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Key Points

Question听 What are the capabilities of a commercially available plasma phosphorylated tau 217 (p-tau217) immunoassay to identify Alzheimer disease pathophysiology?

Findings听 This cohort study found that the p-tau217 immunoassay showed similar accuracies to cerebrospinal fluid biomarkers in identifying abnormal amyloid 尾 (A尾) and tau pathologies. A 3-range reference for detecting abnormal A尾 pathology was consistent across 3 cohorts; over 8 years, the largest change of p-tau217 was in individuals positive for both A尾 and tau.

Meaning听 The wider availability of high-performing assays may expedite the use of blood biomarkers in clinical settings and benefit the research community.

Importance听 Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer disease (AD) pathology, with p-tau217 considered to have the most utility. However, availability of p-tau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests.

Objective听 To determine the utility of a novel and commercially available immunoassay for plasma p-tau217 to detect AD pathology and evaluate reference ranges for abnormal amyloid 尾 (A尾) and longitudinal change across 3 selected cohorts.

Design, Setting, and Participants听 This cohort study examined data from 3 single-center observational cohorts: cross-sectional and longitudinal data from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (visits October 2017鈥揂ugust 2021) and Wisconsin Registry for Alzheimer鈥檚 Prevention (WRAP) cohort (visits February 2007鈥揘ovember 2020) and cross-sectional data from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort (baseline visits March 2009鈥揘ovember 2021). Participants included individuals with and without cognitive impairment grouped by amyloid and tau (AT) status using PET or CSF biomarkers. Data were analyzed from February to June 2023.

Exposures听 Magnetic resonance imaging, A尾 positron emission tomography (PET), tau PET, cerebrospinal fluid (CSF) biomarkers (A尾42/40 and p-tau immunoassays), and plasma p-tau217 (ALZpath pTau217 assay).

Main Outcomes and Measures听 Accuracy of plasma p-tau217 in detecting abnormal amyloid and tau pathology, longitudinal p-tau217 change according to baseline pathology status.

Results听 The study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] and 282 males [35.9%]). High accuracy was observed in identifying elevated A尾 (area under the curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95% CI, 0.84-0.99) across all cohorts. These accuracies were comparable with CSF biomarkers in determining abnormal PET signal. The detection of abnormal A尾 pathology using a 3-range reference yielded reproducible results and reduced confirmatory testing by approximately 80%. Longitudinally, plasma p-tau217 values showed an annual increase only in A尾-positive individuals, with the highest increase observed in those with tau positivity.

Conclusions and Relevance听 This study found that a commercially available plasma p-tau217 immunoassay accurately identified biological AD, comparable with results using CSF biomarkers, with reproducible cut-offs across cohorts. It detected longitudinal changes, including at the preclinical stage.

In Alzheimer disease (AD), blood biomarkers have emerged as scalable tools for clinical evaluation, trial recruitment, and disease monitoring.¹ Their anticipated implementation aims to substantially reduce the reliance on cerebrospinal fluid (CSF) or positron emission tomography (PET) scans in specialized centers.² Moreover, a robust and accurate blood-based biomarker would enable a more comprehensive assessment of cognitive impairment in settings where advanced testing is limited. Therefore, use of a blood biomarker is intended to enhance an early and precise AD diagnosis, leading to improved patient management and, ultimately, timely access to disease-modifying therapies.

Phosphorylated tau (p-tau) is the leading blood biomarker candidate, demonstrating superior diagnostic accuracy and disease specificity compared with other candidates.^3,4 The amyloid 尾 42/40 (A尾42/40) ratio, a validated CSF biomarker,⁵ has limitations in blood^6,7 and lacks the robustness required for routine clinical testing.^8,9 In contrast, high-performing p-tau blood test results exhibit a substantial increase in patients with AD,¹⁰ occurring concurrently with extracellular A尾 plaque deposition, an AD hallmark feature. This relationship is observed across the AD continuum, including the asymptomatic phase in sporadic and genetic forms of AD.^11-14 Yet certain p-tau species, but not all, are also associated with neurofibrillary tangle pathology, the secondary AD pathological hallmark.^15-17 Thus, p-tau is regarded as the primary blood biomarker for AD pathology throughout all stages of the disease.

