Blood test for Alzheimer's risks misdiagnosing rarer brain disease

Alzheimers diagnostiska blodprövningar säkerställer inte diagnos när prionsjukdomar är närvarande. Studien från UCL:s prionklinik testade om plasmamarkörerna p-tau217, p-tau181 och GFAP — som Alzheimers föreningen godkänt som tillräckliga för biologisk diagnos — kan skilja prionsjukdomar från Alzheimers. Forskarna analyserade 345 blodprover från 278 individer: 204 med prionsjukdom (huvudsakligen sporadisk Creutzfeldt-Jakobs sjukdom), 33 med Alzheimers och 41 friska kontroller. P-tau217, p-tau181 och GFAP var opålitliga för särskiljning (AUC 0,51–0,61). Däremot presterade NfL-till-p-tau217-kvoten utmärkt (AUC 0,996) liksom BD-tau-markörerna. Resultaten påpekar ett kliniskt verklighetsproblem: diagnostiska algoritmer baserade på enkel p-tau217-förhöjning riskerar feldiagnoser när båda sjukdomarna kan efterlikna varandra. Laboratorier bör implementera flerplex-markörkombinationer för säker differentialdiagnostik.

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.