PLASMA p-tau217 AS A MINIMALLY INVASIVE BIOMARKER FOR ALZHEIMER’S DISEASE DIAGNOSIS: ANALYTICAL PLATFORMS, DIAGNOSTIC PERFORMANCE, AND CLINICAL IMPLEMENTATION CHALLENGES

SELECTED BLOOD-BASED BIOMARKERS IN ALZHEIMER'S DISEASE: CLINICAL APPLICATIONS, DIAGNOSTIC UTILITY, AND IMPLEMENTATION CHALLENGES

Plasma biomarkers offer a transformative, non-invasive approach to early AD diagnosis and primary care triage, reducing reliance on CSF and PET scans and overcoming demographic and methodological limitations is essential for their widespread clinical adoption.

Diagnostic accuracy of plasma p-tau217 against amyloid PET: A meta-analysis of technical platform variability and ratio versus single marker comparisons

Analytical validation and amyloid-status discrimination of a high-throughput, research-use-only plasma p-Tau217 immunoassay

Cross-Sectional and Longitudinal Diagnostic Performance of Plasma p-tau217 and p-tau217/Aβ42 in Alzheimer's Disease.

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.

Plasma p-tau217 as a two-cutoff approach to improve tau-PET screening and trial recruitment in Alzheimer’s disease

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.

Plasma p-tau217/Aβ42 Ratio vs p-tau217 Alone in Alzheimer's Disease: A Systematic Review and Meta-Analysis

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.