Among proposed blood tau biomarkers,^18-21 phosphorylated tau at threonine 217 (p-tau217) has consistently shown high performance in differentiating AD from other neurodegenerative disorders^10,22 and in detecting AD pathology in patients with mild cognitive impairment (MCI).²² Notably, p-tau217 exhibits larger-fold changes compared with p-tau181 and p-tau231,¹⁰ often achieving high discrimination, with areas under the curve (AUC) exceeding 90%.^19,23 Additionally, p-tau217 demonstrates a unique longitudinal trajectory, showing increases associated with worsening brain atrophy and declining cognitive performance in individuals with elevated A尾 pathology.^24,25

With the imminent implementation of anti-A尾 therapies in dementia management, validated blood biomarkers are urgently needed to guide timely treatment decisions. While plasma p-tau217 has shown promise as a diagnostic tool for AD, its widespread evaluation has been hindered by limited availability of commercial assays. This study aims to address this gap by assessing the utility of ALZpath pTau217, a commercially available immunoassay, to highlight the presence of AD pathology. In addition, we aim to report reference ranges of the plasma p-tau217 that correspond to abnormal amyloid PET and CSF measures.

This study included participants from 3 observational cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD), Wisconsin Registry for Alzheimer鈥檚 Prevention (WRAP), and Sant Pau Initiative on Neurodegeneration (SPIN). Participants gave written or verbal informed consent, and the studies were approved by the relevant ethics boards (eMethods in Supplement 1). The present study followed the Strengthening the Reporting of Observational Studies in Epidemiology () reporting guidelines.

TRIAD included 268 participants who had no cognitive impairment (134 individuals [50%]), MCI (63 [23.5%]), AD dementia (46 [17.2%]), and non-AD dementia (24 [9.0%]). The WRAP study²⁶ included data on 323 participants, predominantly without cognitive impairment at the first plasma sample collection (no impairment, 309 [95.6%]; MCI, 12 [3.7%]; AD dementia, 2 [0.6%]). The SPIN cohort²⁷ included 195 participants: controls without cognitive impairment (82 [42.1%]), individuals with MCI due to AD (72 [36.7%]), and individuals with AD dementia (41 [21.0%]). Diagnosis was based on internationally recognized clinical criteria, and control participants had normal cognitive scores on standard neuropsychological evaluations. A subset of patients with longitudinal follow-up consisted of 392 participants from TRIAD and WRAP defined by PET biomarkers (eTable 1 in Supplement 1). These included participants classified into 3 groups: amyloid- and tau-negative (A鈭扵鈭�; n鈥�=鈥�297), amyloid-positive and tau-negative (A+T鈭�; n鈥�=鈥�66), and amyloid-positive and tau-positive (A+T+; n鈥�=鈥�29). In WRAP, the median number of samples collected per patient was 3 over a mean (SD) of 5.22 (1.41) years. In TRIAD, median samples per patient was 2, collected over a mean of 1.90 (0.61) years.

Detailed imaging methods for TRIAD, WRAP, and SPIN are found in the eMethods in Supplement 1. In TRIAD, A尾 and tau PET were determined by [¹⁸F]-AZD4694²⁸ and [¹⁸F]-MK6240,²⁹ respectively. In WRAP, PET measures were determined by [¹¹C]-PiB³⁰ and [¹⁸F]-MK6240.^31,32 In SPIN, A尾 PET was determined by [¹⁸F]-florbetapir or [¹⁸F]-flutemetamol in a smaller subset of participants, with CSF A尾42/40 used to define A status for most participants as described below. Tau PET was not available for the SPIN cohort, and T was defined by CSF p-tau181. A尾-PET positivity was standardized across cohorts as a centiloid value greater than 24 (standardized uptake value ratio [SUVR] >1.55 for [¹⁸F]-AZD4694³³ or distribution volume ratio >1.2 for [¹¹C]-PiB). Tau positivity with [¹⁸F]-MK6240 was defined as meta-temporal region of interest SUVR greater than 1.24 for TRIAD³⁴ and SUVR greater than 1.3 in WRAP.

