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Plasma pTau 217/β-amyloid 1–42 ratio for enhanced accuracy and reduced uncertainty in detecting amyloid pathology

Benina, Natalya ; Buitrago, Luna ; De Simone, Francesca I. ; Radwan, Rachel R. ; Miller, M. Craig ; Martin, Katie ; Dickson, Diana ; Ho, Sara ; Moghekar, Abhay and Albert, Marilyn , et al. (2026) In Brain 149(4). p.1168-1181
Abstract

Blood biomarkers have the potential to revolutionize Alzheimer's disease diagnosis, offering advantages over CSF and PET due to their accessibility, scalability and cost-effectiveness. This study evaluated the effectiveness of individual plasma biomarkers, such as phosphorylated Tau (pTau) 217, as well as biomarker combinations, with a focus on the pTau 217/β-Amyloid (Aβ) 1–42 ratio to predict amyloid positivity. To improve clinical utility, a dual threshold approach was applied to maximize predictive values and positive likelihood ratios while minimizing the proportion of indeterminate results. Plasma samples from 208 participants (including seven with subjective cognitive decline, 150 with mild cognitive impairment, 12 with... (More)

Blood biomarkers have the potential to revolutionize Alzheimer's disease diagnosis, offering advantages over CSF and PET due to their accessibility, scalability and cost-effectiveness. This study evaluated the effectiveness of individual plasma biomarkers, such as phosphorylated Tau (pTau) 217, as well as biomarker combinations, with a focus on the pTau 217/β-Amyloid (Aβ) 1–42 ratio to predict amyloid positivity. To improve clinical utility, a dual threshold approach was applied to maximize predictive values and positive likelihood ratios while minimizing the proportion of indeterminate results. Plasma samples from 208 participants (including seven with subjective cognitive decline, 150 with mild cognitive impairment, 12 with Alzheimer's disease dementia and 39 with other cognitive conditions) from three cohorts (BioFINDER2, BIOCARD and MissionAD) were analysed to measure Aβ1–42, Aβ1–40 and pTau217 levels using the Fujirebio LUMIPULSE® G1200 platform. Amyloid status was determined by FDA-cleared PET imaging and/or CSF biomarker ratios. Logistic regression modelling evaluated biomarkers either individually or in combination to identify those that best distinguished amyloid positivity. Clinically applicable thresholds were established through likelihood ratio analysis and further evaluated based on predictive values. When assessing the ability of individual plasma biomarkers to differentiate between amyloid-positive and amyloid-negative participants, plasma pTau217 (P < 0.001) and plasma Aβ1–42 (P = 0.0056) demonstrated significant discriminative power, whereas Aβ1–40 (P = 0.30) did not. Notably, the integration of these biomarkers into the plasma pTau217/Aβ1–42 ratio demonstrated enhanced classification performance (P < 0.001). Using a two-threshold approach based on positive and negative likelihood ratios (PLR/NLR) targets of 14/20, respectively, the plasma pTau217/Aβ1–42 ratio achieved a positive predictive value (PPV) of 94.44% and negative predictive value (NPV) of 94.28%, in the parametric model, comparable to plasma pTau217 alone (PPV: 94.44%, NPV: 94.28%), but yielded fewer indeterminate results (26.5% versus 38.6%). Using a non-parametric model, the plasma ratio achieved a PPV and NPV of 94.62% and 91.78%, respectively, while plasma pTau217 alone achieved 92.41% and 92.86%; the ratio once again reduced the proportion of indeterminate results (20.2% versus 35.1%). The plasma pTau217/Aβ1–42 ratio demonstrated superior performance in identifying amyloid pathology and reduced the frequency of indeterminate results compared to plasma pTau217 alone. These findings support the evaluation of the clinical utility of the plasma pTau217/Aβ1–42 ratio as a tool for identifying amyloid pathology in patients presenting with cognitive complaints.

