BACKGROUND AND OBJECTIVES: Prion diseases can mimic Alzheimer disease (AD) at presentation. Alzheimer's Association AD diagnostic criteria suggest that a single abnormal highly specific plasma biomarker (including p-tau217) is sufficient for a biological diagnosis. We investigated the performance of AD plasma biomarkers in distinguishing AD and prion diseases. METHODS: We examined plasma biomarker data from patients with prion disease from a prospective cohort study recruited through the UK National Prion Clinic. Prion diseases were diagnosed clinically or with autopsy confirmation, and AD was diagnosed clinically with CSF biomarker confirmation. Plasma p-tau217, p-tau181, Aβ42/40 ratio, brain-derived tau (BD-tau), neurofilament light chain (NfL), and glial fibrillary acid protein (GFAP) were measured using Simoa. Median biomarker values in different groups were compared with Kruskal-Wallis test, and area under the receiver operating characteristic curve was used to compare accuracy in distinguishing prion diseases from sporadic AD (sAD). Lumipulse p-tau217 and NfL were measured in a validation study in a different laboratory. RESULTS: In the main study, we analyzed 345 samples from 278 individuals (mean age 58 SD 13.5, 48.2% female), including 204 with prion diseases (121 sporadic Creutzfeldt-Jakob disease CJD, 11 iatrogenic CJD, 9 variant CJD, 47 slow-progressing inherited prion disease (IPD) and 16 fast-progressing IPD), 33 with AD, and 41 healthy controls. For discriminating prion disease without AD copathology from sAD, none of p-tau217 (area under the curve AUC 95% CI 0.605 0.486-0.724), p-tau181 (AUC 0.554 0.446-0.661), or GFAP (AUC 0.514 0.389-0.640) performed well. Aβ42/40 discriminated moderately (AUC 0.770 0.684-0.856). NfL/p-tau217 ratio (AUC 0.996 0.987-1.000), NfL (AUC 0.988 0.974-1.000), BD-tau/p-tau217 ratio (AUC 0.963 0.929-0.996), and BD-tau (AUC 0.934 0.890-0.978) discriminated very well. In an independent validation study, consecutive samples were analyzed from 32 patients with sAD and 35 patients with sporadic Creutzfeldt-Jakob disease (mean age 65.0 SD 6.4, 56.7% female). NfL/p-tau217 again discriminated almost perfectly (AUC 0.986 95% CI 0.966-1.000). DISCUSSION: Plasma p-tau217 and p-tau181 are increased in both AD and prion diseases (regardless of burden of AD copathology). Diagnosing AD with a single abnormal p-tau plasma biomarker risks misdiagnosing prion diseases as AD. Plasma NfL/p-tau217 discriminates near-perfectly and could act as a flag to suspect prion diseases where this is a diagnostic possibility. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that plasma NfL/p-tau217 discriminates patients with CJD from those with AD.
Coysh et al. (Mon,) studied this question.