title: A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer's Disease.
abstract: Here, we report proteomic analyses of 129 human cortical tissues to define changes associated with the asymptomatic and symptomatic stages of Alzheimer's disease (AD). Network analysis revealed 16 modules of co-expressed proteins, 10 of which correlated with AD phenotypes. A subset of modules overlapped with RNA co-expression networks, including those associated with neurons and astroglial cell types, showing altered expression in AD, even in the asymptomatic stages. Overlap of RNA and protein networks was otherwise modest, with many modules specific to the proteome, including those linked to microtubule function and inflammation. Proteomic modules were validated in an independent cohort, demonstrating some module expression changes unique to AD and several observed in other neurodegenerative diseases. AD genetic risk loci were concentrated in glial-related modules in the proteome and transcriptome, consistent with their causal role in AD. This multi-network analysis reveals protein- and disease-specific pathways involved in the etiology, initiation, and progression of AD.
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: nseyfri@emory.edu.
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Seyfried
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Dammer
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Swarup
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Nandakumar
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Duc M
authors.initials: DM
authors.lastname: Duong
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Luming
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Qiudong
authors.initials: Q
authors.lastname: Deng
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Tram
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Chadwick M
authors.initials: CM
authors.lastname: Hales
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA; Division of Neurology, Atlanta VA Medical Center, Decatur, GA 30033, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wingo
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Glass
authors.affiliation: Department of Experimental Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Marla
authors.initials: M
authors.lastname: Gearing
authors.affiliation: Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Madhav
authors.initials: M
authors.lastname: Thambisetty
authors.affiliation: Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Lah
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: alevey@emory.edu.
authors.forename: Allan I
authors.initials: AI
authors.lastname: Levey
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology; D001344:Autopsy; D001921:Brain / Q000378:metabolism; D003071:Cognition / Q000502:physiology*; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D020543:Proteome / Q000235:genetics; D040901:Proteomics / Q000379:methods*; D012307:Risk Factors; D059467:Transcriptome / Q000235:genetics
chemical_list: D020543:Proteome