TY - JOUR
T1 - Hypothesis
T2 - cerebrospinal fluid protein markers suggest a pathway toward symptomatic resilience to AD pathology
AU - Meyer, Pierre François
AU - Savard, Melissa
AU - Poirier, Judes
AU - Morgan, David
AU - Breitner, John
N1 - Funding Information:
Data collection and sharing for this project by the Alzheimer's Disease Neuroimaging Initiative (ADNI) were supported by NIH grant U01-AG024904 and the U.S. Department of Defense award number W81XWH-12-2-0012 . ADNI is funded by the National Institute on Aging , the National Institute of Biomedical Imaging and Bioengineering , and through generous contributions from AbbVie , the Alzheimer's Association ; Alzheimer's Drug Discovery Foundation ; Araclon Biotech ; BioClinica, Inc. ; Biogen ; Bristol-Myers Squibb Company ; CereSpir, Inc. ; Cogstate Ltd. ; Eisai , Inc.; Elan Pharmaceuticals, Inc. ; Eli Lilly and Company ; EUROIMMUN ; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc. ; Fujirebio ; GE Healthcare ; IXICO Ltd. ; Janssen Alzheimer Immunotherapy Research & Development, LLC .; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity ; Lundbeck ; Merck & Co., Inc. ; Meso Scale Diagnostics , LLC.; NeuroRx Research ; Neurotrack Technologies ; Novartis Pharmaceuticals Corporation ; Pfizer Inc. ; Piramal Imaging ; Servier ; Takeda Pharmaceutical Company ; and Transition Therapeutics, Inc. 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. The study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of Southern California.
Funding Information:
The authors thank Dr. Sylvia Villeneuve, Dr. Etienne Vachon-Presseau, Dr. Yasser Iturria-Medina, and Manon Boiteux, MSc, for assistance regarding the analytical approach, its implementation, and representation of results. P.-F.M. is supported by the Lazlo & Etelka Kollar fellowship fund for this project.
Funding Information:
The authors thank Dr. Sylvia Villeneuve, Dr. Etienne Vachon-Presseau, Dr. Yasser Iturria-Medina, and Manon Boiteux, MSc, for assistance regarding the analytical approach, its implementation, and representation of results. P.-F.M. is supported by the Lazlo & Etelka Kollar fellowship fund for this project. Data collection and sharing for this project by the Alzheimer's Disease Neuroimaging Initiative (ADNI) were supported by NIH grant U01-AG024904 and the U.S. Department of Defense award number W81XWH-12-2-0012. ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from AbbVie, the Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate Ltd.; Eisai, Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EUROIMMUN; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co. Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics, Inc. 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. The study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of Southern California. Authors' contributions: P.-F.M and J.B contributed to the design of the study. P.-F.M and M.S. contributed to the analysis of the data. P.-F.M. J.P. D.M. and J.B. contributed to data interpretation and critical revision of the manuscript for intellectual content. J.B. supervised the study.
Publisher Copyright:
© 2019 The Authors
PY - 2019/9
Y1 - 2019/9
N2 - Introduction: We sought biological pathways that explained discordance between Alzheimer's disease (AD) pathology and symptoms. Methods: In 306 Alzheimer's Disease Neuroimaging Initiative (ADNI)-1 participants across the AD clinical spectrum, we investigated association between cognitive outcomes and 23 cerebrospinal fluid (CSF) analytes associated with abnormalities in the AD biomarkers amyloid β1-42 and total-tau. In a 200-person “training” set, Least Absolute Shrinkage and Selection Operator regression estimated model weights for the 23 proteins, and for the AD biomarkers themselves, as predictors of ADAS-Cog11 scores. In the remaining 106 participants (“validation” set), fully adjusted regression models then tested the Least Absolute Shrinkage and Selection Operator–derived models and a related protein marker summary score as predictors of ADAS-Cog11, ADNI diagnostic category, and longitudinal cognitive trajectory. Results: AD biomarkers alone explained 26% of the variance in validation set cognitive scores. Surprisingly, the 23 AD-related proteins explained 31% of this variance. The biomarkers and protein markers appeared independent in this respect, jointly explaining 42% of test score variance. The composite protein marker score also predicted ADNI diagnosis and subsequent cognitive trajectory. Cognitive outcome prediction redounded principally to ten markers related to lipid or vascular functions or to microglial activation or chemotaxis. In each analysis, apoE protein and four markers in the latter immune-activation group portended better outcomes. Discussion: CSF markers of vascular, lipid-metabolic and immune-related functions may explain much of the disjunction between AD biomarker abnormality and symptom severity. In particular, our results suggest the hypothesis that innate immune activation improves cognitive outcomes in persons with AD pathology. This hypothesis should be tested by further study of cognitive outcomes related to CSF markers of innate immune activation.
AB - Introduction: We sought biological pathways that explained discordance between Alzheimer's disease (AD) pathology and symptoms. Methods: In 306 Alzheimer's Disease Neuroimaging Initiative (ADNI)-1 participants across the AD clinical spectrum, we investigated association between cognitive outcomes and 23 cerebrospinal fluid (CSF) analytes associated with abnormalities in the AD biomarkers amyloid β1-42 and total-tau. In a 200-person “training” set, Least Absolute Shrinkage and Selection Operator regression estimated model weights for the 23 proteins, and for the AD biomarkers themselves, as predictors of ADAS-Cog11 scores. In the remaining 106 participants (“validation” set), fully adjusted regression models then tested the Least Absolute Shrinkage and Selection Operator–derived models and a related protein marker summary score as predictors of ADAS-Cog11, ADNI diagnostic category, and longitudinal cognitive trajectory. Results: AD biomarkers alone explained 26% of the variance in validation set cognitive scores. Surprisingly, the 23 AD-related proteins explained 31% of this variance. The biomarkers and protein markers appeared independent in this respect, jointly explaining 42% of test score variance. The composite protein marker score also predicted ADNI diagnosis and subsequent cognitive trajectory. Cognitive outcome prediction redounded principally to ten markers related to lipid or vascular functions or to microglial activation or chemotaxis. In each analysis, apoE protein and four markers in the latter immune-activation group portended better outcomes. Discussion: CSF markers of vascular, lipid-metabolic and immune-related functions may explain much of the disjunction between AD biomarker abnormality and symptom severity. In particular, our results suggest the hypothesis that innate immune activation improves cognitive outcomes in persons with AD pathology. This hypothesis should be tested by further study of cognitive outcomes related to CSF markers of innate immune activation.
KW - Alzheimer's disease
KW - Biomarkers
KW - Immunity
KW - Prevention
KW - Resilience
UR - http://www.scopus.com/inward/record.url?scp=85070237459&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070237459&partnerID=8YFLogxK
U2 - 10.1016/j.jalz.2019.05.007
DO - 10.1016/j.jalz.2019.05.007
M3 - Article
C2 - 31405825
AN - SCOPUS:85070237459
SN - 1552-5260
VL - 15
SP - 1160
EP - 1171
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 9
ER -