Rising Clinical Utility of Plasma P-Tau217 in Diagnosing Alzheimer Disease

Masoud Toloue, chief executive officer at Quanterix

As more novel treatments become approved for Alzheimer disease (AD), determining eligibility for these therapies remains an important need for cognitively impaired individuals where AD is a suspected etiology. Antiamyloid treatments like lecanemab (Leqembi; Eisai) and donanemab (Kisulna; Eli Lilly) currently require evidence of amyloid-ß (Aß) pathology from either PET or cerebrospinal fluid (CSF) to initiate treatment. Using the prevalence of Aß pathology from meta-analyses of memory clinic and research settings, a group of study authors determined the age- and clinical dementia syndrome positive predictive values (PPV) and negative predictive values (NPR) of different plasma biomarkers for amyloid pathology.

Published in Nature, the study included 6896 individuals from 11 cohort studies across 6 countries. The plasma biomarkers evaluated in the study included phosphorylated-tau (p-tau)161, p-tau217, p-tau231, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL), with p-tau181 assays from the University of Gothenberg and Quanterix. All told, p-tau217 demonstrated a strong ability to rule in Aß pathology in individuals with probable AD dementia, achieving a PPV above 95%. In mild cognitive impairment, its interpretation varied with patient age, while negative p-tau217 results effectively ruled out Aß pathology in non-AD dementia syndromes, with an NPR of 90% to 99%.

Nicholas J. Ashton, PhD

Following the publication, Masoud Toloue, chief executive officer at Quanterix, and Nicholas J. Ashton, PhD, senior director of the Banner Health Fluid Biomarker Program, provided commentary on the significance of the data, and the rising role of p-tau217 in diagnosing AD dementia. In the discussion, Toloue gave an overview of the most promising takeaways from the data, as well as some of the lesser known, significant findings that came about. In addition, he spoke on the Simoa technology needed to test for p-tau217, the growing knowledge of this biomarker, and the next steps in advancing and expanding this type of research.

NeurologyLive: What were the greatest takeaways from the study? Give some insight on the results and what clinicians should be aware of.

Masoud Toloue : With the increased attention on proteins as a diagnostic methodology, this study evaluated the utility of blood-based biomarkers, especially p-tau217, for detecting AD pathology in individuals with cognitive impairments. By analyzing data from nearly 7000 participants across six countries, the researchers determined that p-tau217 is highly accurate at ruling in or ruling out AD pathology based on specific clinical and demographic contexts.

Depending on the patient’s age, clinical syndrome, and APOE ε4 carrier status, p-tau217 demonstrated >95% PPV in ruling in AD and>90% negative predictive value NPV for ruling it out. Further, the authors were able to deduce that cutting-edge assays like GFAP and NfL complement p-tau217, highlighting the broader potential for multiplex diagnostic panels.

These findings are impactful as they help answer questions about the clinical value of blood-based biomarker tests. Clinicians have traditionally relied on outdated methods to diagnose AD by observing cognitive decline, at which point the disease has already likely caused irreversible brain damage. Hallmarks of the disease include amyloid plaques and hyperphosphorylated tau tangles in the brain, for which amyloid-PET scans and cerebrospinal fluid (CSF) tests have been traditionally relied upon to detect. Limited access and long delays hinder timely assessment by these innovative tools and thus, a delay in intervention during critical treatment windows for anti-amyloid therapies. Earlier diagnosis of AD is critical, as some treatments are more effective in the early stages.

Blood-based biomarkers provide actionable insights for clinicians facing patients with cognitive impairments, helping them streamline decisions. This enables clinicians to confidently determine a diagnosis without requiring multiple confirmation tests, saving precious time on the patient treatment journey.

Were there any lesser known findings that stood out among the data? Anything extra intriguing?

Masoud Toloue: The data further supports that in some contexts, p-tau217 can reduce reliance on costly PET scans and CSF testing, streamlining the diagnostic journey for AD and reducing burden on the health care system. Many patients face a long and difficult diagnostic journey before receiving an accurate diagnosis. The average diagnosis timeline for a patient with AD can take around 2.8 years, and about 75% of people with symptoms don’t even realize they have AD.

