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April 02, 2019; 92 (14) Article

ATN profiles among cognitively normal individuals and longitudinal cognitive outcomes

Anja Soldan, View ORCID ProfileCorinne Pettigrew, Anne M. Fagan, Suzanne E. Schindler, Abhay Moghekar, Christopher Fowler, Qiao-Xin Li, Steven J. Collins, Cynthia Carlsson, Sanjay Asthana, Colin L. Masters, Sterling Johnson, John C. Morris, Marilyn Albert, Alden L. Gross
First published March 6, 2019, DOI: https://doi.org/10.1212/WNL.0000000000007248
Anja Soldan
From the Department of Neurology (A.S., C.P., A.M., M.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (A.M.F., S.E.S., J.C.M.), Washington University School of Medicine, St. Louis, MO; Florey Institute of Neuroscience and Mental Health (C.F., Q.-X.L., S.J.C., C.L.M.), the University of Melbourne, Australia; Geriatric Research Education and Clinical Center (C.C., S.A., S.J.), Wm. S. Middleton Memorial VA Hospital and Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison; and Center on Aging and Health and Department of Epidemiology (A.L.G.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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Corinne Pettigrew
From the Department of Neurology (A.S., C.P., A.M., M.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (A.M.F., S.E.S., J.C.M.), Washington University School of Medicine, St. Louis, MO; Florey Institute of Neuroscience and Mental Health (C.F., Q.-X.L., S.J.C., C.L.M.), the University of Melbourne, Australia; Geriatric Research Education and Clinical Center (C.C., S.A., S.J.), Wm. S. Middleton Memorial VA Hospital and Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison; and Center on Aging and Health and Department of Epidemiology (A.L.G.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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  • ORCID record for Corinne Pettigrew
Anne M. Fagan
From the Department of Neurology (A.S., C.P., A.M., M.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (A.M.F., S.E.S., J.C.M.), Washington University School of Medicine, St. Louis, MO; Florey Institute of Neuroscience and Mental Health (C.F., Q.-X.L., S.J.C., C.L.M.), the University of Melbourne, Australia; Geriatric Research Education and Clinical Center (C.C., S.A., S.J.), Wm. S. Middleton Memorial VA Hospital and Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison; and Center on Aging and Health and Department of Epidemiology (A.L.G.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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Suzanne E. Schindler
From the Department of Neurology (A.S., C.P., A.M., M.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (A.M.F., S.E.S., J.C.M.), Washington University School of Medicine, St. Louis, MO; Florey Institute of Neuroscience and Mental Health (C.F., Q.-X.L., S.J.C., C.L.M.), the University of Melbourne, Australia; Geriatric Research Education and Clinical Center (C.C., S.A., S.J.), Wm. S. Middleton Memorial VA Hospital and Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison; and Center on Aging and Health and Department of Epidemiology (A.L.G.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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Abhay Moghekar
From the Department of Neurology (A.S., C.P., A.M., M.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (A.M.F., S.E.S., J.C.M.), Washington University School of Medicine, St. Louis, MO; Florey Institute of Neuroscience and Mental Health (C.F., Q.-X.L., S.J.C., C.L.M.), the University of Melbourne, Australia; Geriatric Research Education and Clinical Center (C.C., S.A., S.J.), Wm. S. Middleton Memorial VA Hospital and Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison; and Center on Aging and Health and Department of Epidemiology (A.L.G.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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Christopher Fowler
From the Department of Neurology (A.S., C.P., A.M., M.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (A.M.F., S.E.S., J.C.M.), Washington University School of Medicine, St. Louis, MO; Florey Institute of Neuroscience and Mental Health (C.F., Q.-X.L., S.J.C., C.L.M.), the University of Melbourne, Australia; Geriatric Research Education and Clinical Center (C.C., S.A., S.J.), Wm. S. Middleton Memorial VA Hospital and Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison; and Center on Aging and Health and Department of Epidemiology (A.L.G.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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Qiao-Xin Li
From the Department of Neurology (A.S., C.P., A.M., M.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (A.M.F., S.E.S., J.C.M.), Washington University School of Medicine, St. Louis, MO; Florey Institute of Neuroscience and Mental Health (C.F., Q.-X.L., S.J.C., C.L.M.), the University of Melbourne, Australia; Geriatric Research Education and Clinical Center (C.C., S.A., S.J.), Wm. S. Middleton Memorial VA Hospital and Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison; and Center on Aging and Health and Department of Epidemiology (A.L.G.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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Steven J. Collins
