December 08, 2020; 95 (23) Article
Sequence of Alzheimer disease biomarker changes in cognitively normal adults
A cross-sectional study
Jingqin Luo, Folasade Agboola, Elizabeth Grant, Colin L. Masters, Marilyn S. Albert, Sterling C. Johnson, Eric M. McDade, Jonathan Vöglein, Anne M. Fagan, Tammie Benzinger, Parinaz Massoumzadeh, Jason Hassenstab, View ORCID ProfileRandall J. Bateman, John C. Morris, Richard J. Perrin, Jasmeer Chhatwal, View ORCID ProfileMathias Jucker, Bernardino Ghetti, Carlos Cruchaga, Neill R. Graff-Radford, View ORCID ProfilePeter R. Schofield, Hiroshi Mori, Chengjie Xiong
First published September 1, 2020, DOI: https://doi.org/10.1212/WNL.0000000000010747
Jingqin Luo
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.
PhDFolasade Agboola
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.
MPHElizabeth Grant
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.
PhDColin L. Masters
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.
MDMarilyn S. Albert
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.
PhDSterling C. Johnson
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.
PhDEric M. McDade
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.
DOJonathan Vöglein
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.
MDAnne M. Fagan
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.
PhDTammie Benzinger
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.
MD, PhDParinaz Massoumzadeh
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.
PhDJason Hassenstab
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.
PhDRandall J. Bateman
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.
MDJohn C. Morris
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.
MDRichard J. Perrin
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.
MD, PhDJasmeer Chhatwal
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.
MD, PhDMathias Jucker
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.
PhDBernardino Ghetti
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.
MDCarlos Cruchaga
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.
PhDNeill R. Graff-Radford
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.
MBBCh, FRCPPeter R. Schofield
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.
PhD, DScHiroshi Mori
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.
PhDChengjie Xiong
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.
PhDSequence of Alzheimer disease biomarker changes in cognitively normal adults
A cross-sectional study
Jingqin Luo, Folasade Agboola, Elizabeth Grant, Colin L. Masters, Marilyn S. Albert, Sterling C. Johnson, Eric M. McDade, Jonathan Vöglein, Anne M. Fagan, Tammie Benzinger, Parinaz Massoumzadeh, Jason Hassenstab, Randall J. Bateman, John C. Morris, Richard J. Perrin, Jasmeer Chhatwal, Mathias Jucker, Bernardino Ghetti, Carlos Cruchaga, Neill R. Graff-Radford, Peter R. Schofield, Hiroshi Mori, Chengjie Xiong
Neurology Dec 2020, 95 (23) e3104-e3116; DOI: 10.1212/WNL.0000000000010747
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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.
Glossary
- Aβ=
- β-amyloid;
- ACS=
- Adult Children Study;
- AD=
- Alzheimer disease;
- ADRC=
- Alzheimer's Disease Research Center;
- AIBL=
- Australian Imaging, Biomarkers and Lifestyle;
- CI=
- confidence interval;
- DIAN=
- Dominantly Inherited Alzheimer Network;
- HASD=
- Healthy Aging and Senile Dementia;
- PiB=
- Pittsburgh compound B;
- Ptau=
- phosphorylated tau;
- SE=
- standard error;
- SUVR=
- standardized uptake value ratio;
- Tau=
- total tau;
- WU=
- Washington University
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
- Received February 6, 2020.
- Accepted in final form June 12, 2020.
- © 2020 American Academy of Neurology
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