New Blood Test Highly Accurate in Screening for Alzheimer’s

The key focus has been on the tau protein, particularly its phosphorylated form (p-tau), which is a significant player in AD pathology. These new blood-based p-tau biomarkers, especially one variant known as p-tau217, have displayed significant potential as valuable tools for screening individuals with memory issues or early cognitive symptoms hinting at early-stage AD. Despite its strong promise, there has been a concern that categorizing early-stage patients as either having "AD or not AD" could still yield a relatively high rate of false positives (positive test results in individuals without AD) and false negatives (negative test results in individuals who are later confirmed to have AD based on other assessments like amyloid PET scans).

Researchers from the University of Gothenburg (Gothenburg, Sweden), together with colleagues at University of Lund (Lund, Sweden), have developed an innovative strategy for the clinical implementation of blood biomarkers. Their strategy was designed after taking into account the ethical and psychological concerns arising from possible misdiagnoses, as well as the substantial costs and potential medical risks involved in initiating treatments for individuals who don't have the actual target disease. Their novel blood test, named p-tau217, has demonstrated potential as an Alzheimer's disease biomarker. Moreover, when employed in a two-step workflow, the test has shown impressive accuracy in either identifying or excluding brain amyloidosis, which is a critical and early pathology.

In the two-step model, the first step involves a diagnostic model (utilizing plasma p-tau217 along with age and APOE e4) to categorize patients with mild cognitive impairment (MCI) based on their risk of amyloid PET positivity. The second step involves confirmatory testing using CSF Ab42/40 ratio (or amyloid EPT), exclusively for those with uncertain outcomes in step 1. This framework was assessed using 348 MCI participants from the Swedish BioFINDER studies and then validated through the independent TRIAD cohort, utilizing an independent method for plasma p-tau217 analysis.

The researchers evaluated the model at three different thresholding strategies to classify participants into low, intermediate, and high-risk groups for being "Aβ positive" (indicating AD-type pathology). The use of stringent lower probability thresholds with 97.5% sensitivity (to avoid missing Aβ positive patients) revealed merely 6.6% false negatives. Conversely, adopting a stringent 97.5% specificity (to prevent categorizing Aβ negative patients as 'high risk') yielded merely 2.3% false positives. At these stringent sensitivity/specificity thresholds, around 41% of patients fell into the intermediate risk category (in contrast to 29% of patients for the 95% thresholds). Further analysis of this group using CSF Aβ42/40 demonstrated strong concordance (86%) with amyloid PET outcomes. These results were confirmed in the independent McGill patient cohort.

Thus, the study introduced a blood plasma p-tau217-based two-step model for stratifying MCI patients into high, low, and intermediate-risk categories for brain amyloidosis and early AD pathology. The application of the blood test in step 1 showed exceptional accuracy in identifying high-risk patients. Depending on the clinical context, these patients could either receive a diagnosis and commence symptomatic treatments or be referred to specialized clinics for starting potential disease-modifying treatments in the future. For the low-risk group, AD could be confidently ruled out. The intermediate-risk group will encompass only about one-third of patients, substantially reducing the need for confirmatory CSF or PET testing at specialized clinics and leading to cost savings for society. According to the researchers, this two-step model presents a clinically valuable approach for utilizing the p-tau217 blood test in AD screening.

Related Links:
University of Gothenburg 
University of Lund