CSF sample collection procedures were similar across cohorts and are described in the eMethods in Supplement 1. In TRIAD and SPIN, Lumipulse G1200 or G600II was used to quantify CSF A尾42, A尾40, and p-tau181.^35,36 Additionally, CSF p-tau217 was quantified by an in-house single-molecule array (Simoa) developed at the University of Gothenburg.³³ A novel Simoa for CSF p-tau205 was measured in TRIAD only. For WRAP, CSF A尾42, A尾40, and p-tau181 were measured using the Roche NeuroToolKit.³⁷

Plasma samples from TRIAD, WRAP, and SPIN were analyzed at the Department of Psychiatry and Neurochemistry, University of Gothenburg. Plasma A尾42/40, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were quantified using the commercial Neurology 4-plex E kit (103670; Quanterix). Plasma p-tau231 and p-tau181 were analyzed using in-house Simoa assays developed at the University of Gothenburg,^18,38 except in WRAP where plasma p-tau181 was quantified by the commercial Advantage kit version 2.1 (104111; Quanterix).²⁴

The commercial ALZpath pTau217 assay for p-tau217 uses a proprietary monoclonal p-tau217 specific capture antibody, an N-terminal detector antibody, and a peptide calibrator. It has been validated as a fit-for-purpose assay³⁸ with a limit of detection of 0.0052 to 0.0074 pg/mL, a functional lower limit of quantification of 0.06 pg/mL, and a dynamic range of 0.007 to 30 pg/mL. The spike recovery for the endogenous analyte was 80%, and intrarun and interrun precision was 0.5% to 13% and 9.2% to 15.7%, respectively. Here, the assay demonstrated good repeatability (4%-8.7%) and intermediate precision (3.5%-10.7%) as shown in eTable 2 in Supplement 1.

Between-group comparisons were conducted using linear models, adjusting for age and sex. Determining A尾-PET and tau-PET positivity and other outcomes was done using receiver operating characteristics AUC and compared with those of other established biomarkers with the DeLong test. Correlations were always evaluated using Spearman 蟻. A binary reference point for A尾-PET positivity was derived based on the Youden index.

Alternatively, a 3-range strategy comprised a lower reference point to rule out AD (95% sensitivity) and a higher reference point to rule in AD (95% specificity). In both strategies, we evaluated the concordance of a negative p-tau217 result with A尾-PET negativity (negative percent agreement), and the concordance of a positive plasma p-tau217 with A尾-PET positivity (positive percent agreement), as well as the overall percent agreement. In the latter strategy, individuals with p-tau217 levels between the reference point were classified as intermediate risk and would constitute the population referred to confirmatory testing.³⁹

We evaluated the longitudinal trajectories of plasma p-tau217 in participants with no cognitive impairment and those with MCI according to their amyloid (A) and tau (T) status. We used linear mixed-effects models with plasma p-tau217 as the response variable, including as predictors time (since first plasma collection), AT status, age at first plasma collection, years of education, sex, and cognitive status at first visit, as well as an interaction between AT status and time. The model contained random intercepts and random slopes for each participant, and time was modeled as a continuous variable. Post hoc pairwise contrasts were conducted to compare the slopes for group鈥壝椻�塼ime interactions.

All analyses were performed using R version 4.2.2 (R Project for Statistical Computing), with a 2-sided 伪 of .05. No adjustments for multiple comparisons were performed.⁴⁰ Reported results include 95% confidence intervals when applicable.

A total of 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%], 282 males [35.9%]) were included in the study. The TRIAD subsample included 268 participants (69.4 [7.8] years; 167 females [62.3%], 101 males [37.7%]). The WRAP cohort included 323 participants (65.3 [6.9] years; 217 females [67.2%], 106 males [32.8%]), predominantly without cognitive impairment. The SPIN cohort included 195 participants (63.5 [13.8] years; 120 females [61.5%], 75 males [38.5%]). All participants had confirmatory amyloid status (TRIAD and WRAP: A尾 PET; SPIN: CSF A尾42/A尾40), and the majority (716 [91.1%]) also had information on tau status (TRIAD and WRAP: tau PET; SPIN: CSF p-tau181), as described in Table 1 alongside demographic and clinical information for all cross-sectional analyses. eTable 2 in Supplement 1 describes the TRIAD and WRAP longitudinal subsets.

