Aug 2026· Diagnostics· Vol 16, pp. 2702· 0 citations· 53 references
TL;DR
Plasma p-Tau217 showed a stronger association with cerebral amyloid pathology than eZIS indices in this elderly MCI cohort, and eZIS may provide complementary information regarding downstream neurodegenerative and cerebrovascular processes that are not directly captured by plasma biomarkers.
Abstract
(1) Background/Objectives: Blood-based biomarkers have emerged as practical tools for identifying Alzheimer’s disease (AD) pathology in patients with mild cognitive impairment (MCI). Among them, plasma phosphorylated Tau217 (p-Tau217) demonstrates strong associations with cerebral amyloid deposition. In parallel, the easy Z-score Imaging System (eZIS), a quantitative brain perfusion SPECT analysis tool, has been widely used to detect characteristic AD-related hypoperfusion patterns. Although both measures reflect distinct AD processes, the relationship between plasma p-Tau217 and eZIS in MCI remains unclear. (2) Methods: This retrospective study included 62 patients with MCI who underwent plasma p-Tau217 testing and brain perfusion SPECT with eZIS analysis. Associations between plasma p-Tau217 and the three eZIS indices (severity, extent, and ratio) were evaluated. Exploratory subgroup analyses were performed using a previously reported plasma p-Tau217 threshold of 0.63 pg/mL. In addition, a validation sub-cohort of 21 participants who underwent plasma p-Tau217 testing, eZIS, and amyloid PET was analyzed to assess concordance with cerebral amyloid pathology. (3) Results: Among the three eZIS indices, severity demonstrated the highest sensitivity relative to elevated plasma p-Tau217 levels. However, all eZIS indices showed limited discriminative performance. Optimal eZIS cutoff values derived from the present cohort were higher than previously reported thresholds. In the amyloid PET-validated sub-cohort, plasma p-Tau217 demonstrated closer concordance with amyloid positivity than any individual eZIS parameter. The reduced performance of eZIS appeared to be associated with advanced age, substantial vascular burden, white matter lesions, and cerebral atrophy. (4) Conclusions: Plasma p-Tau217 showed a stronger association with cerebral amyloid pathology than eZIS indices in this elderly MCI cohort. Nevertheless, eZIS may provide complementary information regarding downstream neurodegenerative and cerebrovascular processes that are not directly captured by plasma biomarkers. This integrated approach highlights plasma p-Tau217 as a primary screening tool for amyloid pathology to guide disease-modifying therapies (DMTs), alongside eZIS for tracking follow-up mixed co-pathologies.
Blood-based biomarkers could broaden access to Alzheimer’s disease diagnostics, but their ability to approximate tau PET, and to address gray-zone results, remains uncertain. We evaluated plasma p-tau217 against tau PET using a harmonized ADNI baseline cohort and an independently derived temporal meta-ROI tau-PET threshold. We included participants with complete baseline plasma biomarkers (p-tau217, Aβ42, Aβ40, NfL, GFAP), tau PET, and demographics, including: cognitively normal = 229, mild cognitive impairment = 149, and Alzheimer’s disease dementia = 41. ROC analyses assessed discrimination of tau-PET positivity overall and by diagnostic group. A two-cutoff strategy was implemented to minimize indeterminate classifications. Across the pooled cohort, p-tau217 demonstrated the strongest ability to discriminate tau-PET status (AUC 0.671, 95% CI 0.597–0.746), outperforming Aβ42, Aβ40, and Aβ42/Aβ40; Though overall accuracy remained moderate and performance differed based on diagnosis, with AUCs of 0.785 for Alzheimer’s disease dementia and lower values for cognitively normal and mild cognitive impairment. The two-cutoff approach substantially reduced intermediate classifications compared with conventional markers. In ADNI, plasma p-tau217 showed the highest discriminative performance among the single blood biomarker for detecting tau-PET positivity, showing moderate accuracy overall and its strongest performance in Alzheimer’s disease dementia. A two-cutoff approach substantially reduces gray-zone classifications, supporting p-tau217 as a primary screening tool before confirmatory imaging. Further work and validation are needed across different groups.