Scans and tests traditionally used to diagnose AD are often only available at specialized clinics and can take hours to complete. Removing this step from the diagnostic timeline narrows the gap between diagnosis and initiation of anti-amyloid therapies, which is crucial given the narrow therapeutic window. As the healthcare system collectively works to deliver better care while reducing costs and patient burden, this finding could have incredible impacts for future AD diagnostic journeys.

How can we easily and accurately test for p-tau217? Talk about the applicability of Simoa technology platform and how it can be used in clinical care settings.

Masoud Toloue: Blood-based biomarkers, particularly p-tau217, deliver highly accurate diagnostics, rivaling traditional methods. The non-invasive nature of this blood-based biomarker reduces patient burden and expands its accessibility globally. The Simoa technology, an ultra-sensitive immunoassay platform, serves as the backbone for the majority of p-tau217 tests on the market today.

Simoa technology can enable the detection of low-abundance biomarkers that were previously undetectable that are far lower than the Level of Quantification (LoQ) in fluid samples like plasma, CSF, and serum. This results in not only accelerating the drug approval process but also empowers clinicians to manage patient care with greater accuracy.

For neurological biomarkers, this level of detection is important as small changes are critical for diagnosing diseases such as AD, and with the Simoa technology, we’re able to track those subtle changes.

A routine blood draw is easily accessible in primary care settings, making blood-based biomarkers and the Simoa technology that is powering them a revolutionary tool with the ability to detect neurodegenerative diseases sooner to improve patient outcomes.

In recent years, how has our understanding and knowledge base grown regarding p-tau217?

Nicholas J. Ashton, PhD: The diagnostic utility of phosphorylated tau (p-tau) has long been recognized due to its established importance as a cerebrospinal fluid (CSF) biomarker for Alzheimer's disease(AD). Since the early 2000s, multiple p-tau phosphorylation sites, including p-tau199, p-tau231, and p-tau181, have demonstrated significant diagnostic value. These biomarkers have not only enhanced the ability to differentiate AD from other neurodegenerative disorders but have also played a central role in advancing our understanding of AD pathology. Notably, p-tau181 was incorporated into the diagnostic criteria for AD, underscoring its critical importance in clinical practice.

From 2018 onwards, advances in biomarker research translated findings from CSF to blood, allowing for the measurement of p-tau in plasma. Among these, p-tau181 and p-tau231 were initially adapted for blood-based assays, but subsequent studies consistently highlighted p-tau217 as a superior candidate. With higher diagnostic accuracy and predictive value, p-tau217 demonstrated robust performance across multiple immunological platforms. Unlike in CSF, where several p-tau isoforms provide equal value, blood-based biomarker studies increasingly emphasize the importance of p-tau217 for achieving superior diagnostic accuracy for AD, reflecting its remarkable sensitivity and specificity in detecting the disease at both preclinical and clinical stages.

Our current guidelines stipulate that blood biomarker testing should only be deployed in people who are demonstrating clinical symptoms. The two-tier biomarker testing system uses p-tau217 to stratify symptomatic individuals into low, intermediate, or high probability of Alzheimer's pathology, with confirmatory CSF or PET testing reserved for intermediate cases, which is reported to be around 15%.

As a clinical community, how do we expand on this type of research? What are the next steps and unanswered questions?

Nicholas J Ashton, PhD: There are multiple types of p-tau217 tests, all of which measure phosphorylated tau at position 217 but are designed with differing methodologies or partnering antibodies that detect the tau protein. Tests specifically designed to target the brain-derived portion of tau are more likely to reduce false positives caused by peripheral tau sources. While the advantage of such brain-derived tau-focused assays may not always be apparent in research studies with strict exclusion criteria, it becomes increasingly important in heterogeneous populations encountered in primary care settings. In these real-world contexts, where variability in peripheral tau levels and comorbid conditions is more prevalent, the use of such targeted tests can significantly enhance diagnostic accuracy and reliability.

P-tau is often seen as a marker of tau pathology, the secondary hallmark of AD. Yet, the relational correlation (not necessarily the causation) of p-tau in biofluids is stronger with amyloid pathology, the primary pathology of AD. Thus, the usefulness of p-tau217 to determine the level of neurofibrillary tangle pathology, which is required for some clinical trial designs, is debated. While p-tau217 can determine the presence of amyloid pathology, combinational biomarker models or new biomarkers targeting the microtubule-binding region (MTBR) of tau, may prove more useful in determining tau pathology.