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June 01, 2021; 96 (22) Editorial

Cognitive Heterogeneity in Alzheimer Clinical Trials

Harnessing Noise to Achieve Meaningfulness

Rachel F. Buckley, David S. Knopman
First published May 31, 2021, DOI: https://doi.org/10.1212/WNL.0000000000012027
Rachel F. Buckley
From the Department of Neurology (R.F.B.), Massachusetts General Hospital and Harvard Medical School; Center for Alzheimer Research and Treatment (R.F.B.), Department of Neurology, Brigham and Women's Hospital, Boston, MA; Melbourne School of Psychological Science (R.F.B.), University of Melbourne, VIC, Australia; and Department of Neurology (D.K.), Mayo Clinic, Rochester, MN.
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David S. Knopman
From the Department of Neurology (R.F.B.), Massachusetts General Hospital and Harvard Medical School; Center for Alzheimer Research and Treatment (R.F.B.), Department of Neurology, Brigham and Women's Hospital, Boston, MA; Melbourne School of Psychological Science (R.F.B.), University of Melbourne, VIC, Australia; and Department of Neurology (D.K.), Mayo Clinic, Rochester, MN.
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Citation
Cognitive Heterogeneity in Alzheimer Clinical Trials
Harnessing Noise to Achieve Meaningfulness
Rachel F. Buckley, David S. Knopman
Neurology Jun 2021, 96 (22) 1017-1018; DOI: 10.1212/WNL.0000000000012027

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Jutten et al.1 in this issue of Neurology® examine the implications of the intrinsic variability in the measurement of cognitive and behavioral functions for designing and interpreting Alzheimer disease (AD) clinical trials. They first identified participant data from the Alzheimer's Disease Neuroimaging Initiative that matched inclusion criteria from 2 trials of aducanumab.2 Using longitudinal cognitive data, they estimated cognitive change from baseline over 18 months using common clinical trial endpoints, the Mini-Mental State Examination, the Clinical Dementia Rating-Sum of Boxes, and the Alzheimer's Disease Assessment Scale Cognitive (ADAS-cog). With these estimates, they performed thousands of simulations to determine the distribution of treatment-placebo group differences, or average treatment effects that could be expected given that no treatment was administered. In other words, within the context of their inclusion criteria, they sought to define a range of change over time that represented noisy measurement. With the exception of the Phase 3 Study of Aducanumab (BIIB037) in Early Alzheimer's Disease (EMERGE) trial, the average treatment effects of all of the other recent AD trials1 fell within the 95% boundaries of random variation.

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  • 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.

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  • © 2021 American Academy of Neurology
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