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.


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


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