From the Department of Neurology (A.S., C.P., A.M., M.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (A.M.F., S.E.S., J.C.M.), Washington University School of Medicine, St. Louis, MO; Florey Institute of Neuroscience and Mental Health (C.F., Q.-X.L., S.J.C., C.L.M.), the University of Melbourne, Australia; Geriatric Research Education and Clinical Center (C.C., S.A., S.J.), Wm. S. Middleton Memorial VA Hospital and Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison; and Center on Aging and Health and Department of Epidemiology (A.L.G.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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Cynthia Carlsson
From the Department of Neurology (A.S., C.P., A.M., M.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (A.M.F., S.E.S., J.C.M.), Washington University School of Medicine, St. Louis, MO; Florey Institute of Neuroscience and Mental Health (C.F., Q.-X.L., S.J.C., C.L.M.), the University of Melbourne, Australia; Geriatric Research Education and Clinical Center (C.C., S.A., S.J.), Wm. S. Middleton Memorial VA Hospital and Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison; and Center on Aging and Health and Department of Epidemiology (A.L.G.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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Sanjay Asthana
From the Department of Neurology (A.S., C.P., A.M., M.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (A.M.F., S.E.S., J.C.M.), Washington University School of Medicine, St. Louis, MO; Florey Institute of Neuroscience and Mental Health (C.F., Q.-X.L., S.J.C., C.L.M.), the University of Melbourne, Australia; Geriatric Research Education and Clinical Center (C.C., S.A., S.J.), Wm. S. Middleton Memorial VA Hospital and Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison; and Center on Aging and Health and Department of Epidemiology (A.L.G.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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Colin L. Masters
From the Department of Neurology (A.S., C.P., A.M., M.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (A.M.F., S.E.S., J.C.M.), Washington University School of Medicine, St. Louis, MO; Florey Institute of Neuroscience and Mental Health (C.F., Q.-X.L., S.J.C., C.L.M.), the University of Melbourne, Australia; Geriatric Research Education and Clinical Center (C.C., S.A., S.J.), Wm. S. Middleton Memorial VA Hospital and Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison; and Center on Aging and Health and Department of Epidemiology (A.L.G.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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Sterling Johnson
From the Department of Neurology (A.S., C.P., A.M., M.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (A.M.F., S.E.S., J.C.M.), Washington University School of Medicine, St. Louis, MO; Florey Institute of Neuroscience and Mental Health (C.F., Q.-X.L., S.J.C., C.L.M.), the University of Melbourne, Australia; Geriatric Research Education and Clinical Center (C.C., S.A., S.J.), Wm. S. Middleton Memorial VA Hospital and Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison; and Center on Aging and Health and Department of Epidemiology (A.L.G.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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John C. Morris
From the Department of Neurology (A.S., C.P., A.M., M.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (A.M.F., S.E.S., J.C.M.), Washington University School of Medicine, St. Louis, MO; Florey Institute of Neuroscience and Mental Health (C.F., Q.-X.L., S.J.C., C.L.M.), the University of Melbourne, Australia; Geriatric Research Education and Clinical Center (C.C., S.A., S.J.), Wm. S. Middleton Memorial VA Hospital and Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison; and Center on Aging and Health and Department of Epidemiology (A.L.G.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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Marilyn Albert
From the Department of Neurology (A.S., C.P., A.M., M.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (A.M.F., S.E.S., J.C.M.), Washington University School of Medicine, St. Louis, MO; Florey Institute of Neuroscience and Mental Health (C.F., Q.-X.L., S.J.C., C.L.M.), the University of Melbourne, Australia; Geriatric Research Education and Clinical Center (C.C., S.A., S.J.), Wm. S. Middleton Memorial VA Hospital and Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison; and Center on Aging and Health and Department of Epidemiology (A.L.G.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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Alden L. Gross
From the Department of Neurology (A.S., C.P., A.M., M.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (A.M.F., S.E.S., J.C.M.), Washington University School of Medicine, St. Louis, MO; Florey Institute of Neuroscience and Mental Health (C.F., Q.-X.L., S.J.C., C.L.M.), the University of Melbourne, Australia; Geriatric Research Education and Clinical Center (C.C., S.A., S.J.), Wm. S. Middleton Memorial VA Hospital and Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison; and Center on Aging and Health and Department of Epidemiology (A.L.G.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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Citation
ATN profiles among cognitively normal individuals and longitudinal cognitive outcomes
Anja Soldan, Corinne Pettigrew, Anne M. Fagan, Suzanne E. Schindler, Abhay Moghekar, Christopher Fowler, Qiao-Xin Li, Steven J. Collins, Cynthia Carlsson, Sanjay Asthana, Colin L. Masters, Sterling Johnson, John C. Morris, Marilyn Albert, Alden L. Gross
Neurology Apr 2019, 92 (14) e1567-e1579; DOI: 10.1212/WNL.0000000000007248