When stratified by AT status, regardless of clinical diagnosis, plasma p-tau217 significantly increased in a stepwise manner in all cohorts (Figure 1), with highest levels in the A+T+ group. Mean p-tau217 concentrations for A鈭扵鈭� (mean [SD] TRIAD, 0.26 [0.13] pg/mL; WRAP, 0.35 [0.15] pg/mL; SPIN, 0.32 [0.11] pg/mL), A+T鈭� (TRIAD, 0.75 [0.63] pg/mL; WRAP, 0.72 [0.30] pg/mL; SPIN, 0.91 [0.47] pg/mL), and A+T+ (TRIAD, 1.48 [0.65] pg/mL; WRAP, 1.41 [0.70] pg/mL; SPIN, 1.50 [0.70] pg/mL) were remarkably similar across all 3 cohorts. This was also observed when stratifying by amyloid status alone (A鈭�, TRIAD, 0.28 [0.21] pg/mL; WRAP, 0.35 [0.14] pg/mL; SPIN, 0.38 [0.29] pg/mL; and A+, TRIAD, 1.08 [0.72] pg/mL, WRAP, 0.94 [0.54] pg/mL, SPIN, 1.43 [0.70] pg/mL) (eFigure 1 in Supplement 1).

Plasma p-tau217 demonstrated high accuracy in predicting abnormal A尾-PET signal (centiloid >24) in TRIAD (AUC, 0.92; 95% CI, 0.92-0.96) and WRAP (AUC, 0.93; 95% CI, 0.90-0.97) (Figure 2A). In SPIN, p-tau217 also had high accuracy in predicting abnormal CSF A尾42/40 (AUC, 0.96; 95% CI, 0.92-0.99) (Figure 2A). There was equally high accuracy when A尾-PET status was determined by visual read (eFigure 2 in Supplement 1). Further, p-tau217 sustained high accuracy when A尾-PET status was defined by differing centiloid values (eg, centiloid >12 and centiloid >37) in TRIAD and WRAP participants (eFigure 3 in Supplement 1).

Plasma p-tau217 also exhibited high accuracy for predicting abnormal tau in TRIAD (AUC, 0.95; 95% CI, 0.92-0.97) and WRAP (AUC, 0.93; 95% CI, 0.84-0.98) (Figure 2B). In SPIN, p-tau217 had high accuracy for abnormal CSF p-tau181 (AUC, 0.97; 95% CI, 0.94-0.99). Promisingly, p-tau217 could identify abnormal tau PET signal among amyloid-positive participants (A+T鈭� vs A+T+) in TRIAD (AUC, 0.87; 95% CI, 0.81-0.93) and WRAP (AUC, 0.90; 95% CI, 0.85-0.95) (Figure 2C). Moreover, we observed a gradual increase of plasma p-tau217 across tau-PET鈥揹efined Braak stages in TRIAD (eFigure 4 and eTable 3 in Supplement 1).

Next, we compared the performance of plasma p-tau217 to CSF and imaging modalities for predicting abnormal A尾 PET and tau PET. This analysis included the maximum number of participants within each biomarker modality. In WRAP, in determining abnormal A尾 PET, plasma p-tau217 outperformed hippocampal atrophy (AUC, 0.52; 95% CI, 0.44-0.60; P鈥�<鈥�.001), tau PET (AUC, 0.72; 95% CI, 0.64-0.80; P鈥�<鈥�.001), and CSF p-tau181 (AUC, 0.75; 95% CI, 0.66-0.84; P鈥�<鈥�.001) but did not differ significantly from CSF A尾42/40 or CSF p-tau181/A尾42 (eFigure 5A in Supplement 1). Similar findings were observed in TRIAD, where plasma p-tau217 outperformed hippocampal atrophy (AUC, 0.70; 95% CI, 0.63-0.76; P鈥�<鈥�.001) and tau PET (AUC, 0.86; 95% CI, 0.82-0.91; P鈥�=鈥�.05) for detecting abnormal A尾 pathology but did not significantly differ from various CSF biomarkers (eFigure 5B in Supplement 1). In SPIN, plasma p-tau217 outperformed hippocampal volume (AUC, 0.89; 95% CI, 0.83-0.95; P鈥�=鈥�.04) and was comparable with CSF biomarkers (eFigure 5C in Supplement 1).

