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The initial presentation of prion diseases can mimic Alzheimer’s disease (AD). Recently revised AD diagnostic criteria state that a single abnormal highly-specific plasma biomarker (including p-tau217) is sufficient for diagnosis. We investigated the performance of AD plasma biomarkers in distinguishing AD and prion diseases.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 ultrasensitive immunoassay.We analysed 345 samples from 278 individuals, including 204 with prion diseases (121 sporadic CJD, 11 iatrogenic CJD, 9 variant CJD, 47 slow-progressing inherited prion disease (IPD) and 16 fast-progressing IPD), 30 with AD and 41 healthy controls.P-tau217 cannot discriminate prion diseases without concomitant AD neuropathology from AD (AUC [95%CI] 0.605 [0.486-0.724]), nor can p-tau181 (AUC 0.554 [0.446-0.661]) or GFAP (AUC 0.514 [0.389-0.640]). Aβ42/40 discriminates moderately (AUC 0.770 [0.684 - 0.856]). NfL/p-tau217 ratio discriminates near-perfectly (AUC 0.996 [0.987 – 1.000]) and NfL discriminates well (AUC 0.988 [0.974-1.000]) as does BD-tau (AUC 0.934 [0.890-0.978]).Diagnosis of AD on the basis of a single abnormal p-tau plasma AD biomarker would misdiagnose prion diseases as AD. Plasma NfL/p-tau217 ratio discriminates AD and prion diseases near-perfectly and could act as a flag to suspect prion diseases.thomas.coysh@nhs.net