Plasma demonstrated high accuracy for identifying abnormal amyloid beta-positron emission tomography () status with an area under the curve (AUC) of 0.9198.
Plasma p-tau217 had sensitivity and specificity greater than 85% for Aβ-PET status.
All plasma biomarkers, except p-tau231, effectively ruled out Aβ pathology with a negative predictive value (NPV) exceeding 95%.
The Johnson & Johnson p-tau217 showed a covariate-adjusted positive predictive value (PPV) of 0.909 for confirming Aβ pathology.
Plasma biomarkers did not accurately identify cortical thickness despite being elevated in association with Aβ-PET and neurodegeneration profiles.
Correlations of p-tau217, p-tau181, and Aβ42/40 with Aβ-PET were stronger in non-Hispanic Whites compared to Black/African Americans.
Simplified
INTRODUCTION: We evaluated plasma biomarker association with, and classification accuracies for, amyloid beta-positron emission tomography () and cortical thickness in the biracial Human Connectome Project-Connectomics in Brain Aging (HCP-CoBRA) cohort (53% Black/African American [B/AA] and 47% non-Hispanic White [NHW]).
METHODS: In n = 218 participants (median age 62, range: 57-71] years, 65% female and 15% Aβ-PET positive), plasma biomarkers (phosphorylated tau-181 [p-tau181], , p-tau231, glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL], and Aβ42/Aβ40) were compared to Aβ-PET and magnetic resonance imaging (MRI) neuroimaging indicators.
RESULTS: Plasma p-tau217 (Johnson & Johnson and ALZpath [areas under the curve [AUCs] = 0.915 vs. 0.919]) had high sensitivity and specificity (>85%) for Aβ-PET status. All plasma biomarkers except p-tau231 effectively ruled out Aβ pathology (negative predictive value [NPV] >95%) but only Johnson & Johnson p-tau217+ was good for confirmation (covariate-adjusted positive predictive value [PPV] = 0.909). The plasma biomarkers performed poorly for identifying cortical thickness status but were elevated according to joint Aβ-PET and neurodegeneration profiles. Plasma biomarker accuracies for Aβ-PET positivity were unaffected by self-identified race, except for ALZpath p-tau217 (p = 0.024). However, correlations with Aβ-PET standardized uptake value ratio varied by self-identified race.
DISCUSSION: Plasma p-tau217 is a promising tool for Alzheimer's disease-associated Aβ pathology in older/middle-aged individuals. However, apparent race-related performances should be further studied.
HIGHLIGHTS: Plasma phosphorylated tau-217 (p-tau217) and glial fibrillary acidic protein (GFAP) best predicted abnormal brain amyloid beta-positron emission tomography (Aβ-PET). Plasma p-tau217 accurately identified abnormal Aβ-PET (Johnson & Johnson p-tau217: area under the curve [AUC] = 0.9145, 95% confidence interval [CI] = 0.8367-0.9923; ALZpath p-tau217: AUC = 0.9198, 95% CI = 0.8585-0.981) followed by GFAP and Aβ42/40 ratio (GFAP: AUC = 0.8529, 95% CI = 0.7485-0.9573; Aβ42/40:AUC = 0.7962, 95% CI = 0.6581-0.9346). All plasma biomarkers performed poorly in identifying cortical thickness, despite being higher according to combined Aβ-PET and neurodegeneration profiles. Correlations of p-tau217 (Johnson & Johnson p < 0.001), p-tau181 (p = 0.005), and Aβ42/40 (p = 0.004) with Aβ-PET in predicting amyloid burden were stronger in self-identified non-Hispanic Whites vs Black/African Americans. Biomarker accuracies for Aβ-PET positivity were unaffected by self-identified race, except ALZpath p-tau217 (p = 0.024).
Key numbers
0.919
AUC for ALZpath
Predictive accuracy for distinguishing A+ from A– participants
0.914
AUC for Johnson & Johnson +
Predictive accuracy for distinguishing A+ from A– participants
1.33 times
Fold change of
Higher in Black/African American participants compared to non-Hispanic White participants
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Gallen Triana‐Baltzer and Hartmuth Kolb are employees of Johnson & Johnson Research and Development. The plasma p‐tau217+ measurements were performed at Quanterix and managed by Johnson & Johnson Research and Development, but both parties were blinded to sample ID and were not involved in the data analysis. The co‐authors employed by Johnson & Johnson provided comments on the manuscript and provided approval for submission of the manuscript. Xuemei Zeng is an inventor on University of Pittsburgh provisional patents on anti‐tau antibodies and plasma amyloid beta peptide biomarker assays by immunoprecipitation‐mass spectrometry. Thomas K. Karikari has consulted for Quanterix Corporation, SpearBio Inc., Neurogen Biomarking LLC. and Alzheon and has served on advisory boards for Siemens Healthineers and Neurogen Biomarking LLC., outside the submitted work. He has received in‐kind research support from Johnson & Johnson Research Laboratories, SpearBio Inc., and Alamar Biosciences, as well as meeting travel support from the Alzheimer's Association and Neurogen Biomarking LLC., outside the submitted work. Thomas K. Karikari has received royalties from Bioventix for the transfer of specific antibodies and assays to third party organizations. He has received honoraria for speaker/grant review engagements from the National Institute of Health (NIH), Universtiy of Pennsylvania (UPENN), University of Wisconsin‐Madison (UW‐Madison), the Cherry Blossom symposium, the Health and Aging Brain Study‐Health Disparities (HABS‐HD)/Alzheimer's Disease Neuroimaging Initiative 4 (ADNI4) Health Enhancement Scientific Program, Advent Health Translational Research Institute, Brain Health conference, Barcelona‐Pittsburgh conference, the International Neuropsychological Society, the Icahn School of Medicine at Mount Sinai, and the Quebec Center for Drug Discovery, Canada, all outside of the submitted work. Thomas K. Karikari and Xuemei Zeng are inventors on patents and provisional patents regarding biofluid biomarker methods, targets, and reagents/compositions, which may generate income for the institution and/or self should they be licensed and/or transferred to another organization. The other authors report no conflict of interest. Author disclosures are available in the Supporting Information.
