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Plasma Biomarker Strategy for Selecting Patients with Alzheimer Disease for Antiamyloid Immunotherapies

Mattsson-Carlgren, Niklas LU orcid ; Collij, Lyduine E. LU ; Stomrud, Erik LU orcid ; Pichet Binette, Alexa LU ; Ossenkoppele, Rik LU ; Smith, Ruben LU ; Karlsson, Linda LU orcid ; Lantero-Rodriguez, Juan ; Snellman, Anniina and Strandberg, Olof LU , et al. (2024) In JAMA Neurology 81(1). p.69-78
Abstract

Importance: Antiamyloid immunotherapies against Alzheimer disease (AD) are emerging. Scalable, cost-effective tools will be needed to identify amyloid β (Aβ)-positive patients without an advanced stage of tau pathology who are most likely to benefit from these therapies. Blood-based biomarkers might reduce the need to use cerebrospinal fluid (CSF) or positron emission tomography (PET) for this. Objective: To evaluate plasma biomarkers for identifying Aβ positivity and stage of tau accumulation. Design, Setting, and Participants: The cohort study (BioFINDER-2) was a prospective memory-clinic and population-based study. Participants with cognitive concerns were recruited from 2017 to 2022 and divided into a training set (80% of the data)... (More)

Importance: Antiamyloid immunotherapies against Alzheimer disease (AD) are emerging. Scalable, cost-effective tools will be needed to identify amyloid β (Aβ)-positive patients without an advanced stage of tau pathology who are most likely to benefit from these therapies. Blood-based biomarkers might reduce the need to use cerebrospinal fluid (CSF) or positron emission tomography (PET) for this. Objective: To evaluate plasma biomarkers for identifying Aβ positivity and stage of tau accumulation. Design, Setting, and Participants: The cohort study (BioFINDER-2) was a prospective memory-clinic and population-based study. Participants with cognitive concerns were recruited from 2017 to 2022 and divided into a training set (80% of the data) and test set (20%). Exposure: Baseline values for plasma phosphorylated tau 181 (p-tau181), p-tau217, p-tau231, N-terminal tau, glial fibrillary acidic protein, and neurofilament light chain. Main Outcomes and Measures: Performance to classify participants by Aβ status (defined by Aβ-PET or CSF Aβ42/40) and tau status (tau PET). Number of hypothetically saved PET scans in a plasma biomarker-guided workflow. Results: Of a total 912 participants, there were 499 males (54.7%) and 413 females (45.3%), and the mean (SD) age was 71.1 (8.49) years. Among the biomarkers, plasma p-tau217 was most strongly associated with Aβ positivity (test-set area under the receiver operating characteristic curve [AUC] = 0.94; 95% CI, 0.90-0.97). A 2-cut-point procedure was evaluated, where only participants with ambiguous plasma p-tau217 values (17.1% of the participants in the test set) underwent CSF or PET to assign definitive Aβ status. This procedure had an overall sensitivity of 0.94 (95% CI, 0.90-0.98) and a specificity of 0.86 (95% CI, 0.77-0.95). Next, plasma biomarkers were used to differentiate low-intermediate vs high tau-PET load among Aβ-positive participants. Plasma p-tau217 again performed best, with the test AUC = 0.92 (95% CI, 0.86-0.97), without significant improvement when adding any of the other plasma biomarkers. At a false-negative rate less than 10%, the use of plasma p-tau217 could avoid 56.9% of tau-PET scans needed to identify high tau PET among Aβ-positive participants. The results were validated in an independent cohort (n = 118). Conclusions and Relevance: This study found that algorithms using plasma p-tau217 can accurately identify most Aβ-positive individuals, including those likely to have a high tau load who would require confirmatory tau-PET imaging. Plasma p-tau217 measurements may substantially reduce the number of invasive and costly confirmatory tests required to identify individuals who would likely benefit from antiamyloid therapies.

