Perspective: Clinical relevance of the dichotomous classification of Alzheimer's disease biomarkers: Should there be a “gray zone”?

Abstract

The 2018 National Institute on Aging and the Alzheimer's Association (NIA-AA) research framework recently redefined Alzheimer's disease (AD) as a biological construct, based on in vivo biomarkers reflecting key neuropathologic features. Combinations of normal/abnormal levels of three biomarker categories, based on single thresholds, form the AD signature profile that defines the biological disease state as a continuum, independent of clinical symptomatology. While single thresholds may be useful in defining the biological signature profile, we provide evidence that their use in studies with cognitive outcomes merits further consideration. Using data from the Alzheimer's Disease Neuroimaging Initiative with a focus on cortical amyloid binding, we discuss the limitations of Conflict of interest: Prof. Roy M. Anderson is a nonexecutive board member of GlaxoSmithKline (GSK). GSK played no part in this research, its funding, or the preparation of the manuscript. Prof. Lefkos T. Middleton has consultancy agreements with Eli Lilly, Astra Zeneca, Novartis, and Takeda; is a National (UK) Coordinator for the TOMMORROW, Amaranth and Generation I&II Clinical Trials, and the Janssen Chariot PRO studies; has received research funding for his Imperial team from Janssen, Takeda, AstraZeneca, Novartis, and UCB Pharmaceuticals; and does not hold any agreement with any of the funders in relation to patents, products in development relevant to this study, or marketed products. Prof. Frank de Wolf was employed by the Janssen Prevention Center until February 2019. The Janssen Prevention Center played no part in this research, its funding, or the preparation of the manuscript.Ethical approval (humans): As per ADNI protocols, all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. More details can be found at adni.loni.usc.edu. (This article does not contain any studies with human participants performed by any of the authors).Ethical approval (animals): This article does not contain any studies performed on animals by any of the authors.The study was approved by the institutional review boards of all the participating institutions, and informed written consent was obtained from all participants at each site. One such institution is the Office for the Protection of Research Subjects at the University of Southern California. More details can be found at adni.loni.usc.edu.Consent for publication has been granted by ADNI administrators. Availability of data and material: Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). The primary goal of ADNI has been to test whether serial MRI, PET, other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment and early Alzhe...

Grey zone amyloid burden affects memory function: the SCIENCe project

“…Our demonstration of the potential significance of grey zone amyloid burden may have several clinical consequences. Especially for individuals with amyloid burden within the grey zone, a single threshold might not be very good at distinguishing individuals with a high and a low risk of cognitive decline [4,40]. When a binary division is warranted, our results imply that only lower thresholds that include the grey zone capture all individuals at risk of memory decline, which corresponds to a previous study that showed existing thresholds for Pittsburgh compound B (PIB) seem too high [24].…”

“…Studies that focused on peri-or subthreshold amyloid levels have had different approaches, for example studying amyloid negative subthreshold individuals [25,26,38], or CSF/PET discordant cases [39]. In a recent article, the grey zone is proposed as a region of uncertainty around the threshold for which more data is needed to actually estimate the risk of cognitive decline or clinical progression [40]. These Cohen's kappa was used to determine the degree of concordance between visual assessment and the six different thresholds BP ND binding potential, GMM Gaussian mixture modelling, SUVr standardized uptake value ratio previous studies found that individuals in the subthreshold range can be on the path to further neurodegeneration (i.e.…”

Associations Between Microstructure, Amyloid, and Cognition in Amnestic Mild Cognitive Impairment and Dementia

“…We note that three MCI and one AD participant did not meet criteria for amyloid-positivity. However, dichotomized AD risk has recently been questioned [46], as biomarker sensitivity may improve when assessed as a continuum, with even subthreshold amyloid levels predicting subsequent AD pathology [47]. Though we cannot rule out the presence of non-AD etiology, or subthreshold AD pathology, in our amyloidnegative group, this would not preclude our finding that microstructure predicts cognitive impairment regardless of amyloid.…”

Changes in NfL Plasma Levels and Association with Cognitive and Imaging Markers of Alzheimer’s Disease

“…We have analysed a subset of the ADNI population which is at a higher risk of developing AD in the future, on the basis of the amyloid levels at baseline. For this we have used strict dichotomous cut-offs and acknowledge that this itself comes with limitations of not being able to clearly distinguish between individuals near the cut-off level set in the analyses 29 . This assumption simpli es the complex realities of the dynamical behaviour of the biomarkers.…”