotype
Humans
LDL-Receptor Related Proteins / genetics
LDL-Receptor Related Proteins / metabolism
Magnetic Resonance Imaging
Male
Membrane Transport Proteins / genetics
Membrane Transport Proteins / metabolism
Polymorphism, Single Nucleotide
Positron-Emission Tomography

Substances

Amyloid beta-Peptides
Aniline Compounds
Brain-Derived Neurotrophic Factor
Ethylene Glycols
LDL-Receptor Related Proteins
Membrane Transport Proteins
SORL1 protein, human
florbetapir

Abstract

MeSH terms

Substances

Grants and funding