Predictive value of plasma p-tau217 for Alzheimer’s dementia compared to other blood-based biomarkers

Blood-based multimodal biomarker models for differentiating early-onset Alzheimer’s disease from frontotemporal dementia: a longitudinal study of early-onset dementia and family members (LEAF) study

Plasma p-tau217 and p-tau181 are effective biomarkers for distinguishing biologically defined EOAD from EOFTD and adding NfL, GFAP, and APOE ε4 status further improves the discriminative accuracy for differentiating EOAD from EOFTD.

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 and NfL predict incident dementia in the community

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 for detecting Aβ-PET positivity and tracking early amyloid accumulation in cognitively unimpaired ADNI participants

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.

CSF p-tau205: a biomarker of Alzheimer's disease progression and biological staging.

Among soluble tau biomarkers, tau phosphorylation at position T205 (p-tau205) has been suggested to distinctly emergence across Alzheimer's disease (AD) continuum compared to other p-tau and non-phosphorylated tau forms, and a moderate relationship with both amyloid-β and tau aggregated pathologies. To evaluate this and further expand the characterization of this biomarker, we measured cerebrospinal fluid (CSF) p-tau205 using an in-house developed immunoassay in a total of 2069 samples from the BioFINDER-2 (n = 1364) and BioFINDER-1 (n = 705) cohorts. These two cohorts spanned the full AD continuum and were analyzed to assess cross-sectional and longitudinal associations with imaging and clinical measures. CSF p-tau205 levels were elevated in both biologically and clinically advanced disease stages. In Aβ-positive individuals, baseline p-tau205 levels correlated with Aβ-PET (R² = 0.28), tau-PET (medial temporal: R2 = 0.35, neocortical: R² = 0.29), cortical atrophy (R² = 0.15) and cognition (MMSE, R² = 0.15). Baseline p-tau205 predicted subsequent Aβ accumulation (R² = 0.44) and tau-accumulation measured by PET (R² = 0.33). Longitudinal p-tau205 levels increased more steeply longitudinally in Aβ-positive than Aβ-negative participants (β[95%CI] = 0.16[0.12-0.21], p < 0.001). Longitudinal p-tau205 changes were associated with cortical thinning (R² = 0.32) and cognitive decline (R² ≥ 0.41). When incorporating Aβ42/40, p-tau217 and p-tau205 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 (HR = 6.40[4.28-9.59]). These findings support CSF p-tau205 as a biomarker of Alzheimer's disease pathology and progression with potential value for biological staging.