High Resolution Discovery Proteomics Reveals Candidate Disease Progression Markers of Alzheimer's Disease in Human Cerebrospinal Fluid.
Disease modifying treatments for Alzheimer's disease (AD) constitute a major goal in medicine. Current trends suggest that biomarkers reflective of AD neuropathology and modifiable by treatment would provide supportive evidence for disease modification. Nevertheless, a lack of quantitative tools to assess disease modifying treatment effects remains a major hurdle. Cerebrospinal fluid (CSF) biochemical markers such as total tau, p-tau and Ab42 are well established markers of AD; however, global quantitative biochemical changes in CSF in AD disease progression remain largely uncharacterized. Here we applied a high resolution open discovery platform, dMS, to profile a cross-sectional cohort of lumbar CSF from post-mortem diagnosed AD patients versus those from non-AD/non-demented (control) patients. Multiple markers were identified to be statistically significant in the cohort tested. We selected two markers SME-1 (p<0.0001) and SME-2 (p = 0.0004) for evaluation in a second independent longitudinal cohort of human CSF from post-mortem diagnosed AD patients and age-matched and case-matched control patients. In cohort-2, SME-1, identified as neuronal secretory protein VGF, and SME-2, identified as neuronal pentraxin receptor-1 (NPTXR), in AD were 21% (p = 0.039) and 17% (p = 0.026) lower, at baseline, respectively, than in controls. Linear mixed model analysis in the longitudinal cohort estimate a decrease in the levels of VGF and NPTXR at the rate of 10.9% and 6.9% per year in the AD patients, whereas both markers increased in controls. Because these markers are detected by mass spectrometry without the need for antibody reagents, targeted MS based assays provide a clear translation path for evaluating selected AD disease-progression markers with high analytical precision in the clinic.
Departments of Exploratory and Translational Sciences, Merck & Co., Rahway, NJ, United States of America.
Ronald C
RC
Hendrickson
Departments of Exploratory and Translational Sciences, Merck & Co., Rahway, NJ, United States of America.
Anita Y H
AY
Lee
Biometrics, Merck & Co., Rahway, NJ, United States of America.
Qinghua
Q
Song
Biometrics, Merck & Co., Rahway, NJ, United States of America.
Andy
A
Liaw
Applied Computer Science and Mathematics, Merck & Co., Rahway, NJ, United States of America.
Matt
M
Wiener
Departments of Exploratory and Translational Sciences, Merck & Co., Rahway, NJ, United States of America.
Cloud P
CP
Paweletz
Clinical Neuroscience and Ophthalmology, Merck & Co., West Point, PA, United States of America.
Jeffrey L
JL
Seeburger
Departments of Exploratory and Translational Sciences, Merck & Co., Rahway, NJ, United States of America.
Jenny
J
Li
Departments of Exploratory and Translational Sciences, Merck & Co., Rahway, NJ, United States of America.
Fanyu
F
Meng
Departments of Exploratory and Translational Sciences, Merck & Co., Rahway, NJ, United States of America.
Ekaterina G
EG
Deyanova
Departments of Exploratory and Translational Sciences, Merck & Co., Rahway, NJ, United States of America.
Matthew T
MT
Mazur
Departments of Exploratory and Translational Sciences, Merck & Co., Rahway, NJ, United States of America.
Robert E
RE
Settlage
Departments of Exploratory and Translational Sciences, Merck & Co., Rahway, NJ, United States of America.
Xuemei
X
Zhao
Departments of Exploratory and Translational Sciences, Merck & Co., Rahway, NJ, United States of America.
Katie
K
Southwick
Departments of Exploratory and Translational Sciences, Merck & Co., Rahway, NJ, United States of America.
Yi
Y
Du
Biometrics, Merck & Co., West Point, PA, United States of America.
Dan
D
Holder
Applied Computer Science and Mathematics, Merck & Co., Rahway, NJ, United States of America.
Jeffrey R
JR
Sachs
Clinical Development Laboratory, Merck & Co., Rahway, NJ, United States of America.
Omar F
OF
Laterza
Clinical Development Laboratory, Merck & Co., Rahway, NJ, United States of America.
Aimee
A
Dallob
Clinical Development Laboratory, Merck & Co., Rahway, NJ, United States of America.
Derek L
DL
Chappell
Clinical Development Laboratory, Merck & Co., Rahway, NJ, United States of America.
Karen
K
Snyder
Neuroscience Basic Research, Merck & Co., West Point, PA, United States of America.
Vijay
V
Modur
OPTIMA, University of Oxford, Department of Pharmacology, Oxford United Kingdom.
Elizabeth
E
King
OPTIMA, University of Oxford, Department of Pharmacology, Oxford United Kingdom.
Catharine
C
Joachim
Rosetta Biosoftware, Seattle, WA, United States of America.
Andrey Y
AY
Bondarenko
Neuroscience Basic Research, Merck & Co., West Point, PA, United States of America.
Mark
M
Shearman
Biometrics, Merck & Co., West Point, PA, United States of America.
Keith A
KA
Soper
OPTIMA, University of Oxford, Department of Pharmacology, Oxford United Kingdom.
A David
AD
Smith
Clinical Neuroscience and Ophthalmology, Merck & Co., West Point, PA, United States of America.
William Z
WZ
Potter
Neuroscience Basic Research, Merck & Co., West Point, PA, United States of America.
Ken S
KS
Koblan
Departments of Exploratory and Translational Sciences, Merck & Co., Rahway, NJ, United States of America.
Alan B
AB
Sachs
Departments of Exploratory and Translational Sciences, Merck & Co., Rahway, NJ, United States of America.
Nathan A
NA
Yates
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002097:C-Reactive Protein / Q000134:cerebrospinal fluid*; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009414:Nerve Growth Factors / Q000134:cerebrospinal fluid*; D009419:Nerve Tissue Proteins / Q000134:cerebrospinal fluid*; D040901:Proteomics; D000099153:Pentraxins
D015415:Biomarkers; D002097:C-Reactive Protein; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000099153:Pentraxins; C510637:VGF protein, human