In predicting abnormal tau-PET burden (eFigure 5D-E in Supplement 1), plasma p-tau217 significantly outperformed hippocampal volume (WRAP AUC, 0.65; 95% CI, 0.50-0.81; P鈥�=鈥�.01; TRIAD AUC, 0.83; 95% CI, 0.76-0.89; P鈥�=鈥�.01; SPIN AUC, 0.91; 95% CI, 0.86-0.96, P鈥�=鈥�.049). Plasma p-tau217 significantly outperformed CSF p-tau181 in WRAP (AUC, 0.69; 95% CI, 0.66-0.84; P鈥�=鈥�.02) but not TRIAD. Plasma p-tau217 outperformed A尾 PET in TRIAD (AUC, 0.90; 95% CI, 0.86-0.95; P鈥�=鈥�.04), while in WRAP they were comparable (AUC, 0.96; 95% CI, 0.93-0.99; P鈥�=鈥�.35). Plasma p-tau217 showed comparable performance with other measures, except for CSF p-tau217 in SPIN.

Additionally, we conducted comparisons in subsets only including participants with all modalities (WRAP: n鈥�=鈥�131; TRIAD: n鈥�=鈥�106; SPIN: n鈥�=鈥�41), finding no marked differences (eFigure 6 in Supplement 1). Plasma p-tau217 also discriminated A+T+ from A+T鈭� individuals comparably with CSF and imaging biomarkers (eFigure 7 in Supplement 1).

Plasma p-tau217 alone or p-tau217 plus demographic variables (age, sex, and APOE status) outperformed all other plasma biomarkers (p-tau181, p-tau231, A尾42/40, GFAP, and NfL), and their optimal combinations, for predicting both amyloid and tau status in all cohorts (eTables 4 and 5 and eFigure 7 in Supplement 1). A minimal improvement in model metrics of goodness-of-fit (Akaike information criterion) was observed in p-tau217 plus demographic data but not in discriminatory performance. The correlations of plasma p-tau217 with A尾 PET, tau PET, and CSF p-tau217 are shown in eFigures 9 and 10 in Supplement 1.

We first derived a binary reference point for A尾 positivity using the Youden index, derived in WRAP (>0.42 pg/mL) (Table 2 and eFigure 11 in Supplement 1). This reference point was cross-validated in TRIAD (A尾 positivity based on PET) and SPIN (A尾 positivity based on CSF A尾42/40). We next applied a 3-range approach,⁴¹ creating lower (95% sensitivity, <0.4 pg/mL) and upper (95% specificity, >0.63 pg/mL) reference points in WRAP (Table 2 and eFigure 11 in Supplement 1). This approach improved the positive percent agreement (TRIAD: 97.7%; SPIN: 95.3%) while maintaining a similar negative percent agreement. The 鈥渋ntermediate鈥� zone (p-tau217 levels 0.4-0.63 pg/mL), which could in practice be referred to confirmatory testing with CSF or PET, was largest in WRAP (22.9%), as expected because of lower A尾-positivity prevalence, and smaller in TRIAD (15.8%) and SPIN (13.0%). A binary reference point for tau positivity is demonstrated in eTable 6 in Supplement 1.

In up to 8 years of longitudinal sampling in WRAP (mean [SD], 5.22 [1.41] years), the A+T+ group demonstrated a significantly higher annual increase rate in plasma p-tau217 levels compared with the A鈭扵鈭� group (尾 estimate, 0.12; 95% CI, 0.10-0.13; P鈥�<鈥�.001). The A+T鈭� group also demonstrated a significantly higher annual rate of change in plasma p-tau217 compared with A鈭扵鈭� (尾 estimate, 0.04; 95% CI, 0.02-0.05; P鈥�<鈥�.001). Slope comparisons showed the A+T+ group to have a significantly higher rate compared with the A+T鈭� group (尾 estimate, 0.08; 95% CI, 0.06-0.09; P鈥�<鈥�.001) (Figure 3A). In TRIAD, similar results were observed, even with a shorter follow-up (mean [SD], 1.90 [0.61] years) (Figure 3B).

