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. 2025 Jun;21(6):e70316.
doi: 10.1002/alz.70316.

Diagnostic performance of plasma p-tau217 and Aβ42/40 biomarkers in the outpatient memory clinic

Yoav D Piura  1 , Daniel J Figdore  2 , Christian Lachner  1   3 , Joshua Bornhorst  2 , Alicia Algeciras-Schimnich  2 , Neill R Graff-Radford  1 , Gregory S Day  1
Affiliations

Diagnostic performance of plasma p-tau217 and Aβ42/40 biomarkers in the outpatient memory clinic

Yoav D Piura et al. Alzheimers Dement. 2025 Jun.

Abstract

Introduction: Plasma biomarkers of Alzheimer's disease (AD) represent accessible alternatives to positron emission tomography (PET) and cerebrospinal fluid (CSF)-based biomarkers in well-characterized cohorts. It remains to be determined whether performance is maintained in outpatient clinics comprised of patients with multiple causes of cognitive impairment.

Methods: Plasma phosphorylated tau217 (p-tau217) and amyloid beta (Aβ) 42/40 were measured in 509 patients evaluated in a tertiary-care memory clinic. Biomarker performance was compared across diagnoses, referencing established cutpoints for positive and negative biomarkers.

Results: Plasma p-tau217 distinguished patients with diagnoses of symptomatic AD with 95% sensitivity and 82% specificity. Integration of Aβ42 measurements (p-tau217/Aβ42) incrementally improved specificity (86%). Plasma p-tau217 and p-tau217/Aβ42 concentrations closely associated with established CSF biomarkers of AD (area under the curve [AUC]: 0.94 and 0.96, respectively). Reduced kidney function associated with elevated plasma p-tau217 and p-tau217/Aβ42 concentrations in patients without AD (referencing CSF biomarkers).

Discussion: Plasma p-tau217 and p-tau217/Aβ42 concentrations demonstrated robust diagnostic performance in a heterogeneous clinical cohort; interpretation requires consideration of kidney function.

Highlights: Plasma phosphorylated tau217 (p-tau217) reliably identified clinic patients with Alzheimer's disease. A two-cutpoint strategy yielded definitive results in 86% of patients. Integration of plasma amyloid beta (Aβ; p-tau217/Aβ42) minimally improved diagnostic performance. Plasma p-tau217 levels were increased in patients with kidney dysfunction.

Keywords: Alzheimer's disease; cerebrospinal fluid; dementia; diagnosis; kidney function; memory clinic; plasma biomarker.

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Conflict of interest statement

