Network-driven plasma proteomics expose molecular changes in the Alzheimer's brain.
Biological pathways that significantly contribute to sporadic Alzheimer's disease are largely unknown and cannot be observed directly. Cognitive symptoms appear only decades after the molecular disease onset, further complicating analyses. As a consequence, molecular research is often restricted to late-stage post-mortem studies of brain tissue. However, the disease process is expected to trigger numerous cellular signaling pathways and modulate the local and systemic environment, and resulting changes in secreted signaling molecules carry information about otherwise inaccessible pathological processes.



To access this information we probed relative levels of close to 600 secreted signaling proteins from patients' blood samples using antibody microarrays and mapped disease-specific molecular networks. Using these networks as seeds we then employed independent genome and transcriptome data sets to corroborate potential pathogenic pathways.



We identified Growth-Differentiation Factor (GDF) signaling as a novel Alzheimer's disease-relevant pathway supported by in vivo and in vitro follow-up experiments, demonstrating the existence of a highly informative link between cellular pathology and changes in circulatory signaling proteins.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. pjaeger@ucsd.edu.|Institute of Chemistry and Biochemistry, Free University Berlin, Berlin, Germany. pjaeger@ucsd.edu.|Departments of Bioengineering and Medicine, University of California San Diego, La Jolla, CA, USA. pjaeger@ucsd.edu.
Philipp A
PA
Jaeger
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.|Present address: Biology Department, Eastern Connecticut State University, Willimantic, CT, USA.
Kurt M
KM
Lucin
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.|Present address: Roche Pharma Research and Early Development, NORD DTA, Roche Innovation, Center Basel, Basel, Switzerland.
Markus
M
Britschgi
Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine, Boston, MA, USA.
Badri
B
Vardarajan
RayBiotech, Guangzhou, China.|RayBiotech, Norcrosse, GA, USA.
Ruo-Pan
RP
Huang
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Elizabeth D
ED
Kirby
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Rachelle
R
Abbey
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Bradley F
BF
Boeve
Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
Adam L
AL
Boxer
Department of Medicine (Biomedical Genetics), Boston University Schools of Medicine, Boston, MA, USA.|Departments of Neurology, Ophthalmology, Genetics and Genomics, Epidemiology, and Biostatistics, Boston University Schools of Medicine and Public Health, Boston, MA, USA.
Lindsay A
LA
Farrer
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
NiCole
N
Finch
Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
Neill R
NR
Graff-Radford
Departments of Pharmacology and Nutritional Sciences and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
Elizabeth
E
Head
Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA.
Matan
M
Hofree
RayBiotech, Guangzhou, China.|RayBiotech, Norcrosse, GA, USA.
Ruochun
R
Huang
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Hudson
H
Johns
Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
Anna
A
Karydas
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
David S
DS
Knopman
Genetics and Pharmacogenomics, Merck Research Laboratories, West Point, PA, USA.
Andrey
A
Loboda
Department of Pathology, University of California San Diego, La Jolla, CA, USA.
Eliezer
E
Masliah
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Ramya
R
Narasimhan
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Ronald C
RC
Petersen
Genetics and Pharmacogenomics, Merck Research Laboratories, West Point, PA, USA.
Alexei
A
Podtelezhnikov
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Suraj
S
Pradhan
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Rosa
R
Rademakers
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Chung-Huan
CH
Sun
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Steven G
SG
Younkin
Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
Bruce L
BL
Miller
Departments of Bioengineering and Medicine, University of California San Diego, La Jolla, CA, USA.
Trey
T
Ideker
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. twc@stanford.edu.|Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System, Palo Alto, CA, USA. twc@stanford.edu.
Tony
T
Wyss-Coray
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D006801:Humans; D009415:Nerve Net / Q000378:metabolism*; D040901:Proteomics; D015398:Signal Transduction / Q000502:physiology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor