CSF phosphorylated tau‐217 is increased in Alzheimer’s and Creutzfeldt‐Jakob diseases and correlates with amyloid pathology

Abstract

AbstractBackgroundCerebrospinal fluid (CSF) phospho‐tau181 (p‐tau181) is an established biomarker of tangle pathology in Alzheimer’s disease (AD), but does not detect aberrant tau phosphorylation in other tauopathies. Recently, tau phosphorylation at threonine‐217 (p‐tau217) was suggested to be a superior biomarker for AD pathology. However, it is unclear if p‐tau217 is increased in other neurodegenerative diseases, including Creutzfeldt–Jakob disease (CJD) with concomitant amyloid/tau pathology or in primary tauopathies such as progressive supranuclear palsy (PSP).MethodWe validated an ultrasensitive Single molecule array (Simoa) p‐tau217 immunoassay and tested its diagnostic performance in the CSF of AD (n=110), CJD (n=22), and PSP (n=22) patients as well as age‐matched controls (n=106). Prospectively recruited patients were classified based on clinical presentation and the core CSF biomarker profile (amyloid‐beta‐42[Aβ1‐42 <650 pg/ml], [Aβ1‐42/Aβ1‐40 ratio<0.08], total‐tau <400 pg/ml and p‐tau181 >60 pg/ml) measured by INNOTEST® immunoassays (Fujirebio). Diagnostic performance was compared against INNOTEST® p‐tau181 using area under the curve (AUC).ResultThe in‐house p‐tau217 assay demonstrated a lower limit of quantification of 1.4pg/ml with robust analytical performance, including dilution linearity (mean recovery=104%), spike recovery (mean recovery=97%) and antibody specificity. P‐tau217 correlated strongly with p‐tau181 in all participants (r=0.82, p<0.0001) and showed six‐fold mean increase in both AD and CJD versus either controls or PSP (p<0.0001). In contrast, p‐tau181 was only increased 2.5‐fold in AD patients (p>0.05), but not CJD. P‐tau217 and p‐tau181 had similar performances in separating AD from controls (AUC>97%), and AD from PSP (AUC>95%). P‐tau217 poorly differentiated AD from CJD (AUC=63%, compared with 87% for p‐tau181) due to the highly overlapping p‐tau217 concentrations in both groups. However, p‐tau217 better distinguished CJD from controls (AUC=96%) compared with p‐tau181 (AUC=76%). Cross‐sectionally, p‐tau217 associated with CSF Aβ1‐42 (r= ‐0.76, p<0.0001). In diagnostic group‐stratified analyses, p‐tau217 correlated with Aβ1‐42/Aβ1‐40 only in AD (r= ‐0.31, p<0.05).ConclusionUnlike the AD‐specific p‐tau181, p‐tau217 had a very high diagnostic accuracy in distinguishing both AD and CJD from controls. P‐tau217 increases in CJD appear independent of amyloidosis. P‐tau217 identifies tau pathology in both diseases whilst p‐tau181 is useful for confirming AD diagnosis.