Y.D. Piura reports no conflicts of interest. D.J. Figdore reports no conflicts of interest. C. Lachner reports no conflicts of interest. His research is supported by the NIH (UH2‐AG083186, ARDC AG062677 Clinical Core, AG075802, NS125417). J. Bornhorst has participated on an advisory board for Sunbird Bio and received an honorarium from Roche Diagnostics. A. Algeciras‐Schimnich has participated on advisory boards for Roche Diagnostics and Fujirebio Diagnostis, and has received a honorarium from Roche Diagnostics. N.R. Graff‐Radford reports no conflicts of interest. His research is supported by NIH. He has participated in multicenter therapy studies sponsored by Biogen, Eisai and Lilly. G.S. Day reports no conflicts of interest. His research is supported by NIH (R01AG089380, U01AG057195, U01NS120901, U19AG032438). He serves as a consultant for Arialys Therapeutics and Parabon Nanolabs Inc, and as a Topic Editor (Dementia) for DynaMed (EBSCO). He is a co‐Project PI for a clinical trial in anti‐NMDAR encephalitis, which receives support from NINDS (U01NS120901) and Amgen Pharmaceuticals. He has developed educational materials for Continuing Education Inc and Ionis Pharmaceuticals. He owns stock in ANI pharmaceuticals. Dr. Day's institution has received in‐kind contributions for radiotracer precursors for tau‐PET neuroimaging in studies of memory and aging (via Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly). Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Distribution of plasma AD biomarkers by diagnosis and CSF p‐tau181/Aβ42. Density plots showing the distribution of plasma AD biomarkers: Aβ42/40 (top), p‐tau217 (middle), and p‐tau217/Aβ42 (bottom). (A) Plasma biomarker values in patients with (red) and without a clinical diagnosis of AD (green). (B) Plasma AD biomarkers in patients with (red) and without (green) CSF p‐tau181/Aβ42 consistent with AD. The x‐axis represents z‐scores of log2‐transformed biomarker values; the y‐axis shows density (i.e., proportion of patients). Histograms with fitted normal distribution curves demonstrate the separation between groups for each biomarker. Aβ, amyloid beta; AD, Alzheimer's disease; CSF, cerebrospinal fluid; p‐tau, phosphorylated tau.
FIGURE 2
FIGURE 2
Correlation between plasma and CSF AD biomarker concentrations. Spearman's correlation coefficients (rho) are shown between CSF ratio values (y‐axis) and plasma measures of Aβ42/40 (A), p‐tau217 (B), and p‐tau217/Aβ42 (C). Results are stratified by the presence (blue triangles) and absence (green squares) of AD neuropathology, defined by CSF p‐tau181/Aβ42 concentrations. Aβ, amyloid beta; AD, Alzheimer's disease; CSF, cerebrospinal fluid; p‐tau, phosphorylated tau.
FIGURE 3
FIGURE 3
Distribution of plasma versus CSF AD biomarkers concentrations stratified by CSF p‐tau181/Aβ42 status. Scatterplots show the relationship between CSF p‐tau181/Aβ42 ratio (y‐axis) and plasma Aβ42/40 ratio (A), p‐tau217 concentrations (B) or p‐tau217/Aβ42ratio (C). Green circles and red triangles represent CSF‐negative and CSF‐positive cases, respectively. Gray areas indicate intermediate zones between established cutoff values for plasma biomarkers (Aβ42/40: 0.0778–0.0996; p‐tau217: 0.186–0.324 pg/mL; p‐tau217/Aβ42: 0.0075–0.0131). Aβ, amyloid beta; AD, Alzheimer's disease; CSF, cerebrospinal fluid; p‐tau, phosphorylated tau.
FIGURE 4
FIGURE 4
Comparative diagnostic performance of plasma AD biomarkers. Receiver operating characteristic curves compare the relative diagnostic performance of plasma AD biomarkers, referencing clinical consensus diagnoses (A) and established CSF AD biomarkers (“positive” CSF p‐tau181/Aβ42; B). Aβ, amyloid beta; AD, Alzheimer's disease; CSF, cerebrospinal fluid; p‐tau, phosphorylated tau.
FIGURE 5
FIGURE 5
The association between creatinine clearance and plasma AD biomarker concentrations. Box and scatter plots depict plasma concentrations of Aβ42/40 (A), p‐tau217 (B), and p‐tau217/Aβ42 (C) in patients with normal creatine clearance (eGFR ≥ 60 mL/min/1.73 m2, blue), and mild (45 ≤ eGFR < 60 mL/min/1.73 m2, yellow) and severe kidney dysfunction (eGFR < 45 mL/min/1.73 m2, red). Analyses are stratified by the presence (CSF AD +) and absence (CSF AD ‐) of AD neuropathology, referencing CSF p‐tau181/Aβ42 concentrations. Red dashed lines depict established cutpoints for plasma biomarkers (abnormal values: Aβ42/40 ≤ 0.0777 [“positive”], ≤ 0.0996 [“intermediate”]; p‐tau217 ≥ 0.325 pg/mL [“positive”], ≥ 0.186 pg/mL [“intermediate”]; p‐tau217/Aβ42 ≥ 0.0132 [“positive”], ≥ 0.0075 [“intermediate”]). . Aβ, amyloid beta; AD, Alzheimer's disease; CSF, cerebrospinal fluid; eGFR, estimated glomerular filtration rate; p‐tau, phosphorylated tau.
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