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A two-step workflow based on plasma p-tau217 to screen for amyloid β positivity with further confirmatory testing only in uncertain cases

Brum, Wagner S. ; Cullen, Nicholas C. LU ; Janelidze, Shorena LU ; Ashton, Nicholas J. ; Zimmer, Eduardo R. ; Therriault, Joseph ; Benedet, Andrea L. ; Rahmouni, Nesrine ; Tissot, Cécile and Stevenson, Jenna , et al. (2023) In Nature Aging 3(9). p.1079-1090
Abstract

Cost-effective strategies for identifying amyloid-β (Aβ) positivity in patients with cognitive impairment are urgently needed with recent approvals of anti-Aβ immunotherapies for Alzheimer’s disease (AD). Blood biomarkers can accurately detect AD pathology, but it is unclear whether their incorporation into a full diagnostic workflow can reduce the number of confirmatory cerebrospinal fluid (CSF) or positron emission tomography (PET) tests needed while accurately classifying patients. We evaluated a two-step workflow for determining Aβ-PET status in patients with mild cognitive impairment (MCI) from two independent memory clinic-based cohorts (n = 348). A blood-based model including plasma tau protein 217 (p-tau217), age and APOE ε4... (More)

Cost-effective strategies for identifying amyloid-β (Aβ) positivity in patients with cognitive impairment are urgently needed with recent approvals of anti-Aβ immunotherapies for Alzheimer’s disease (AD). Blood biomarkers can accurately detect AD pathology, but it is unclear whether their incorporation into a full diagnostic workflow can reduce the number of confirmatory cerebrospinal fluid (CSF) or positron emission tomography (PET) tests needed while accurately classifying patients. We evaluated a two-step workflow for determining Aβ-PET status in patients with mild cognitive impairment (MCI) from two independent memory clinic-based cohorts (n = 348). A blood-based model including plasma tau protein 217 (p-tau217), age and APOE ε4 status was developed in BioFINDER-1 (area under the curve (AUC) = 89.3%) and validated in BioFINDER-2 (AUC = 94.3%). In step 1, the blood-based model was used to stratify the patients into low, intermediate or high risk of Aβ-PET positivity. In step 2, we assumed referral only of intermediate-risk patients to CSF Aβ42/Aβ40 testing, whereas step 1 alone determined Aβ-status for low- and high-risk groups. Depending on whether lenient, moderate or stringent thresholds were used in step 1, the two-step workflow overall accuracy for detecting Aβ-PET status was 88.2%, 90.5% and 92.0%, respectively, while reducing the number of necessary CSF tests by 85.9%, 72.7% and 61.2%, respectively. In secondary analyses, an adapted version of the BioFINDER-1 model led to successful validation of the two-step workflow with a different plasma p-tau217 immunoassay in patients with cognitive impairment from the TRIAD cohort (n = 84). In conclusion, using a plasma p-tau217-based model for risk stratification of patients with MCI can substantially reduce the need for confirmatory testing while accurately classifying patients, offering a cost-effective strategy to detect AD in memory clinic settings.

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Contribution to journal
publication status
published
subject
in
Nature Aging
volume
3
issue
9
pages
12 pages
publisher
Springer
external identifiers
  • pmid:37653254
  • scopus:85169168773
DOI
10.1038/s43587-023-00471-5
language
English
LU publication?
yes
id
9e5ce35b-5b4d-4331-bffc-006240f59f85
date added to LUP
2023-11-10 14:44:50
date last changed
2024-04-22 07:11:13
@article{9e5ce35b-5b4d-4331-bffc-006240f59f85,
  abstract     = {{<p>Cost-effective strategies for identifying amyloid-β (Aβ) positivity in patients with cognitive impairment are urgently needed with recent approvals of anti-Aβ immunotherapies for Alzheimer’s disease (AD). Blood biomarkers can accurately detect AD pathology, but it is unclear whether their incorporation into a full diagnostic workflow can reduce the number of confirmatory cerebrospinal fluid (CSF) or positron emission tomography (PET) tests needed while accurately classifying patients. We evaluated a two-step workflow for determining Aβ-PET status in patients with mild cognitive impairment (MCI) from two independent memory clinic-based cohorts (n = 348). A blood-based model including plasma tau protein 217 (p-tau217), age and APOE ε4 status was developed in BioFINDER-1 (area under the curve (AUC) = 89.3%) and validated in BioFINDER-2 (AUC = 94.3%). In step 1, the blood-based model was used to stratify the patients into low, intermediate or high risk of Aβ-PET positivity. In step 2, we assumed referral only of intermediate-risk patients to CSF Aβ42/Aβ40 testing, whereas step 1 alone determined Aβ-status for low- and high-risk groups. Depending on whether lenient, moderate or stringent thresholds were used in step 1, the two-step workflow overall accuracy for detecting Aβ-PET status was 88.2%, 90.5% and 92.0%, respectively, while reducing the number of necessary CSF tests by 85.9%, 72.7% and 61.2%, respectively. In secondary analyses, an adapted version of the BioFINDER-1 model led to successful validation of the two-step workflow with a different plasma p-tau217 immunoassay in patients with cognitive impairment from the TRIAD cohort (n = 84). In conclusion, using a plasma p-tau217-based model for risk stratification of patients with MCI can substantially reduce the need for confirmatory testing while accurately classifying patients, offering a cost-effective strategy to detect AD in memory clinic settings.</p>}},
  author       = {{Brum, Wagner S. and Cullen, Nicholas C. and Janelidze, Shorena and Ashton, Nicholas J. and Zimmer, Eduardo R. and Therriault, Joseph and Benedet, Andrea L. and Rahmouni, Nesrine and Tissot, Cécile and Stevenson, Jenna and Servaes, Stijn and Triana-Baltzer, Gallen and Kolb, Hartmuth C. and Palmqvist, Sebastian and Stomrud, Erik and Rosa-Neto, Pedro and Blennow, Kaj and Hansson, Oskar}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{1079--1090}},
  publisher    = {{Springer}},
  series       = {{Nature Aging}},
  title        = {{A two-step workflow based on plasma p-tau217 to screen for amyloid β positivity with further confirmatory testing only in uncertain cases}},
  url          = {{http://dx.doi.org/10.1038/s43587-023-00471-5}},
  doi          = {{10.1038/s43587-023-00471-5}},
  volume       = {{3}},
  year         = {{2023}},
}