A highly accurate blood test for Alzheimer’s disease pathology has performance equivalent or superior to clinically used CSF tests

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.