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Nat Neurosci DOI:10.1038/s41593-018-0154-9

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

Publication TypeJournal Article
Year of Publication2018
AuthorsMostafavi, S, Gaiteri, C, Sullivan, SE, White, CC, Tasaki, S, Xu, J, Taga, M, Klein, H-U, Patrick, E, Komashko, V, McCabe, C, Smith, R, Bradshaw, EM, Root, DE, Regev, A, Yu, L, Chibnik, LB, Schneider, JA, Young-Pearse, TL, Bennett, DA, De Jager, PL
JournalNat Neurosci
Volume21
Issue6
Pages811-819
Date Published2018 06
ISSN1546-1726
KeywordsAged, Aged, 80 and over, Aging, Alzheimer Disease, Amyloid beta-Peptides, Astrocytes, Cognitive Dysfunction, Databases, Factual, Female, Gene Expression Regulation, Genetic Association Studies, Humans, Male, Metabolic Networks and Pathways, Neural Stem Cells, Neurons, tau Proteins, Transcriptome
Abstract

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.

DOI10.1038/s41593-018-0154-9
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/29802388?dopt=Abstract

Alternate JournalNat Neurosci
PubMed ID29802388
PubMed Central IDPMC6599633
Grant ListU01 AG046152 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
R01 AG057911 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
RC2 AG036547 / AG / NIA NIH HHS / United States
R01 AG036836 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States