In 3 independent cohorts, this study presents the performance of a commercially available plasma assay targeting p-tau217. Our findings demonstrate high accuracy in identifying abnormal A尾 and tau pathologies, comparable with CSF measures and superior to brain atrophy assessments. A 3-range approach demonstrated high negative and positive concordance with A尾 status, with approximately 20% of individuals in an intermediate zone that would require confirmatory CSF or PET, as previously proposed.⁴¹ Longitudinally, this assay exhibited increases solely in individuals with A尾 pathology at baseline, and those with both elevated A尾 and tau pathologies demonstrated a greater rate of annual increase.

Plasma biomarkers have emerged as important tools for AD evaluation. Their specificity to underlying pathology offers great potential for rapid screening, reducing the dependence on advanced confirmatory tests. A clinical AD diagnosis often lacks sensitivity and specificity, resulting in many individuals with MCI (40%-60%) or dementia (20%-30%) who exhibit typical AD symptoms lacking A尾 pathology.¹ In primary care, it is estimated that more than 50% of patients with cognitive impairment remain undiagnosed or incorrectly diagnosed because of the lack of accessible and cost-effective tools.¹ Thus, blood biomarkers are set to revolutionize clinical care by providing objective biomarker-based information. As anti-A尾 trials move toward targeting a preclinical population with lower prevalence of A尾 abnormalities,⁴² a cost-effective screening strategy becomes paramount. In previous studies, targeting p-tau217 in blood has yielded the best results as a diagnostic and prognostic tool that tracks longitudinal change.

There has been limited access to immunoassays targeting p-tau217 for broader evaluation. This study evaluates a commercially available assay for p-tau217 that exhibits similar advantageous features to those previously reported. Consistent with Palmqvist et al,¹⁹ this assay outperformed magnetic resonance imaging and showed comparable performance with CSF biomarkers in detecting A尾 PET positivity and tau PET positivity.⁴³ Further, significant superiority to other plasma p-tau epitopes, A尾42/40, NfL, and GFAP and their optimal combinations was shown. When combined with APOE status and age, only modest improvements in diagnostic accuracy were observed, whereas other plasma biomarkers relied more heavily on these variables for their performance. Notably, the assay demonstrated high accuracy in identifying tau pathology within A尾-positive individuals. This is particularly important as antiamyloid therapies may be less effective in patients with advanced tau pathology.^44,45 Our findings suggest that p-tau217 has the potential to identify elevated tau-PET uptake and promising utility in early AD trials. Our study did not define elevated tau in the same manner as the TRAILBLAZER trials but warrants further studies applying p-tau217 to intermediate-tau trial inclusion designs.⁴⁵

Integrating blood biomarkers into diagnostic workflows remains challenging despite their promise. Therefore, this study also aimed to establish reference points based on abnormal A尾 pathology. The study evaluated a 3-range approach as recommended by Alzheimer鈥檚 Association guidelines³⁹ and recently proposed by Brum et al,⁴¹ which suggests confirmatory testing for patients with uncertain plasma p-tau217 results. Evaluating this approach using a commercial immunoassay showed high negative and positive predictive accuracy at screening, indicating only 12% to 23% of individuals warranted advanced testing, depending on the clinical stage. However, we acknowledge that the cohorts used in this study may not fully represent real-world clinical settings. Importantly, the reported negative and positive predictive accuracy of these reference ranges can vary based on the prevalence of the outcome in the target population. Lower positive percent agreements are expected in settings with lower prevalence,⁴⁶ as observed in the preclinical WRAP cohort compared with the higher prevalence seen in TRIAD and SPIN cohorts. Therefore, future studies should prospectively evaluate plasma p-tau217 reference points in memory clinic populations with wider diversity to ensure optimized implementation, accounting for higher rates of important comorbidities.⁴⁷

This study is not without limitations. First, one-third of our participants were classified as cognitively impaired, and this may limit our generalizability to the symptomatic stages of the disease but highlights promise for future preclinical recruitment. In addition, our results cannot be generalized to all individuals without detailed examination in cohorts with a larger representation of diverse ethnic populations. We acknowledge that CSF p-tau181, utilized as a T marker in SPIN, is not interchangeable with other methods that more accurately reflect neurofibrillary tangle pathology.⁴⁸

This study highlights the effectiveness of a commercially available plasma p-tau217 assay in identifying AD pathology. Our findings demonstrate the substantial reduction of confirmatory testing, by approximately 80%, by implementing a 3-range approach for A尾 positivity based on plasma p-tau217. These results emphasize the important role of plasma p-tau217 as an initial screening tool in the management of cognitive impairment by underlining those who may benefit from antiamyloid immunotherapies.

