Open AccessA three‐range approach enhances the prognostic utility of CSF biomarkers in Alzheimer's disease
Author(s) -
Brum Wagner S.,
Bastiani Marco Antônio,
Bieger Andrei,
Therriault Joseph,
FerrariSouza João P.,
Benedet Andréa L.,
SahaChaudhuri Paramita,
Souza Diogo O.,
Ashton Nicholas J.,
Zetterberg Henrik,
Pascoal Tharick A.,
Karikari Thomas,
Blennow Kaj,
RosaNeto Pedro,
Zimmer Eduardo R.
Publication year - 2022
Publication title -
alzheimer's and dementia: translational research and clinical interventions
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.49
H-Index - 30
ISSN - 2352-8737
DOI - 10.1002/trc2.12270
Subject(s) - biomarker , neuroimaging , dementia , oncology , positron emission tomography , cognitive decline , disease , medicine , cerebrospinal fluid , cognition , imaging biomarker , clinical trial , psychology , receiver operating characteristic , neuroscience , magnetic resonance imaging , radiology , biology , biochemistry
Alzheimer's disease consensus recommends biomarker dichotomization, a practice with well‐described clinical strengths and methodological limitations. Although neuroimaging studies have explored alternative biomarker interpretation strategies, a formally defined three‐range approach and its prognostic impact remains under‐explored for cerebrospinal fluid (CSF) biomarkers . Methods With two‐graph receiver‐operating characteristics based on different reference schemes, we derived three‐range cut‐points for CSF Elecsys biomarkers. According to baseline CSF status, we assessed the prognostic utility of this in predicting risk of clinical progression and longitudinal trajectories of cognitive decline and amyloid–beta (Aβ) positron emission tomography (PET) accumulation in non‐demented individuals (Alzheimer's Disease Neuroimaging Initiative [ADNI]; n = 1246). In all analyses, we compared herein‐derived three‐range CSF cut‐points to previously described binary ones. Results In our main longitudinal analyses, we highlight CSF p‐tau 181 /Aβ 1‐42 three‐range cut‐points derived based on the cognitively normal Aβ‐PET negative versus dementia Aβ‐PET positive reference scheme for best depicting a prognostically relevant biomarker abnormality range. Longitudinally, our approach revealed a divergent intermediate cognitive trajectory undetected by dichotomization and a clearly abnormal group at higher risk for cognitive decline, with power analyses suggesting the latter group as potential trial enrichment candidates. Furthermore, we demonstrate that individuals with intermediate‐range CSF status have similar rates of Aβ deposition to those in the clearly abnormal group. Discussion The proposed approach can refine clinico‐biological prognostic assessment and potentially enhance trial recruitment, as it captures faster biomarker‐related cognitive decline in comparison to binary cut‐points. Although this approach has implications for trial recruitment and observational studies, further discussion is needed regarding clinical practice applications.