In a recent study published in JAMA Neurology a group of researchers determined the utility of a novel and commercially available immunoassay for plasma phosphorylated tau 217 (p-tau217) to detect Alzheimer's Disease (AD) pathology and evaluate reference ranges for abnormal amyloid β (Aβ) and longitudinal change across three selected cohorts.
Study: Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology. Image Credit: nobeastsofierce/Shutterstock.com
Background
Blood biomarkers have become key in AD diagnosis, 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 precise 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 detecting AD in mild cognitive impairment cases, often outperforming other tau biomarkers.
As the medical community moves towards anti-Aβ therapies for dementia, validated blood biomarkers like p-tau217 are crucial for guiding treatment. Further research is necessary to validate plasma p-tau217 across diverse memory clinic populations, addressing comorbidities to enhance its clinical utility for AD.
About the study
The present study engaged participants from three observational cohorts: Translational Biomarkers in Aging and Dementia (TRIAD), Wisconsin Registry for Alzheimer's Prevention (WRAP), and Sant Pau Initiative on Neurodegeneration (SPIN). Participants provided consent, and the study complied with ethical guidelines and observational study reporting standards.
TRIAD's 268 participants included individuals with no cognitive impairment, mild cognitive impairment (MCI), AD dementia, and non-AD dementia. WRAP's 323 participants were mostly without cognitive impairment, and SPIN's 195 participants ranged from controls without impairment to those with AD dementia.
Diagnoses adhered to international criteria, with control participants scoring normally on neuropsychological evaluations. Longitudinal follow-up involved 392 participants from TRIAD and WRAP, classified into three groups based on amyloid and tau status.
The study detailed imaging methods and biomarker measurements across 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 utilized Lumipulse for CSF biomarkers, while WRAP used the Roche NeuroToolKit. The study evaluated the novel ALZpath pTau217 assay for p-tau217, demonstrating its repeatability and precision.
Statistical analysis included linear models, receiver operating characteristics, and Spearman correlations, establishing a binary reference point for Aβ-PET positivity and a three-range AD diagnosis strategy. Longitudinal p-tau217 trajectories were analyzed using linear mixed-effects models, incorporating factors like cognitive 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 stepwise across all cohorts, with the highest levels in the A+T+ group viz individuals who are positive for both A and tau biomarkers. This increase was consistent regardless of the clinical diagnosis and was similarly observed when stratifying by amyloid status alone.
The accuracy of plasma p-tau217 in discriminating 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 detecting abnormal tau, p-tau217 showed high accuracy in TRIAD and WRAP and was effective in predicting abnormal CSF p-tau181 in SPIN. Additionally, p-tau217 could identify abnormal tau PET signals among amyloid-positive participants in TRIAD and WRAP.
When comparing p-tau217 with imaging and CSF biomarkers in identifying AD pathology, plasma p-tau217 showed superior performance to hippocampal atrophy and tau PET in determining 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 with CSF and imaging biomarkers in discriminating A+T+ from A+T− individuals.
Regarding the comparison of p-tau217 with other plasma biomarkers, p-tau217 alone or combined with demographic variables was more effective than all other tested plasma biomarkers for predicting both amyloid and tau status. The correlations of plasma p-tau217 with Aβ PET, tau PET, and CSF p-tau217 were also explored.
The study established reference ranges for plasma p-tau217 with abnormal Aβ and tau pathologies. A binary reference point for Aβ positivity was derived using the Youden index, and a three-range approach was applied to create lower and upper reference points. This method improved the positive percent agreement while maintaining a similar negative percent agreement. The study also demonstrated a binary reference point for tau positivity.
In examining longitudinal changes in plasma p-tau217 levels, significant increases were observed in the A+T+ group over time in WRAP, with a higher annual increase rate compared to the A−T− group. A similar pattern was observed in TRIAD, albeit over a shorter follow-up period. These findings suggest that plasma p-tau217 levels can effectively indicate changes in AD pathology over time.
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