Aug 2026· Scientific Reports· Vol 16· 0 citations· 31 references
Medicine
Abstract
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, Guo-Yu Lan, Jiayi Zhu et al.· Annals of Neurology· 0 citations
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.
I-Lun Huang, Hiroshi Matsuda, Ya-Tang Pai et al.· Diagnostics· 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
Plasma p-tau217 showed high diagnostic performance for identifying amyloid and tau pathology and generally outperformed other phosphorylated tau isoforms, but it should not be interpreted as a stand-alone test.
Oliwia Lenkiewicz, Julia Lenkiewicz, Z. Chmielewska et al.· International Journal of Inn...· 0 citations
CSF p-tau205 as a biomarker of Alzheimer's disease pathology and progression with potential value for biological staging is supported and when incorporated into a conceptual CSF-based staging model, the final p-tau205-positive stage showed the strongest association with cortical atrophy, cognitive impairment, and risk of progression to dementia.
J. Lantero-Rodríguez, S. Janelidze, S. Palmqvist et al.· Molecular Psychiatry· 0 citations
Background & Objective: Plasma phosphorylated tau 217 (p-tau217) is an incredibly accurate blood test for Alzheimer's disease (AD). While calculating the p-tau217/amyloid-β42 (Aβ42) ratio is thought to enhance precision, its true clinical advantage over p-tau217 alone remains debated. This systematic review and meta-analysis evaluates whether the plasma p-tau217/Aβ42 ratio actually improves our overall ability to detect AD pathology.
Methodology: Following PRISMA guidelines, we searched PubMed, ClinicalTrials.gov, and the Cochrane Library. Studies were included if they directly compared the plasma p-tau217/Aβ42 ratio to p-tau217 alone, utilizing amyloid PET or cerebrospinal fluid biomarkers as the reference standard. The primary outcome was the reduction in intermediate (gray-zone) classifications. The secondary outcome was the mean difference (MD) in the area under the receiver operating characteristic curve (ΔAUC). Random-effects models were used to pool effect estimates using the R software.
Results: Nine studies comprising ten cohorts met the inclusion criteria. Seven cohorts (n=2,052 unique patients) contributed to the gray-zone analysis, and nine perfectly matched cohorts (n=3,886 unique patients, following the exclusion of one study utilizing an inverted ratio) contributed to the ΔAUC analysis. Compared with p-tau217 alone, the p-tau217/Aβ42 ratio significantly reduced intermediate "gray-zone" classifications (RR=0.75, 95% CI 0.60–0.93; I²=42.3%), representing a 25% reduction in diagnostically ambiguous results. No significant difference in overall diagnostic discrimination (AUC) was observed between the ratio and p-tau217 alone (MD=0.00, 95% CI −0.01 to 0.02; I²=0.0%). Leave-one-out sensitivity analyses confirmed these findings were highly robust.
Conclusion: The plasma p-tau217/Aβ42 ratio functions as an effective first-line screening tool that resolves ambiguous cases, significantly decreases gray-zone classifications, and increases diagnostic confidence. And it lowers the need for invasive confirmatory procedures, including lumbar punctures and costly PET scans. However, it does not significantly enhance absolute diagnostic discrimination (AUC) relative to p-tau217 alone.
Key Words: p-tau217/Ab42 ratio, Alzheimer’s Disease.
Adil Khan, Awais Ahmad, Usman Khan et al.· Journal of Saidu Medical Col...· 0 citations
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