Jingqin Luo1, Folasade Agboola1, Elizabeth Grant1, Colin L Masters1, Marilyn S Albert1, Sterling C Johnson1, Eric M McDade1, Jonathan Vöglein1, Anne M Fagan1, Tammie Benzinger1, Parinaz Massoumzadeh1, Jason Hassenstab1, Randall J Bateman1, John C Morris1, Richard J Perrin1, Jasmeer Chhatwal1, Mathias Jucker1, Bernardino Ghetti1, Carlos Cruchaga1, Neill R Graff-Radford1, Peter R Schofield1, Hiroshi Mori1, Chengjie Xiong2. 1. From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., F.A., E.G., C.X.), Knight Alzheimer Disease Research Center (F.A., E.G., A.M.F., T.B., P.M., J.H., R.J.B., J.C.M., R.J.P., C.X.), Department of Neurology (E.M.M., A.M.F., J.H., R.J.B., J.C.M., R.J.P.), Department of Radiology (T.B., P.M.), Department of Pathology (J.C.M., R.J.P.), Department of Immunology (J.C.M., R.J.P.), and Department of Psychiatry (C.C.), Washington University School of Medicine, St. Louis, MO; The Florey Institute (C.L.M.), University of Melbourne, Australia; Department of Neurology (M.S.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Wisconsin Alzheimer's Institute and Alzheimer's Disease Research Center (S.C.J.), University of Wisconsin-Madison School of Medicine and Public Health; Geriatric Research Education and Clinical Center (S.C.J.), William S. Middleton Veterans Memorial Hospital, Madison, WI; German Center for Neurodegenerative Diseases (J.V.); Department of Neurology (J.V.), Ludwig-Maximilians-Universität München, Munich, Germany; Department of Neurology (J.C.), Massachusetts General Hospital, Harvard Medical School, Boston; Hertie-Institute for Clinical Brain Research (M.J.), University of Tübingen; German Center for Neurodegenerative Diseases (M.J.), Tübingen, Germany; Department of Pathology and Laboratory Medicine (B.G.), Indiana University, Indianapolis; Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL; Neuroscience Research Australia (P.R.S.), Randwick; School of Medical Sciences (P.R.S.), University of New South Wales, Sydney, Australia; and Department of Clinical Neuroscience (H.M.), Osaka City University Medical School, Abenoku, Osaka, Japan. 2. From the Division of Public Health Sciences (J.L.), Department of Surgery, Siteman Cancer Center Biostatistics Core (J.L.), Division of Biostatistics (J.L., F.A., E.G., C.X.), Knight Alzheimer Disease Research Center (F.A., E.G., A.M.F., T.B., P.M., J.H., R.J.B., J.C.M., R.J.P., C.X.), Department of Neurology (E.M.M., A.M.F., J.H., R.J.B., J.C.M., R.J.P.), Department of Radiology (T.B., P.M.), Department of Pathology (J.C.M., R.J.P.), Department of Immunology (J.C.M., R.J.P.), and Department of Psychiatry (C.C.), Washington University School of Medicine, St. Louis, MO; The Florey Institute (C.L.M.), University of Melbourne, Australia; Department of Neurology (M.S.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Wisconsin Alzheimer's Institute and Alzheimer's Disease Research Center (S.C.J.), University of Wisconsin-Madison School of Medicine and Public Health; Geriatric Research Education and Clinical Center (S.C.J.), William S. Middleton Veterans Memorial Hospital, Madison, WI; German Center for Neurodegenerative Diseases (J.V.); Department of Neurology (J.V.), Ludwig-Maximilians-Universität München, Munich, Germany; Department of Neurology (J.C.), Massachusetts General Hospital, Harvard Medical School, Boston; Hertie-Institute for Clinical Brain Research (M.J.), University of Tübingen; German Center for Neurodegenerative Diseases (M.J.), Tübingen, Germany; Department of Pathology and Laboratory Medicine (B.G.), Indiana University, Indianapolis; Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL; Neuroscience Research Australia (P.R.S.), Randwick; School of Medical Sciences (P.R.S.), University of New South Wales, Sydney, Australia; and Department of Clinical Neuroscience (H.M.), Osaka City University Medical School, Abenoku, Osaka, Japan. chengjie@wustl.edu.
Abstract
OBJECTIVE: To determine the ordering of changes in Alzheimer disease (AD) biomarkers among cognitively normal individuals. METHODS: Cross-sectional data, including CSF analytes, molecular imaging of cerebral fibrillar β-amyloid (Aβ) with PET using the [11C] benzothiazole tracer Pittsburgh compound B (PiB), MRI-based brain structures, and clinical/cognitive outcomes harmonized from 8 studies, collectively involving 3,284 cognitively normal individuals 18 to 101 years of age, were analyzed. The age at which each marker exhibited an accelerated change (called the change point) was estimated and compared across the markers. RESULTS: Accelerated changes in CSF Aβ1-42 (Aβ42) occurred at 48.28 years of age and in Aβ42/Aβ40 ratio at 46.02 years, followed by PiB mean cortical standardized uptake value ratio (SUVR) with a change point at 54.47 years. CSF total tau (Tau) and tau phosphorylated at threonine 181 (Ptau) had a change point at ≈60 years, similar to those for MRI hippocampal volume and cortical thickness. The change point for a cognitive composite occurred at 62.41 years. The change points for CSF Aβ42 and Aβ42/Aβ40 ratio, albeit not significantly different from that for PiB SUVR, occurred significantly earlier than that for CSF Tau, Ptau, MRI markers, and the cognitive composite. Adjusted analyses confirmed that accelerated changes in CSF Tau, Ptau, MRI markers, and the cognitive composite occurred at ages not significantly different from each other. CONCLUSIONS: Our findings support the hypothesized early changes of amyloid in preclinical AD and suggest that changes in neuronal injury and neurodegeneration markers occur close in time to cognitive decline.
OBJECTIVE: To determine the ordering of changes in Alzheimer disease (AD) biomarkers among cognitively normal individuals. METHODS: Cross-sectional data, including CSF analytes, molecular imaging of cerebral fibrillar β-amyloid (Aβ) with PET using the [11C] benzothiazole tracer Pittsburgh compound B (PiB), MRI-based brain structures, and clinical/cognitive outcomes harmonized from 8 studies, collectively involving 3,284 cognitively normal individuals 18 to 101 years of age, were analyzed. The age at which each marker exhibited an accelerated change (called the change point) was estimated and compared across the markers. RESULTS: Accelerated changes in CSF Aβ1-42 (Aβ42) occurred at 48.28 years of age and in Aβ42/Aβ40 ratio at 46.02 years, followed by PiB mean cortical standardized uptake value ratio (SUVR) with a change point at 54.47 years. CSF total tau (Tau) and tau phosphorylated at threonine 181 (Ptau) had a change point at ≈60 years, similar to those for MRI hippocampal volume and cortical thickness. The change point for a cognitive composite occurred at 62.41 years. The change points for CSF Aβ42 and Aβ42/Aβ40 ratio, albeit not significantly different from that for PiB SUVR, occurred significantly earlier than that for CSF Tau, Ptau, MRI markers, and the cognitive composite. Adjusted analyses confirmed that accelerated changes in CSF Tau, Ptau, MRI markers, and the cognitive composite occurred at ages not significantly different from each other. CONCLUSIONS: Our findings support the hypothesized early changes of amyloid in preclinical AD and suggest that changes in neuronal injury and neurodegeneration markers occur close in time to cognitive decline.
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