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Neurology. 2019 Apr 2;92(14):e1567-e1579. doi: 10.1212/WNL.0000000000007248. Epub 2019 Mar 6.

ATN profiles among cognitively normal individuals and longitudinal cognitive outcomes.

Author information

1
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. asoldan1@jhmi.edu.
2
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.

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.

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