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type
Contribution to journal
publication status
published
subject
keywords
Alzheimer’s disease, amyloid pathology, blood-based biomarkers, Fujirebio Lumipulse, phosphorylated Tau 217 plasma assay, phosphorylated Tau 217/β-Amyloid 1–42 plasma ratio
in
Brain
volume
149
issue
4
pages
14 pages
publisher
Oxford University Press
external identifiers
  • scopus:105035250234
  • pmid:41562409
ISSN
0006-8950
DOI
10.1093/brain/awag001
language
English
LU publication?
yes
id
3ea8b855-7070-4ce1-b86b-47180e03a28a
date added to LUP
2026-04-30 12:46:50
date last changed
2026-05-01 03:16:50
@article{3ea8b855-7070-4ce1-b86b-47180e03a28a,
  abstract     = {{<p>Blood biomarkers have the potential to revolutionize Alzheimer's disease diagnosis, offering advantages over CSF and PET due to their accessibility, scalability and cost-effectiveness. This study evaluated the effectiveness of individual plasma biomarkers, such as phosphorylated Tau (pTau) 217, as well as biomarker combinations, with a focus on the pTau 217/β-Amyloid (Aβ) 1–42 ratio to predict amyloid positivity. To improve clinical utility, a dual threshold approach was applied to maximize predictive values and positive likelihood ratios while minimizing the proportion of indeterminate results. Plasma samples from 208 participants (including seven with subjective cognitive decline, 150 with mild cognitive impairment, 12 with Alzheimer's disease dementia and 39 with other cognitive conditions) from three cohorts (BioFINDER2, BIOCARD and MissionAD) were analysed to measure Aβ1–42, Aβ1–40 and pTau217 levels using the Fujirebio LUMIPULSE® G1200 platform. Amyloid status was determined by FDA-cleared PET imaging and/or CSF biomarker ratios. Logistic regression modelling evaluated biomarkers either individually or in combination to identify those that best distinguished amyloid positivity. Clinically applicable thresholds were established through likelihood ratio analysis and further evaluated based on predictive values. When assessing the ability of individual plasma biomarkers to differentiate between amyloid-positive and amyloid-negative participants, plasma pTau217 (P &lt; 0.001) and plasma Aβ1–42 (P = 0.0056) demonstrated significant discriminative power, whereas Aβ1–40 (P = 0.30) did not. Notably, the integration of these biomarkers into the plasma pTau217/Aβ1–42 ratio demonstrated enhanced classification performance (P &lt; 0.001). Using a two-threshold approach based on positive and negative likelihood ratios (PLR/NLR) targets of 14/20, respectively, the plasma pTau217/Aβ1–42 ratio achieved a positive predictive value (PPV) of 94.44% and negative predictive value (NPV) of 94.28%, in the parametric model, comparable to plasma pTau217 alone (PPV: 94.44%, NPV: 94.28%), but yielded fewer indeterminate results (26.5% versus 38.6%). Using a non-parametric model, the plasma ratio achieved a PPV and NPV of 94.62% and 91.78%, respectively, while plasma pTau217 alone achieved 92.41% and 92.86%; the ratio once again reduced the proportion of indeterminate results (20.2% versus 35.1%). The plasma pTau217/Aβ1–42 ratio demonstrated superior performance in identifying amyloid pathology and reduced the frequency of indeterminate results compared to plasma pTau217 alone. These findings support the evaluation of the clinical utility of the plasma pTau217/Aβ1–42 ratio as a tool for identifying amyloid pathology in patients presenting with cognitive complaints.</p>}},
  author       = {{Benina, Natalya and Buitrago, Luna and De Simone, Francesca I. and Radwan, Rachel R. and Miller, M. Craig and Martin, Katie and Dickson, Diana and Ho, Sara and Moghekar, Abhay and Albert, Marilyn and Mattsson-Carlgren, Niklas and Palmqvist, Sebastian and Ossenkoppele, Rik and Jonsson, Magnus Förnvik and Hansson, Oskar and Stomrud, Erik and Sachdev, Pallavi and Niu, Hongmei and Verbel, David and Hawkins, Douglas M.}},
  issn         = {{0006-8950}},
  keywords     = {{Alzheimer’s disease; amyloid pathology; blood-based biomarkers; Fujirebio Lumipulse; phosphorylated Tau 217 plasma assay; phosphorylated Tau 217/β-Amyloid 1–42 plasma ratio}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{1168--1181}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain}},
  title        = {{Plasma pTau 217/β-amyloid 1–42 ratio for enhanced accuracy and reduced uncertainty in detecting amyloid pathology}},
  url          = {{http://dx.doi.org/10.1093/brain/awag001}},
  doi          = {{10.1093/brain/awag001}},
  volume       = {{149}},
  year         = {{2026}},
}