Biomarkers

Abstract

Background: With the emergence of Alzheimer's disease (AD) disease-modifying therapies, identifying patients who could benefit from these treatments becomes critical. We evaluated whether a precise blood test could perform as well as established cerebrospinal fluid (CSF) tests in detecting amyloid-β (Aβ) plaques and tau tangles.

Method: Plasma %p-tau217 (ratio of phosporylated-tau217 to non-phosphorylated mid-region tau) was analyzed by mass spectrometry in the Swedish BioFINDER-2 cohort (n=1,422) and the US Knight ADRC cohort (n=337, Table 1). Matched CSF samples were analyzed with clinically used and FDA-approved automated immunoassays for Aβ42/40 and p-tau181/Aβ42. The primary and secondary outcomes were detection of brain Aβ or tau pathology (Braak I-IV), respectively, using PET imaging as the reference standard. Main analyses were focused on individuals with cognitive impairment (mild cognitive impairment and mild dementia), which is the target population for available disease-modifying treatments. We assessed accuracy, positive and negative predictive values, and sensitivity of each biomarker, using cut-offs derived at 90% specificity for a one cut-off approach. We also tested a two cut-off approach using cut-offs derived at 95% specificity and 95% sensitivity, classifying participants as positive (above higher cut-off), negative (below lower cut-off) or intermediate (between these two cut-offs).

Result: Plasma %p-tau217 was clinically equivalent to FDA-approved CSF tests in classifying Aβ PET status, with an area-under-the-curve (AUC) for both cohorts between 0.95-0.97 (Figure 1A-B). Plasma %p-tau217 was generally superior to CSF tests in classification of tau-PET with AUCs of 0.95-0.98 (Figure 1C-D). In cognitively impaired sub-cohorts (BioFINDER-2: n=720; Knight ADRC: n=50), plasma %p-tau217 had an accuracy, positive predictive value and negative predictive value of 89-90% for Aβ PET (Figure 2A) and 87-88% for tau-PET status (Figure 2C), which was clinically equivalent to CSF tests. These statistics further improved up to 95% using a two cut-off approach (Figure 2B-2D, respectively).

Conclusion: Blood plasma %p-tau217 demonstrated performance clinically equivalent or superior to clinically used FDA-approved CSF tests in the detection of AD pathology. Use of high performance blood tests in clinical practice can improve access to accurate AD diagnosis and AD-specific treatments.