A new blood test termed p-tau217 shows promise as an Alzheimer’s disease biomarker, with very high accuracy when employed in a two-step workflow to either identify or exclude brain amyloidosis, the most common and early pathology. This is a new idea introduced by researchers at the University of Gothenburg in collaboration with colleagues from the University of Lund and Montreal, Canada.
A lot of effort has been spent on discovering biomarkers in blood that could potentially aid in identifying Alzheimer’s disease (AD) in recent years. Tau protein, particularly its phosphorylated variety (p-tau), has been the focus of intensive research and development in recent years and is one of the primary proteins involved in AD pathogenesis.
The new blood-based p-tau biomarkers, particularly p-tau217, have shown significant promise as clinically helpful tools for screening individuals with memory issues or other early cognitive symptoms suggestive of early Alzheimer’s disease.
The new blood-based p-tau biomarkers, particularly p-tau217, have shown significant promise as clinically helpful tools for screening individuals with memory issues or other early cognitive symptoms suggestive of early Alzheimer’s disease.
However, even if promising, there is concern that classifying early patients as having “AD or not AD” will result in a high percentage of false positives (individuals with a positive test result who do not have AD) and false negatives (individuals with a negative test result who have AD based on other examinations such as amyloid PET scans).
Considering not only ethical and psychological concerns induced by possible misdiagnosis but also the high costs and potential medical risks of initiating treatments on people not having the target disease), the scientists at the University of Gothenburg and their colleagues developed a novel strategy for the clinical implementation of blood biomarkers.
Two-step workflow
The two-step strategy is founded on a first step with a diagnostic model (based on plasma p-tau217 together with age and APOE e4) to stratify patients with moderate cognitive impairment (MCI) for risk of amyloid PET positive. Only individuals with unclear results in step 1 are subjected to confirmatory testing with a CSF Ab42/40 ratio (or amyloid EPT).
The approach was tested in 348 MCI subjects from the Swedish BioFINDER trials (Lund University) and validated in the independent TRIAD cohort (McGill University, Montreal, Canada) using an independent method for plasma p-tau217 analysis.
Very high accuracy
The model was evaluated at three different thresholding strategies that were explored to classify participants into groups with low, intermediate, and high risk for being “Aβ positive” (having AD-type pathology). At the stringent lower probability thresholds with 97.5% sensitivity (to avoid missing detection of patients who are Aβ positive), as little as 6.6% false negatives were found, while the stringent 97.5% specificity (to avoid classifying patients who are Aβ negative as ‘high risk’) gave only 2.3% false positives.
At the stringent sensitivity/specificity thresholds, 41% of patients fell into the intermediate risk group (compared to 29% of patients for the 95% thresholds). Further evaluations of this group with CSF Aβ42/40 showed very good agreement (86%) with amyloid PET results. Results were verified in the independent McGill cohort of patients.
A clinically useful strategy for p-tau217 blood test for AD screening
The work proposes a two-step blood plasma p-tau217-based approach for stratifying MCI patients into high, low, and intermediate risk of brain amyloidosis and early AD pathology. The blood test used in step 1 has a very high accuracy in identifying high-risk patients, who can then be given a diagnosis and started on symptomatic treatments, or referred to a specialist clinic for possible disease-modifying treatment.
Alzheimer’s disease can be ruled out with a high degree of certainty in the low-risk group. Because the intermediate risk group will only include about one-third of patients, the requirement for confirmatory CSF or PET tests at the specialized clinic will be significantly reduced, resulting in significant cost savings for society.