OBJECTIVE
Recent studies suggest that combining plasma phosphorylated tau (p-tau) with β-amyloid (Aβ) may improve diagnosis accuracy for Alzheimer's disease (AD). However, the cross-sectional and longitudinal concordance of these markers with Aβ positron emission tomography (PET) positivity remains incompletely understood. This study aimed to evaluate the diagnostic performance of plasma p-tau, alone and in combination with plasma Aβ, in AD.
METHODS
We included 326 participants from the Alzheimer's Disease Neuroimaging Initiative and 357 Chinese older adults from the Greater-Bay-Area Healthy Aging Brain Study who underwent Aβ-PET imaging. Longitudinal data were available for 285 Alzheimer's Disease Neuroimaging Initiative participants. Plasma p-tau181, p-tau217, Aβ42, and Aβ40 were measured on different analytical platforms. Diagnostic performance for Aβ-PET positivity was assessed using a two-cutoff approach.
RESULTS
Combining plasma p-tau with Aβ42 or the Aβ42/40 ratio reduced the intermediate zone. Notably, p-tau217/Aβ42 showed stronger agreement with Aβ-PET positivity than p-tau217 alone. Among individuals classified as p-tau217/Aβ42 positive but p-tau217 intermediate, 57.1 to 83.3% were Aβ-PET positive. Longitudinally, most Stable Positive (88.0-96.1%) and Stable Negative (89.4-90.9%) cases defined by p-tau217 or p-tau217/Aβ42 were Aβ-PET positive and Aβ-PET negative, respectively. Critically, 69.7 to 75.8% of Non-positive to Positive cases defined by p-tau217/Aβ42 were Aβ-PET positive.
INTERPRETATION
These findings provide novel insights into the cross-sectional and longitudinal diagnostic performance of plasma p-tau217/Aβ42 in AD. To be specific, plasma p-tau217/Aβ42 can reduce the intermediate zone and improve agreement with Aβ-PET positivity, and longitudinal p-tau217/Aβ42 monitoring is particularly informative for identifying Aβ-PET-positive patients who were p-tau217/Aβ42 negative or intermediate at baseline and were misclassified as low risk of AD. ANN NEUROL 2026.
Mingxing Jiang, Guoyu Lan, Jiayi Zhu et al.· Annals of Neurology· 0 citations
Amyloid-β (Aβ) accumulation begins before cognitive impairment, highlighting the need for scalable blood-based biomarkers to identify individuals at risk during the preclinical stage of Alzheimer's disease.
To evaluate whether plasma %p-tau217 detects Aβ-PET positivity and whether longitudinal plasma %p-tau217 change is associated with early Aβ accumulation in cognitively unimpaired participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI).
This retrospective longitudinal study included 98 cognitively unimpaired ADNI participants with plasma %p-tau217, plasma Aβ
42/40
, Aβ-PET, and clinical/genetic data. Aβ-PET positivity was defined as Centiloid (CL) ≥ 40. Among participants with baseline Aβ-PET <40 CL, participant-specific annual slopes for Aβ-PET CL and plasma biomarkers were estimated from matched longitudinal measurements using linear mixed-effects models. Regression and receiver operating characteristic analyses assessed associations with Aβ-PET change and discrimination of Aβ-PET positivity and Aβ accumulator status.
Plasma %p-tau217 showed excellent discrimination of Aβ-PET positivity (area under the curve (AUC) = 0.962) and yielded a higher AUC than plasma Aβ
42/40
. In participants with baseline Aβ-PET <40 CL, longitudinal plasma %p-tau217 slope was the only plasma biomarker independently associated with annual Aβ-PET CL increase in fully adjusted models (β = 1.38; FDR-adjusted p < 0.001). Plasma %p-tau217 slope also yielded a higher AUC for Aβ accumulator status than baseline plasma %p-tau217.
