TY - JOUR
T1 - Staging biomarkers in preclinical autosomal dominant Alzheimer's disease by estimated years to symptom onset
AU - Dominantly Inherited Alzheimer Network (DIAN)
AU - Wang, Guoqiao
AU - Coble, Dean
AU - McDade, Eric M.
AU - Hassenstab, Jason
AU - Fagan, Anne M.
AU - Benzinger, Tammie L.S.
AU - Bateman, Randall J.
AU - Morris, John C.
AU - Xiong, Chengjie
N1 - Funding Information:
G.W., D.C., T.L.S.B., J.C.M., and C.X. reported no disclosures. E.M.M. is a member of the scientific advisory board of Elli Lilly; UpToDate. J.H is a consultant of Biogen and Lundbeck. A.M.F. is a member of the advisory board of Roche Diagnostics, IBL international, and Genentech and is a consultant of DiamiR and AbbVie. R.J.B. receives lab research funding from the National Institutes of Health, Alzheimer’s Association, BrightFocus Foundation, Rainwater Foundation Tau Consortium, Association for Frontotemporal Degeneration, the Cure Alzheimer’s Fund, the Tau SILK Consortium (AbbVie, Biogen, and Eli Lilly and Co.), and an anonymous foundation. Funding for clinical trials include the National Institutes of Health, Alzheimer's Association, Eli Lilly and Co, Hoffman La-Roche, Janssen, Avid Radiopharmaceuticals, GHR Foundation, and an anonymous foundation. R.J.B. also receives research funding from the DIAN Pharma Consortium (Abbvie, Amgen, AstraZeneca, Biogen, Eisai, Eli Lilly and Co, Hoffman La-Roche, Janssen, Pfizer, and Sanofi). R.J.B. has received honoraria from Janssen, Pfizer, and Roche as a speaker, Eisai as a consultant, and from Merck and Pfizer as an Advisory Board member. Washington University, R.J.B., and DMH have equity ownership interest in C2N Diagnostics and receive royalty income based on technology (stable isotope labeling kinetics and blood plasma assay) licensed by Washington University to C2N Diagnostics. R.J.B. receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with R.J.B. as co-inventor, has submitted the US nonprovisional patent application “Methods for Measuring the Metabolism of CNS Derived Biomolecules In Vivo” and provisional patent application “Plasma Based Methods for Detecting CNS Amyloid Deposition.”
Funding Information:
This study was supported by National Institute on Aging (NIA) grant R01 AG053550 (Dr. Xiong) and NIA grant U19 AG032438 (Dr. Bateman).
Publisher Copyright:
© 2018 the Alzheimer's Association
PY - 2019/4
Y1 - 2019/4
N2 - Introduction: Staging preclinical Alzheimer disease (AD) by the expected years to symptom onset (EYO) in autosomal dominant AD (ADAD) through biomarker correlations is important. Methods: We estimated the correlation matrix between EYO/cognition and imaging/CSF biomarkers, and searched for the EYO cutoff where a change in the correlations occurred before and after the cutoff among the asymptomatic mutation carriers of ADAD. We then estimated the longitudinal rate of change for biomarkers/cognition within each preclinical stage defined by the EYO. Results: Based on the change in the correlations, the preclinical ADAD was divided by EYOs −7 and −13 years. Mutation carriers demonstrated a temporal ordering of biomarker/cognition changes across the three preclinical stages. Discussion: Duration of each preclinical stage can be estimated in ADAD, facilitating better planning of prevention trials with the EYO cutoffs under the recently released FDA guidance. The generalization of these results to sporadic AD warrants further investigation.
AB - Introduction: Staging preclinical Alzheimer disease (AD) by the expected years to symptom onset (EYO) in autosomal dominant AD (ADAD) through biomarker correlations is important. Methods: We estimated the correlation matrix between EYO/cognition and imaging/CSF biomarkers, and searched for the EYO cutoff where a change in the correlations occurred before and after the cutoff among the asymptomatic mutation carriers of ADAD. We then estimated the longitudinal rate of change for biomarkers/cognition within each preclinical stage defined by the EYO. Results: Based on the change in the correlations, the preclinical ADAD was divided by EYOs −7 and −13 years. Mutation carriers demonstrated a temporal ordering of biomarker/cognition changes across the three preclinical stages. Discussion: Duration of each preclinical stage can be estimated in ADAD, facilitating better planning of prevention trials with the EYO cutoffs under the recently released FDA guidance. The generalization of these results to sporadic AD warrants further investigation.
KW - Autosomal dominant Alzheimer disease
KW - Biomarkers
KW - Dominantly inherited Alzheimer Network
KW - Preclinical Alzheimer disease
UR - http://www.scopus.com/inward/record.url?scp=85061622382&partnerID=8YFLogxK
U2 - 10.1016/j.jalz.2018.12.008
DO - 10.1016/j.jalz.2018.12.008
M3 - Article
C2 - 30773445
AN - SCOPUS:85061622382
SN - 1552-5260
VL - 15
SP - 506
EP - 514
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 4
ER -