Accepted for Publication: November 10, 2023.

Published Online: January 22, 2024. doi:10.1001/jamaneurol.2023.5319

Open Access: This is an open access article distributed under the terms of the CC-BY License. 漏 2024 Ashton NJ et al. JAMA Neurology.

Corresponding Author: Nicholas J. Ashton, PhD, Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at Gothenburg University, M枚lndal Hospital, Hus V3, 43180 M枚lndal, Sweden (nicholas.ashton@gu.se).

Author Contributions: Dr Ashton had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr Ashton and Mr Brum contributed equally as co鈥揻irst authors.

Concept and design: Ashton, Brum, Benedet, Vanmechelen, Montoliu-Gaya, Servaes, Therriault, Pascoal, Johnson, Blennow, Zetterberg.

Acquisition, analysis, or interpretation of data: Ashton, Brum, Di Molfetta, Benedet, Arslan, Jonaitis, Langhough, Cody, Wilson, Carlsson, Montoliu-Gaya, Lantero-Rodriguez, Rahmouni, Tissot, Stevenson, Therriault, Pascoal, Lle贸, Alcolea, Fortea, Rosa-Neto, Johnson, Jeromin, Blennow, Zetterberg.

Drafting of the manuscript: Ashton, Brum, Arslan, Johnson.

Critical review of the manuscript for important intellectual content: Ashton, Brum, Di Molfetta, Benedet, Jonaitis, Langhough, Cody, Wilson, Carlsson, Vanmechelen, Montoliu-Gaya, Lantero-Rodriguez, Rahmouni, Tissot, Stevenson, Servaes, Therriault, Pascoal, Lle贸, Alcolea, Fortea, Rosa-Neto, Johnson, Jeromin, Blennow, Zetterberg.

Statistical analysis: Ashton, Brum, Jonaitis, Therriault.

Obtained funding: Tissot, Fortea, Rosa-Neto, Johnson, Zetterberg.

Administrative, technical, or material support: Ashton, Benedet, Jonaitis, Cody, Wilson, Carlsson, Vanmechelen, Montoliu-Gaya, Rahmouni, Tissot, Stevenson, Servaes, Therriault, Lle贸, Fortea, Rosa-Neto, Jeromin, Zetterberg.

Supervision: Ashton, Fortea, Blennow.

Conflict of Interest Disclosures: Dr Jonaitis reported grants from National Institutes of Health and tau tracer from Cerveau during the conduct of the study. Dr Langhough reported grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Cody reported grants from NIH during the conduct of the study. Dr Wilson reported grants from University of Wisconsin鈥揗adison during the conduct of the study. Dr Carlsson reported grants from NIH during the conduct of the study. Dr Lle贸 reported personal fees from Fujirebio-Europe, Roche, Biogen, Lilly, and Nutricia outside the submitted work and having had a patent for markers of synaptopathy in neurodegenerative disease licensed to ADx. Dr Alcolea reported grants from Fondo de Investigaciones Sanitario, Carlos III Health Institute, and Departament de Salut de la Generalitat de Catalunya during the conduct of the study; advisory board services and/or speaker honoraria from Fujirebio-Europe, Roche, Nutricia, Krka Farmac茅utica, Grifols, Lilly, Zambon, Esteve, and Neuraxpharm outside the submitted work; and having had a patent for EPI8382175.0 licensed to ADx. Dr Fortea reported grants from Fondo de Investigaciones Sanitario (FIS), Instituto de Salud Carlos III, NIH, and Horizon 2020 (European Commission) during the conduct of the study; personal fees from Roche, Novo Nordisk, Esteve, Biogen, Laboratorios Carnot, LMI, AC Immune, Alzheon, Lundbeck, and Lilly outside the submitted work; and having had a patent issued for WO2019175379 A1, 鈥淢arkers of synaptopathy in neurodegenerative disease,鈥� with royalties paid. Dr Rosa-Neto reported funding from the Weston Brain Institute, Canadian Institutes of Health Research (MOP-11-51-31, FRN, 152985); salary award from the Fonds de Recherche du Qu茅bec鈥揝ant茅 and Colin J. Adair Charitable Foundation; serving on the advisory board for Novo Nordisk, Eisai, and Eli Lilly; and serving as a consultant for Eisai and Cerveau Radiopharmaceuticals. Dr Johnson reported grants from NIH and advisory board fees from ALZpath during the conduct of the study, grants from Cerveau Technologies paid to his institution outside of the submitted work, and advisory board fees from Roche Diagnostics and Prothena outside the submitted work. Dr Jeromin reported equity from ALZpath and having had a patent pending for ALZpath. Dr Blennow reported having served as a consultant and at advisory boards for Acumen, ALZpath, BioArctic, Biogen, Eisai, Lilly, Moleac, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; having served at data monitoring committees for Julius Clinical and Novartis; having given lectures, produced educational materials, and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai, and Roche Diagnostics; and being a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Dr Zetterberg reported advisory board fees from AbbVie, Acumen, Alector, Alzinova, ALZpath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave Scientific; sponsored lecture fees from Cellectricon, Fujirebio, Alzecure, Biogen, and Roche; and being a co-founder and stockholder for Brain Biomarker Solutions in Gothenburg AB outside the submitted work. No other disclosures were reported.