Plasma %p-tau217 is a strong blood-based biomarker for detecting Aβ-PET positivity in cognitively unimpaired individuals. Longitudinal plasma %p-tau217 change provides additional information beyond baseline plasma biomarkers and may support enrichment or monitoring strategies in Alzheimer's disease prevention trials, pending validation in larger independent cohorts.
E. Kazemi· Journal of Alzheimer's Disea...· 0 citations
P-tau217, NfL and GFAP showed strong associations with AD risk, especially within the first 9 years of follow-up, outperforming p-tau181, and over the later years of follow-up, the predictive accuracy of p-tau217 was significantly reduced.
K. Trares, D. Duman, L. Beyer et al.· EMBO Molecular Medicine· 0 citations
Background: Plasma phosphorylated tau at threonine 217 (p-tau217) has emerged as a promising minimally invasive biomarker for the biological detection of Alzheimer’s disease. This review aimed to evaluate the analytical platforms used for plasma p-tau217 measurement, their diagnostic performance, and the principal challenges associated with its implementation in clinical practice.
Methods: A structured narrative review of publications issued between 2019 and 2026 was conducted using PubMed/MEDLINE, Scopus, and Web of Science, with Google Scholar and reference-list screening used as supplementary sources. Studies evaluating plasma p-tau217 assays, analytical validation, diagnostic accuracy, comparison with positron emission tomography or cerebrospinal fluid biomarkers, and clinical implementation were included. Owing to substantial methodological and analytical heterogeneity, findings were synthesised narratively.
Results: Plasma p-tau217 showed high diagnostic performance for identifying amyloid and tau pathology and generally outperformed other phosphorylated tau isoforms. Mass-spectrometry-based measurement, particularly percentage p-tau217, demonstrated the highest analytical selectivity and diagnostic accuracy. However, fully automated immunoassays showed greater potential for routine laboratory use because of their higher throughput and reduced technical complexity. Diagnostic performance varied according to the assay, cut-off values, clinical setting, disease prevalence, and patient characteristics. A two-cut-off strategy improved classification while retaining an intermediate group requiring confirmatory testing.
Conclusions: Plasma p-tau217 may substantially improve access to biological Alzheimer’s disease diagnostics, but it should not be interpreted as a stand-alone test. Clinical implementation requires assay-specific validation, standardization, external quality control, and integration with clinical assessment and confirmatory diagnostic methods.
Oliwia Lenkiewicz, Julia Lenkiewicz, Z. Chmielewska et al.· International Journal of Inn...· 0 citations
BACKGROUND
Currently, no single biomarker can reliably identify preclinical Alzheimer's disease (AD), particularly at or before the mild cognitive impairment (MCI) stage. Given the heterogeneity of MCI, integrative approaches are needed to improve early risk stratification.
OBJECTIVES
(i) To derive robust latent cognitive components from a multicenter, clinically defined MCI cohort using principal component analysis (PCA); (ii) to investigate the associations between these components and plasma p-tau217 and p-tau181 levels.
METHODS
Data from 742 MCI participants in the AI-Mind cohort were analyzed. Cognitive domains were derived using PCA with varimax rotation and tested for associations with plasma p-tau biomarkers using site-specific linear regressions, adjusted for age, sex, and education.
RESULTS
A reproducible four-component cognitive structure emerged (memory, executive/processing speed, verbal fluency, visuospatial ability), with memory as the most p-tau-sensitive domain. The p-tau217 measure showed stronger associations with memory than p-tau181, though effects varied by site.
CONCLUSION
The findings indicate that a robust four-factor cognitive structure can be identified in clinically defined MCI cohorts without prior biological selection. The association between latent memory factors and plasma p-tau217, observed primarily in cohorts with higher biomarker burden or clearer amnestic profiles, highlights the potential for blood-based biomarkers to refine risk assessment in routine clinical practice.
Ana S. Perez, Hugo L. Hammer, V. Andersson et al.· GeroScience· 0 citations
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