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Abstract

Objective To examine the long-term cognitive trajectories of individuals with normal cognition at baseline and distinct amyloid/tau/neurodegeneration (ATN) profiles.

Methods Pooling data across 4 cohort studies, 814 cognitively normal participants (mean baseline age = 59.6 years) were classified into 8 ATN groups using baseline CSF levels of β-amyloid 1–42 as a measure of amyloid (A), phosphorylated tau 181 as a measure of tau (T), and total tau as a measure of neurodegeneration (N). Cognitive performance was measured using a previously validated global factor score and with the Mini-Mental State Examination. We compared the cognitive trajectories across groups using growth curve models (mean follow-up time = 7 years).

Results Using different model formulations and cut points for determining biomarker abnormality, only the group with abnormal levels of amyloid, tau, and neurodegeneration (A+T+N+) showed consistently greater cognitive decline than the group with normal levels of all biomarkers (A−T−N−). Replicating prior findings using the 2011 National Institute on Aging–Alzheimer's Association/suspected non–Alzheimer disease pathophysiology schema, only individuals with abnormal levels of both amyloid and phosphorylated tau 181 or total tau (stage 2) showed greater cognitive decline than those with normal biomarker levels (stage 0).

Conclusion The results are consistent with the hypothesis that both elevated brain amyloid and neurofibrillary tangles are necessary to observe accelerated neurodegeneration, which in turn leads to cognitive decline.

Glossary

AA=
Alzheimer's Association;
Aβ1–42=
β-amyloid 1–42;
ACS=
Adult Children Study;
AD=
Alzheimer disease;
AIBL=
Australian Imaging, Biomarker, and Lifestyle;
ATN=
amyloid/tau/neurodegeneration;
BIOCARD=
Biomarkers of Cognitive Decline Among Normal Individuals;
IMPACT=
Investigating Memory in Preclinical AD—Causes and Treatment;
MMSE=
Mini-Mental State Examination;
NIA=
National Institute on Aging;
p-tau=
phosphorylated tau;
SNAP=
suspected non–Alzheimer disease pathophysiology;
t-tau=
total tau;
WRAP=
Wisconsin Registry for Alzheimer's Prevention

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.

  • Editorial, page 643

  • Received April 9, 2018.
  • Accepted in final form November 27, 2018.
  • © 2019 American Academy of Neurology
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