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type
Contribution to journal
publication status
published
subject
in
JAMA Neurology
volume
81
issue
1
pages
10 pages
publisher
American Medical Association
external identifiers
  • pmid:38048096
  • scopus:85180733150
ISSN
2168-6149
DOI
10.1001/jamaneurol.2023.4596
language
English
LU publication?
yes
id
e59c012b-3ddd-4bf6-9be3-589faa532233
date added to LUP
2024-02-08 16:09:23
date last changed
2024-04-24 23:46:57
@article{e59c012b-3ddd-4bf6-9be3-589faa532233,
  abstract     = {{<p>Importance: Antiamyloid immunotherapies against Alzheimer disease (AD) are emerging. Scalable, cost-effective tools will be needed to identify amyloid β (Aβ)-positive patients without an advanced stage of tau pathology who are most likely to benefit from these therapies. Blood-based biomarkers might reduce the need to use cerebrospinal fluid (CSF) or positron emission tomography (PET) for this. Objective: To evaluate plasma biomarkers for identifying Aβ positivity and stage of tau accumulation. Design, Setting, and Participants: The cohort study (BioFINDER-2) was a prospective memory-clinic and population-based study. Participants with cognitive concerns were recruited from 2017 to 2022 and divided into a training set (80% of the data) and test set (20%). Exposure: Baseline values for plasma phosphorylated tau 181 (p-tau181), p-tau217, p-tau231, N-terminal tau, glial fibrillary acidic protein, and neurofilament light chain. Main Outcomes and Measures: Performance to classify participants by Aβ status (defined by Aβ-PET or CSF Aβ42/40) and tau status (tau PET). Number of hypothetically saved PET scans in a plasma biomarker-guided workflow. Results: Of a total 912 participants, there were 499 males (54.7%) and 413 females (45.3%), and the mean (SD) age was 71.1 (8.49) years. Among the biomarkers, plasma p-tau217 was most strongly associated with Aβ positivity (test-set area under the receiver operating characteristic curve [AUC] = 0.94; 95% CI, 0.90-0.97). A 2-cut-point procedure was evaluated, where only participants with ambiguous plasma p-tau217 values (17.1% of the participants in the test set) underwent CSF or PET to assign definitive Aβ status. This procedure had an overall sensitivity of 0.94 (95% CI, 0.90-0.98) and a specificity of 0.86 (95% CI, 0.77-0.95). Next, plasma biomarkers were used to differentiate low-intermediate vs high tau-PET load among Aβ-positive participants. Plasma p-tau217 again performed best, with the test AUC = 0.92 (95% CI, 0.86-0.97), without significant improvement when adding any of the other plasma biomarkers. At a false-negative rate less than 10%, the use of plasma p-tau217 could avoid 56.9% of tau-PET scans needed to identify high tau PET among Aβ-positive participants. The results were validated in an independent cohort (n = 118). Conclusions and Relevance: This study found that algorithms using plasma p-tau217 can accurately identify most Aβ-positive individuals, including those likely to have a high tau load who would require confirmatory tau-PET imaging. Plasma p-tau217 measurements may substantially reduce the number of invasive and costly confirmatory tests required to identify individuals who would likely benefit from antiamyloid therapies.</p>}},
  author       = {{Mattsson-Carlgren, Niklas and Collij, Lyduine E. and Stomrud, Erik and Pichet Binette, Alexa and Ossenkoppele, Rik and Smith, Ruben and Karlsson, Linda and Lantero-Rodriguez, Juan and Snellman, Anniina and Strandberg, Olof and Palmqvist, Sebastian and Ashton, Nicholas J. and Blennow, Kaj and Janelidze, Shorena and Hansson, Oskar}},
  issn         = {{2168-6149}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{69--78}},
  publisher    = {{American Medical Association}},
  series       = {{JAMA Neurology}},
  title        = {{Plasma Biomarker Strategy for Selecting Patients with Alzheimer Disease for Antiamyloid Immunotherapies}},
  url          = {{http://dx.doi.org/10.1001/jamaneurol.2023.4596}},
  doi          = {{10.1001/jamaneurol.2023.4596}},
  volume       = {{81}},
  year         = {{2024}},
}