Funding/Support: ALZpath provided the materials for this study at no cost. This work was supported by National Institutes of Health (NIH) grants (1R01AG056850-01A1; R21AG056974 and R01AG061566 to Dr Lle贸) and Department de Salut de la Generalitat de Catalunya, Pla Estrat猫gic de Recerca I Innovaci贸 en Salut (SLT006/17/00119 to Dr Fortea; SLT002/16/00408 to Dr Lle贸; SLT006/17/125 to Dr Alcolea). It was also supported by Horizon 2020鈥揜esearch and Innovation Framework Programme from the European Union (H2020-SC1-BHC-2018-2020 to Dr Fortea). Drs Lle贸, Alcolea, and Fortea were supported by the Fondo de Investigaciones Sanitario, Carlos III Health Institute (PI20/01330 to Dr Lle贸, PI18/00435 and INT19/00016 to Dr Alcolea, PI20/01473 to Dr Fortea) and the Centro de Investigaci贸n Biom茅dica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Program 1. Dr Blennow is supported by the Swedish Research Council (2017-00915 and 2022-00732), Swedish Alzheimer Foundation (AF-930351, AF-939721, and AF-968270), Hj盲rnfonden, Sweden (FO2017-0243 and ALZ2022-0006), Swedish state under the agreement between the Swedish government and the County Councils, ALF-agreement (ALFGBG-715986 and ALFGBG-965240), European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), Alzheimer鈥檚 Association 2021 Zenith Award (ZEN-21-848495), and Alzheimer鈥檚 Association 2022-2025 grant (SG-23-1038904 QC). Dr Zetterberg is a Wallenberg Scholar supported by grants from the Swedish Research Council (2022-01018 and 2019-02397), European Union鈥檚 Horizon Europe research and innovation programme (grant agreement 101053962), Swedish State Support for Clinical Research (ALFGBG-71320), Alzheimer Drug Discovery Foundation (201809-2016862), AD Strategic Fund, and Alzheimer鈥檚 Association (ADSF-21-831376-C, ADSF-21-831381-C, and ADSF-21-831377-C), Bluefield Project, Olav Thon Foundation, Erling-Persson Family Foundation, Stiftelsen f枚r Gamla Tj盲narinnor, Hj盲rnfonden, Sweden (FO2022-0270), European Union鈥檚 Horizon 2020 research and innovation programme (Marie Sk艂odowska-Curie grant agreement 860197, MIRIADE), European Union Joint Programme鈥揘eurodegenerative Disease Research (JPND2021-00694), National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and UK Dementia Research Institute at UCL (UKDRI-1003). The Wisconsin Registry for Alzheimer鈥檚 Prevention is supported by NIH grants AG027161 and AG021155.

Role of the Funder/Sponsor: ALZpath reviewed the manuscript before submission. Otherwise, the funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.

Additional Contributions: We thank Jeroen Vanbrabant, PhD, and Erik Stoops, PhD, from ADx Neuroscience, now Fujirebio, and the accelerator lab at Quanterix, for the initial prototyping of the ALZpath pTau217 assay.