Eric McDade1, Guoqiao Wang2, Brian A Gordon2, Jason Hassenstab2, Tammie L S Benzinger2, Virginia Buckles2, Anne M Fagan2, David M Holtzman2, Nigel J Cairns2, Alison M Goate2, Daniel S Marcus2, John C Morris2, Katrina Paumier2, Chengjie Xiong2, Ricardo Allegri2, Sarah B Berman2, William Klunk2, James Noble2, John Ringman2, Bernardino Ghetti2, Martin Farlow2, Reisa A Sperling2, Jasmeer Chhatwal2, Stephen Salloway2, Neill R Graff-Radford2, Peter R Schofield2, Colin Masters2, Martin N Rossor2, Nick C Fox2, Johannes Levin2, Mathias Jucker2, Randall J Bateman1. 1. From the Department of Neurology (E.M., J.H., V.B., A.M.F., D.M.H., J.C.M., K.P., R.J.B.), Division of Biostatistics (G.W., C.X.), Department of Radiology (B.A.G., T.L.S.B., D.S.M.), and Department of Pathology (N.J.C.), Washington University School of Medicine, Saint Louis, MO; Department of Neuroscience (A.M.J.), Icahn School of Medicine at Mount Sinai, New York, NY; Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI) (R.A.), Instituto de Investigaciones Neurológicas Raúl Correa, Buenos Aires, Argentina; University of Pittsburgh School of Medicine (S.B.B., W.K.), PA; College of Physicians and Surgeons (J.N.), Columbia University, New York, NY; Department of Neurology (J.R.), Keck School of Medicine of University of Southern California, Los Angeles; Department of Neurology (B.G., M.F.), Indiana University, Indianapolis; Massachusetts General Hospital (R.A.S., J.C.), Harvard Medical School, Boston; Butler Hospital and Brown University (S.S.), Providence, RI; Department of Neurology (N.R.G.-R.), Mayo Clinic Jacksonville, FL; Neuroscience Research Australia (P.R.S.); School of Medical Sciences (P.R.S.), University of New South Wales, Sydney; The Florey Institute and the University of Melbourne (C.M.), Parkville, Australia; Dementia Research Centre, Institute of Neurology (M.N.R., N.C.F.), University College London, UK; German Center for Neurodegenerative Diseases (DZNE) Munich (J.L.); Department of Neurology (J.L.), Ludwig-Maximilians Universität München; German Center for Neurodegenerative Diseases (DZNE) Tübingen (M.J.); and Hertie-Institute for Clinical Brain Research (M.J.), University of Tübingen, Germany. ericmcdade@wustl.edu batemanr@wustl.edu. 2. From the Department of Neurology (E.M., J.H., V.B., A.M.F., D.M.H., J.C.M., K.P., R.J.B.), Division of Biostatistics (G.W., C.X.), Department of Radiology (B.A.G., T.L.S.B., D.S.M.), and Department of Pathology (N.J.C.), Washington University School of Medicine, Saint Louis, MO; Department of Neuroscience (A.M.J.), Icahn School of Medicine at Mount Sinai, New York, NY; Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia (FLENI) (R.A.), Instituto de Investigaciones Neurológicas Raúl Correa, Buenos Aires, Argentina; University of Pittsburgh School of Medicine (S.B.B., W.K.), PA; College of Physicians and Surgeons (J.N.), Columbia University, New York, NY; Department of Neurology (J.R.), Keck School of Medicine of University of Southern California, Los Angeles; Department of Neurology (B.G., M.F.), Indiana University, Indianapolis; Massachusetts General Hospital (R.A.S., J.C.), Harvard Medical School, Boston; Butler Hospital and Brown University (S.S.), Providence, RI; Department of Neurology (N.R.G.-R.), Mayo Clinic Jacksonville, FL; Neuroscience Research Australia (P.R.S.); School of Medical Sciences (P.R.S.), University of New South Wales, Sydney; The Florey Institute and the University of Melbourne (C.M.), Parkville, Australia; Dementia Research Centre, Institute of Neurology (M.N.R., N.C.F.), University College London, UK; German Center for Neurodegenerative Diseases (DZNE) Munich (J.L.); Department of Neurology (J.L.), Ludwig-Maximilians Universität München; German Center for Neurodegenerative Diseases (DZNE) Tübingen (M.J.); and Hertie-Institute for Clinical Brain Research (M.J.), University of Tübingen, Germany.
Abstract
OBJECTIVE: To assess the onset, sequence, and rate of progression of comprehensive biomarker and clinical measures across the spectrum of Alzheimer disease (AD) using the Dominantly Inherited Alzheimer Network (DIAN) study and compare these to cross-sectional estimates. METHODS: We conducted longitudinal clinical, cognitive, CSF, and neuroimaging assessments (mean of 2.7 [±1.1] visits) in 217 DIAN participants. Linear mixed effects models were used to assess changes in each measure relative to individuals' estimated years to symptom onset and to compare mutation carriers and noncarriers. RESULTS: Longitudinal β-amyloid measures changed first (starting 25 years before estimated symptom onset), followed by declines in measures of cortical metabolism (approximately 7-10 years later), then cognition and hippocampal atrophy (approximately 20 years later). There were significant differences in the estimates of CSF p-tau181 and tau, with elevations from cross-sectional estimates preceding longitudinal estimates by over 10 years; further, longitudinal estimates identified a significant decline in CSF p-tau181 near symptom onset as opposed to continued elevations. CONCLUSION: These longitudinal estimates clarify the sequence and temporal dynamics of presymptomatic pathologic changes in autosomal dominant AD, information critical to a better understanding of the disease. The pattern of biomarker changes identified here also suggests that once β-amyloidosis begins, additional pathologies may begin to develop less than 10 years later, but more than 15 years before symptom onset, an important consideration for interventions meant to alter the disease course.
OBJECTIVE: To assess the onset, sequence, and rate of progression of comprehensive biomarker and clinical measures across the spectrum of Alzheimer disease (AD) using the Dominantly Inherited Alzheimer Network (DIAN) study and compare these to cross-sectional estimates. METHODS: We conducted longitudinal clinical, cognitive, CSF, and neuroimaging assessments (mean of 2.7 [±1.1] visits) in 217 DIAN participants. Linear mixed effects models were used to assess changes in each measure relative to individuals' estimated years to symptom onset and to compare mutation carriers and noncarriers. RESULTS: Longitudinal β-amyloid measures changed first (starting 25 years before estimated symptom onset), followed by declines in measures of cortical metabolism (approximately 7-10 years later), then cognition and hippocampal atrophy (approximately 20 years later). There were significant differences in the estimates of CSF p-tau181 and tau, with elevations from cross-sectional estimates preceding longitudinal estimates by over 10 years; further, longitudinal estimates identified a significant decline in CSF p-tau181 near symptom onset as opposed to continued elevations. CONCLUSION: These longitudinal estimates clarify the sequence and temporal dynamics of presymptomatic pathologic changes in autosomal dominant AD, information critical to a better understanding of the disease. The pattern of biomarker changes identified here also suggests that once β-amyloidosis begins, additional pathologies may begin to develop less than 10 years later, but more than 15 years before symptom onset, an important consideration for interventions meant to alter the disease course.
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