A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer's disease

Nat Neurosci. 2018 Jun;21(6):811-819. doi: 10.1038/s41593-018-0154-9. Epub 2018 May 25.


There is a need for new therapeutic targets with which to prevent Alzheimer's disease (AD), a major contributor to aging-related cognitive decline. Here we report the construction and validation of a molecular network of the aging human frontal cortex. Using RNA sequence data from 478 individuals, we first build a molecular network using modules of coexpressed genes and then relate these modules to AD and its neuropathologic and cognitive endophenotypes. We confirm these associations in two independent AD datasets. We also illustrate the use of the network in prioritizing amyloid- and cognition-associated genes for in vitro validation in human neurons and astrocytes. These analyses based on unique cohorts enable us to resolve the role of distinct cortical modules that have a direct effect on the accumulation of AD pathology from those that have a direct effect on cognitive decline, exemplifying a network approach to complex diseases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aging / pathology*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Alzheimer Disease / psychology*
  • Amyloid beta-Peptides / genetics
  • Astrocytes / metabolism
  • Cognitive Dysfunction / metabolism
  • Cognitive Dysfunction / pathology*
  • Cognitive Dysfunction / psychology*
  • Databases, Factual
  • Female
  • Gene Expression Regulation
  • Genetic Association Studies
  • Humans
  • Male
  • Metabolic Networks and Pathways*
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / pathology
  • Neurons / metabolism
  • Transcriptome
  • tau Proteins / genetics


  • Amyloid beta-Peptides
  • tau Proteins