TY - JOUR
T1 - Phosphorylated tau-Aβ42 ratio as a continuous trait for biomarker discovery for early-stage Alzheimer's disease in multiplex immunoassay panels of cerebrospinal fluid
AU - Harari, Oscar
AU - Cruchaga, Carlos
AU - Kauwe, John S.K.
AU - Ainscough, Benjamin J.
AU - Bales, Kelly
AU - Pickering, Eve H.
AU - Bertelsen, Sarah
AU - Fagan, Anne M.
AU - Holtzman, David M.
AU - Morris, John C.
AU - Goate, Alison M.
N1 - Funding Information:
Data collection and sharing for this project were funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (NIH Grant No. U01 AG024904) and Department of Defense ADNI (Department of Defense Award No. W81XWH-12-2-0012). The ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and generous contributions from the following: Alzheimer’s Association, Alzheimer’s Drug Discovery Foundation, BioClinica, Inc., Biogen Idec, Inc., Bristol-Myers Squibb Company, Eisai, Inc., Elan Pharmaceuticals, Inc., Eli Lilly and Company, F. Hoffmann-La Roche Ltd. and its affiliated company Genentech, Inc., GE Healthcare, Innogenetics N.V., IXICO Ltd., Janssen Alzheimer Immunotherapy Research & Development, LLC, Johnson & Johnson Pharmaceutical Research & Development, LLC, Medpace, Inc., Merck & Co., Inc., Meso Scale Diagnostics, LLC, NeuroRx Research, Novartis Pharmaceuticals Corporation, Pfizer, Inc., Piramal Imaging, Servier, Synarc, Inc., and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH Grant No. P30 AG010129 and K01 AG030514.
Funding Information:
This work was supported by Pfizer, grants from the National Institutes of Health (NIH) (Grant Nos. P30 NS069329-01 , R01 AG035083 , R01 AG16208 , P50 AG05681 , P01 AG03991 , P01 AG026276 , UL1 TR000448 ), and the Barnes-Jewish Hospital Foundation. We acknowledge the support of the BrightFocus Foundation Alzheimer’s Disease Research Grant No. A2013359S. We thank the Clinical and Genetics Cores of the Knight Alzheimer’s Disease Research Center at Washington University for clinical and cognitive assessments of the participants and for apolipoprotein E genotypes. We also thank the Biomarker Core of the Adult Children Study at Washington University for the cerebrospinal fluid collection and assays.
Funding Information:
KB and EHP are employed by Pfizer, Inc. AMF served as an advisory board member for F. Hoffmann-La Roche Ltd. and Eli Lilly and Company. DMH is a consultant for Bristol-Myers Squibb, AstraZeneca, and Genentech, Inc.; is on the scientific advisory board of C2N Diagnostics; and receives research grant support from the NIH, Ellison Medical Foundation, Cure Alzheimer’s Fund, AstraZeneca, C2N Diagnostics, and Integrated Diagnostics, Inc. JCM has participated or is currently participating in clinical trials of antidementia drugs sponsored by Janssen Alzheimer Immunotherapy Research & Development, LLC, Pfizer, Inc, and Eli Lilly and Company; has served as a consultant for Eisai, Inc., Esteve, Janssen Alzheimer Immunotherapy Research & Development, LLC, GlaxoSmithKline, Novartis, Eli Lily and Company, and Pfizer, Inc; receives research support from Eli Lilly & Company/Avid Radiopharmaceuticals; and is funded by the NIH National Institute on Aging. AMG is a consultant for Finnegan and Amgen; has received research grant support from Genentech, Inc., Pfizer, Inc., and AstraZeneca; and has received royalties from Taconic. OH, CC, JSKK, BJA, and SB report no biomedical financial interests or potential conflicts of interest. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PY - 2014/5/1
Y1 - 2014/5/1
N2 - Background Identification of the physiologic changes that occur during the early stages of Alzheimer's disease (AD) may provide critical insights for the diagnosis, prognosis, and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome. Methods A novel approach was applied to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay, and common associations were detected in the Knight Alzheimer's Disease Research Center (N = 311) and the Alzheimer's Disease Neuroimaging Initiative (N = 293) cohorts. Rather than case-control status, the ratio of CSF levels of tau phosphorylated at threonine 181 (ptau181) and Aβ42 was used as a continuous trait in these analyses. Results The ptau181-Aβ42 ratio has more statistical power than traditional modeling approaches, and the levels of CSF heart-type fatty acid binding protein (FABP) and 12 other correlated analytes increase as AD progresses. These results were validated using the traditional case-control status model. Stratification of the dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in nondemented individuals with AD pathology (low ptau181, low Aβ42) compared with elderly control subjects with no pathology (low ptau181, high Aβ42). The FABP-Aβ42 ratio demonstrates a similar hazard ratio for disease conversion to ptau181-Aβ42 even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor of AD. Conclusions Our results indicate that the approach presented here can be used to identify novel biomarkers for AD correctly and that CSF heart FABP levels start to increase at very early stages of AD.
AB - Background Identification of the physiologic changes that occur during the early stages of Alzheimer's disease (AD) may provide critical insights for the diagnosis, prognosis, and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome. Methods A novel approach was applied to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay, and common associations were detected in the Knight Alzheimer's Disease Research Center (N = 311) and the Alzheimer's Disease Neuroimaging Initiative (N = 293) cohorts. Rather than case-control status, the ratio of CSF levels of tau phosphorylated at threonine 181 (ptau181) and Aβ42 was used as a continuous trait in these analyses. Results The ptau181-Aβ42 ratio has more statistical power than traditional modeling approaches, and the levels of CSF heart-type fatty acid binding protein (FABP) and 12 other correlated analytes increase as AD progresses. These results were validated using the traditional case-control status model. Stratification of the dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in nondemented individuals with AD pathology (low ptau181, low Aβ42) compared with elderly control subjects with no pathology (low ptau181, high Aβ42). The FABP-Aβ42 ratio demonstrates a similar hazard ratio for disease conversion to ptau181-Aβ42 even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor of AD. Conclusions Our results indicate that the approach presented here can be used to identify novel biomarkers for AD correctly and that CSF heart FABP levels start to increase at very early stages of AD.
KW - Alzheimer's disease
KW - biomarkers
KW - brain proteome - Rules Based Medicine Discovery Multi-Analyte Profile 1.0
KW - cerebrospinal fluid (CSF)
KW - heart-type fatty acid binding protein
UR - http://www.scopus.com/inward/record.url?scp=84898852630&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2013.11.032
DO - 10.1016/j.biopsych.2013.11.032
M3 - Article
C2 - 24548642
AN - SCOPUS:84898852630
VL - 75
SP - 723
EP - 731
JO - Biological Psychiatry
JF - Biological Psychiatry
SN - 0006-3223
IS - 9
ER -