In a recent study published in JAMA Neurology a group of researchers determined the utility of a novel and commercially available immunoassay for phosphorylated plasma tau 217 (p-tau217) to detect Alzheimer’s disease (AD) pathology and assess reference regions for abnormal amyloid β (Aβ) and longitudinal change in three selected cohorts.
Study: Diagnostic accuracy of a plasma phosphorylated Tau 217 immunoassay for Alzheimer’s disease pathology. Image credit: nobeastsofierce/Shutterstock.com
Record
Blood biomarkers have become essential in the diagnosis of AD, offering a more scalable option than cerebrospinal fluid (CSF) or positron emission tomography (PET) scans. They are particularly beneficial in settings with limited access to advanced testing, paving the way for early and accurate diagnosis and better patient management. p-tau, especially p-tau at threonine 217 (p-tau217), stands out as a leading blood biomarker. It excels in differentiating AD from other conditions and in detecting AD in cases of mild cognitive impairment, often outperforming other tau biomarkers.
As the medical community moves toward anti-Aβ therapies for dementia, validated blood biomarkers such as p-tau217 are critical to guide therapy. Further research is needed to validate plasma p-tau217 in various memory clinic populations, to address comorbidities to strengthen its clinical utility in AD.
About the study
The present study included participants from three observational cohorts: Translational Biomarkers in Aging and Dementia (TRIAD), the Wisconsin Registry for Alzheimer’s Prevention (WRAP), and the Sant Pau Initiative on Neurodegeneration (SPIN). Participants gave informed consent and the study complied with ethical guidelines and observational study reporting standards.
The 268 TRIAD participants included individuals without cognitive impairment, mild cognitive impairment (MCI), AD dementia, and non-AD dementia. The 323 WRAP participants were mostly without cognitive impairment, and the 195 SPIN participants ranged from nonimpaired controls to those with AD dementia.
Diagnoses conform to international criteria, with control participants scoring normally on neuropsychological assessments. Longitudinal follow-up included 392 participants from TRIAD and WRAP, classified into three groups based on amyloid and tau status.
The study conducted detailed imaging and biomarker measurements in the TRIAD, WRAP and SPIN cohorts, using standardized PET scans, CSF sample collections and various biomarker analyses, including p-tau231 and p-tau181. TRIAD and SPIN used Lumipulse for CSF biomarkers, while WRAP used the Roche NeuroToolKit. The study evaluated the new ALZpath pTau217 assay for p-tau217, demonstrating its reproducibility and accuracy.
Statistical analysis included linear models, receiver operating characteristics, and Spearman correlations, establishing a binary benchmark for Aβ-PET positivity and a three-region AD diagnostic strategy. Longitudinal p-tau217 trajectories were analyzed using linear mixed-effects models, incorporating factors such as cognitive status and amyloid-tau status, with results presented with 95% confidence intervals.
Study results
In the analysis of p-Tau217 levels by amyloid and tau status, it was found that plasma p-tau217 levels increased gradually in all cohorts, with the highest levels in the A+T+ group that is individuals who are positive for both A and tau biomarkers. This increase was consistent regardless of clinical diagnosis and was similarly observed when stratified by amyloid status alone.
The accuracy of plasma p-tau217 in distinguishing abnormal Aβ and tau pathologies was high. In TRIAD and WRAP, p-tau217 effectively predicted abnormal Aβ-PET signal, while in SPIN, it accurately predicted abnormal CSF Aβ42/40. For the detection of abnormal tau, p-tau217 showed high accuracy in TRIAD and WRAP and was effective in predicting abnormal CSF p-tau181 in SPIN. In addition, p-tau217 could identify abnormal tau PET signals among amyloid-positive TRIAD and WRAP participants.
When comparing p-tau217 with imaging and CSF biomarkers to identify AD pathology, plasma p-tau217 showed superior performance to hippocampal atrophy and tau PET in identifying abnormal Aβ PET. It also outperformed hippocampal volume in predicting abnormal tau-PET burden in all cohorts. In specific subsets, plasma p-tau217 was comparable to CSF ​​and imaging biomarkers in discriminating A+T+ from A+T− subjects.
Regarding the comparison of p-tau217 with other plasma biomarkers, p-tau217 alone or in combination with demographic variables was more effective than all other tested plasma biomarkers in predicting amyloid and tau status. Correlations of plasma p-tau217 with Aβ PET, tau PET and CSF p-tau217 were also investigated.
The study established reference ranges for plasma p-tau217 with abnormal Aβ and tau pathologies. A binary cut-off point for Aβ positivity was derived using the Youden index, and a three-region approach was applied to generate lower and upper cut-off points. This method improved positive percent agreement while maintaining a similar negative percent agreement. The study also showed a binary benchmark for tau positivity.
When examining longitudinal changes in plasma p-tau217 levels, significant increases were observed in the A+T+ group over time in the WRAP, with a higher annual rate of increase compared to the A−T− group. A similar pattern was seen in TRIAD, albeit at a shorter follow-up period. These findings suggest that plasma p-tau217 levels can effectively indicate changes in AD pathology over time.
