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. 2024 Feb;20(2):1214-1224.
doi: 10.1002/alz.13542. Epub 2023 Nov 6.

Plasma Aβ42/Aβ40 and phospho-tau217 concentration ratios increase the accuracy of amyloid PET classification in preclinical Alzheimer's disease

Robert A Rissman  1   2   3 , Oliver Langford  2 , Rema Raman  2 , Michael C Donohue  2 , Sara Abdel-Latif  2 , Matthew R Meyer  4 , Traci Wente-Roth  4 , Kristopher M Kirmess  4 , Jennifer Ngolab  2 , Charisse N Winston  1   2 , Gustavo Jimenez-Maggiora  2 , Michael S Rafii  2 , Pallavi Sachdev  5 , Tim West  4 , Kevin E Yarasheski  4 , Joel B Braunstein  4 , Michael Irizarry  5 , Keith A Johnson  6 , Paul S Aisen  2 , Reisa A Sperling  6 ; AHEAD 3-45 Study team
Affiliations

Plasma Aβ42/Aβ40 and phospho-tau217 concentration ratios increase the accuracy of amyloid PET classification in preclinical Alzheimer's disease

Robert A Rissman et al. Alzheimers Dement. 2024 Feb.

Abstract

Introduction: Incorporating blood-based Alzheimer's disease biomarkers such as tau and amyloid beta (Aβ) into screening algorithms may improve screening efficiency.

Methods: Plasma Aβ, phosphorylated tau (p-tau)181, and p-tau217 concentration levels from AHEAD 3-45 study participants were measured using mass spectrometry. Tau concentration ratios for each proteoform were calculated to normalize for inter-individual differences. Receiver operating characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by > 20 Centiloids. Mixture of experts analysis assessed the value of including tau concentration ratios into the existing predictive algorithm for amyloid positron emission tomography status.

Results: The area under the receiver operating curve (AUC) was 0.87 for Aβ42/Aβ40, 0.74 for phosphorylated variant p-tau181 ratio (p-tau181/np-tau181), and 0.92 for phosphorylated variant p-tau217 ratio (p-tau217/np-tau217). The Plasma Predicted Centiloid (PPC), a predictive model including p-tau217/np-tau217, Aβ42/Aβ40, age, and apolipoprotein E improved AUC to 0.95.

Discussion: Including plasma p-tau217/np-tau217 along with Aβ42/Aβ40 in predictive algorithms may streamline screening preclinical individuals into anti-amyloid clinical trials.

Clinicaltrials: gov Identifier: NCT04468659 HIGHLIGHTS: The addition of plasma phosphorylated variant p-tau217 ratio (p-tau217/np-tau217) significantly improved plasma biomarker algorithms for identifying preclinical amyloid positron emission tomography positivity. Prediction performance at higher NAV Centiloid levels was improved with p-tau217/np-tau217. All models generated for this study are incorporated into the Plasma Predicted Centiloid (PPC) app for public use.

Keywords: blood-based biomarkers; mass spectrometry; plasma; tau.

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Conflict of interest statement

Sara Abdel‐Latif, Jennifer Ngolab, and Keith A. Johnson have nothing to disclose. Oliver Langford is an employee of the Keck School of Medicine of USC. Matthew R. Meyer, Traci Wente‐Roth, Kristopher M. Kirmess, Tim West, Kevin E. Yarasheski, and Joel B. Braunstein are paid employees of C2N Diagnostics. Kevin E. Yarasheski has research grants from the NIH, BrightFocus Foundation, GHR Foundation, and Alzheimer's Drug Discovery Foundation. Pallavi Sachdev and Michael Irizarry are paid employees of Eisai. Robert A. Rissman, Rema Raman, Michael C. Donohue, and Charisse N. Winston have grants from the NIH. Rema Raman has received grants from Eisai, Eli Lilly, the Alzheimer's Association, and the American Heart Association. Michael C. Donohue serves as a consultant for Roche and has a spouse working at Janssen. Gustavo Jimenez‐Maggiora has received support from C2N Diagnostics, Eisai Co, Ltd, and the NIH. Michael S. Rafii serves as a consultant for AC Immune, Ionis, Keystone Bio, and Positrigo. Paul S. Aisen has research grants from Eisai, NIH, Lilly, the Alzheimer's Association, and Janssen and serves as a consultant for Merck, Bristol Myers Squibb, Switch Therapeutics, Roche, Arrowhead, ImmunoBrain, Checkpoint, Biogen, Abbvie, Genetech, and NewAmsterdam Pharma. Reisa A. Sperling has grants from the NIH, the Alzheimer's Association, the GHR Foundation, Eli Lilly, and Eisai, and has consulted for AC Immune, Acumen, Alector, Alnylam, Cytox, Genentech, Janssen, JOMDD, Nervgen, Neuraly, Neurocentria, Oligomerix, Prothena, Renew, Shionogi, Vigil Neuroscience, Ionis, Vaxxinity, and Bristol Myers Squibb. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Univariable analysis of plasma biomarker ratios. Scatter plots of biomarker ratio values for Aβ42/Aβ40 (left), p‐tau181/np‐tau181 (middle), and p‐tau‐217/np‐tau217 (right) plotted against PET Centiloid. Higher phosphorylation ratio at p‐tau181 and p‐tau217 plasma are associated with higher amyloid PET Centiloid levels. R value corresponds to the Pearson correlation coefficient and corresponding P‐value. Aβ, amyloid beta; PET, positron emission tomography; p‐tau, phosphorylated tau
FIGURE 2
FIGURE 2
Increased diagnostic performance with the addition of phosphorylated ratio p‐tau217/np‐tau217. A. ROC curves for p‐tau217/np‐tau217 (light gray solid), p‐tau181/np‐tau181 (light blue, dashed), p‐tau217 (dark gray solid), p‐tau181 (blue broken), Aβ42/Aβ40 (dark red dashed), APS (tan broken), and APS‐Plus (yellow solid) for predicting brain amyloid PET status. B, The corresponding AUC and 95% confidence intervals for each biomarker. The phosphorylation at p‐tau217/np‐tau217 ratio exhibited high sensitivity and specificity for amyloid PET status. C, ROC curves from the raw p‐tau217 (dark gray dashed), p‐tau217/np‐tau217 (light gray solid), and prediction models incorporating covariates ptau217/np‐tau217, Aβ42/Aβ40, age and APOE status (full model, orange solid), p‐tau217/np‐tau217, age and APOE status (full model minus Aβ, teal solid), ptau217/np‐tau217, age and APOE status (full model minus ptau217, lavender dash), ptau217/np‐tau217, Aβ42/Aβ40 and age (full model minus APOE, pink broken), ptau217/np‐tau217 and age (full model minus Aβ & APOE, dark blue solid), along with APS (tan solid) and APS‐Plus (yellow broken). D, AUC and 95% confidence intervals for each modeled biomarker. Aβ, amyloid beta; APOE, apolipoprotein E; APS, Amyloid Probability Score; AUC, area under the receiver operating curve; PET, positron emission tomography; ROC, receiver operating characteristic
FIGURE 3
FIGURE 3
The combination of Aβ42/40 of p‐tau217/np‐tau217 improves amyloid status prediction in individuals with CL > 20. AUC plotted against NAV PET cut point. Predictors plotted: full model (black), full model minus Aβ (yellow), and full model minus p‐tau217 (blue). Shaded regions signify confidence intervals (CI). Aβ, amyloid beta; AUC, area under the curve; CL, Centiloid; PET, positron emission tomography; p‐tau, phosphorylated tau
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