Multiscale causal networks identify VGF as a key regulator of Alzheimer's disease

Nat Commun. 2020 Aug 7;11(1):3942. doi: 10.1038/s41467-020-17405-z.


Though discovered over 100 years ago, the molecular foundation of sporadic Alzheimer's disease (AD) remains elusive. To better characterize the complex nature of AD, we constructed multiscale causal networks on a large human AD multi-omics dataset, integrating clinical features of AD, DNA variation, and gene- and protein-expression. These probabilistic causal models enabled detection, prioritization and replication of high-confidence master regulators of AD-associated networks, including the top predicted regulator, VGF. Overexpression of neuropeptide precursor VGF in 5xFAD mice partially rescued beta-amyloid-mediated memory impairment and neuropathology. Molecular validation of network predictions downstream of VGF was also achieved in this AD model, with significant enrichment for homologous genes identified as differentially expressed in 5xFAD brains overexpressing VGF. Our findings support a causal role for VGF in protecting against AD pathogenesis and progression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / etiology*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / pathology*
  • Datasets as Topic
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling
  • Gene Regulatory Networks
  • Genome-Wide Association Study
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / metabolism*
  • Protein Interaction Mapping
  • Protein Interaction Maps*
  • Proteomics


  • Amyloid beta-Peptides
  • Nerve Growth Factors
  • VGF protein, human
  • Vgf protein, mouse