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[Preprint]. 2025 Jan 20:2025.01.20.25320851.
doi: 10.1101/2025.01.20.25320851.

Evaluation of plasma p-tau217 for detecting amyloid pathology in a diverse and heterogeneous community-based cohort

Marc D Rudolph  1 , Courtney L Sutphen  1 , Thomas C Register  1 , Samuel N Lockhart  1 , Melissa M Rundle  1 , Timothy M Hughes  1 , James R Bateman  1 , Kiran K Solingapuram Sai  1 , Christopher T Whitlow  1 , Suzanne Craft  1 , Michelle M Mielke  1
Affiliations

Evaluation of plasma p-tau217 for detecting amyloid pathology in a diverse and heterogeneous community-based cohort

Marc D Rudolph et al. medRxiv. .

Update in

Abstract

Introduction: Studies suggest excellent performance of plasma p-tau217 for detecting amyloid pathology, though studies in more diverse populations are needed to validate previously determined cutpoints.

Methods: Plasma p-tau217 utility for detecting amyloid pathology (Aβ) via amyloid PET (n=598) and/or cerebrospinal fluid (CSF; n=154) was assessed in a heterogeneous, community-based cohort in the Wake Forest Alzheimer's Disease Research Center (WFADRC). Participants (n=598) were 21% Black; 313 cognitive unimpaired (CU), 214 mild cognitive impairment (MCI), and 64 dementia (DEM); 49% prediabetic, 44% hypertensive; 29% overweight/obese; and 64% with mild-to-moderate kidney disease. Gaussian-mixture models, logistic regression, and receiver operating curve analyses were performed.

Results: Plasma p-tau217 was associated with elevated Aβ deposition and accurately classified Aβ-positive participants (PET: AUC: 94%-97%, cutpoint≥.338 pg/mL; CSF: AUC = .84, cutpoint≥.307 pg/mL).

Discussion: Plasma p-tau217 is an accurate indicator of amyloid pathology in a heterogeneous cohort, and superior to other plasma biomarkers assessed. Longitudinal analyses assessing impact of comorbidities on p-tau217 utility for disease progression are underway.

Keywords: Biomarkers; Dementia; PET; Plasma; Risk.

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Conflict of interest statement

Conflict of Interest Statement Drs. Rudolph, Sutphen, Register, Rundle, Hughes, Solingapuram Sai, and Whitlow, have no conflicts of interest to disclose. Drs. Bateman and Lockhart receive funding from the Alzheimer’s Association. Dr. Bateman has also received honoraria from Efficient CME, PeerView CME, and Novo Nordisck in the last two years. Dr. Craft reports disclosures for vTv Therapeutics, T3D Therapeutics, Cyclerion Inc., and Cognito Inc. Dr. Mielke consults for or serves on advisory boards for Biogen, Eisai, Lilly, Merck, Roche, and Siemens Healthineers.

Figures

Figure 1.
Figure 1.
Associations between amyloid PET deposition (Centiloids) and plasma p-tau181 and p-tau217 Note: Associations between amyloid PET deposition (Centiloids) and plasma p-tau181 (panel a) and p-tau217(panel b). Scatterplots highlight a stronger correlation between p-tau217 and amyloid PET deposition across cognitive status groups compared to p-tau181 and amyloid PET. Dotted lines represent optimal (binary) and two-point detection cutpoints for each p-tau variable observed when classifying amyloid PET positivity. Data points are color-coded by diagnosis and of different shapes based on eGFR status (Stage 1 [Normal High] eGFR >= 90; Stage 2 [Mild] > 60 eGFR < 90; Stage 3 [Mild-Moderate] > 45 eGFR < 60; Stage 4 [Moderate Severe] eGFR < 45); Abbreviations: CU = Cognitively Unimpaired; MCI = Mild Cognitive Impairment; DEM = Dementia; CL = Centiloids; SENS = Sensitivity; SPEC = Specificity; eGFRg = Estimated Glomerular Filtration Rate.
Figure 2.
Figure 2.
Performance of p-tau181 and p-tau217 for classifying amyloid PET positivity defined as ≥ 24 Centiloids. Note: Figure 2 depicts cutpoints derived using receiver operating curve analyses and gaussian-mixture models for both plasma (a) p-tau181 and (b) p-tau217. Optimal (e.g., binary; Youden index = .338 pg/mL) and two-point ROC detection thresholds (MAX-SENS=.253 pg/mL; MAX-SPEC=.472 pg/mL) were combined resulting in a 4-tier system: (1) Negative [<0.253; N~39%]; (2) Intermediate-Low [0.253-.338; N~20%]; (3) Intermediate-High [0.338-.472; 13%]; and (4) Positive [>0.472; 28%]. Abbreviations: Aβ = Amyloid Beta; CL = Centiloids; SENS = Sensitivity; SPEC = Specificity; GMM = Gaussian-Mixture Models; NA = Missing (e.g., Plasma p-tau217 datapoints without a corresponding amyloid PET scan).
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