Comparing the clinical utility and diagnostic performance of cerebrospinal fluid P-tau181, P-tau217 and P-tau231 assays

Background and Objectives: Phosphorylated tau (P-tau) in
cerebrospinal fluid (CSF) is considered an important biomarker in
Alzheimer’s disease (AD) and has been incorporated in recent
diagnostic criteria. Several variants exist, including P-tau
at threonines 181 (P-tau181), 217 (P-tau217) and 231
(P-tau231). However, no studies have compared their diagnostic
performance or association to amyloid-β (Aβ) and
Tau positron emission tomography (PET). Understanding which P-tau
variant to use remains an important yet answered question. We
aimed to compare the diagnostic accuracy of P-tau181, P-tau217 and
P-tau231 in CSF for AD and their association with Aβ and Tau-PET.
Methods: 629 subjects from the Swedish BioFINDER-2 study were
included (cognitively unimpaired, n=334; Aβ-positive mild cognitive
impairment, n=84; AD dementia, n=119; and non-AD disorders, n=92). In
addition to P-tau181 and P-tau217 measured using assays with the
same detector antibodies from Eli Lilly (P-tau181Lilly,
P-tau217Lilly) and P-tau231, we also included
P-tau181 measurements from two commonly used assays (Innotest and
Elecsys).  Results: Though all P-tau variants increased
across the AD continuum, P-tau217Lilly showed the greatest
dynamic range (13-fold-increase vs 1.9-5.4-fold-increase for other P-tau
variants for AD dementia vs non-AD). P-tau217Lilly showed
stronger correlations with Aβ- and Tau-PET (P<0.0001).
P-tau217Lilly exhibited higher accuracy than other P-tau variants
for separating AD dementia from non-AD (AUC, 0.991vs
0.906-0.982, P<0.0001) and for identifying Aβ- (AUC, 0.951
vs 0.816-0.924, P<0.0001) and Tau-PET positivity (AUC,
0.957 vs 0.836-0.938, P<0.0001).
Finally, P-tau181Lillygenerally performed better than the other
P-tau181 assays, (e.g., AD dementia vs non-AD, AUC, 0.976 vs
0.923, P<0.0001).  Discussion:
CSF P-tau217Lilly seem to be more useful than other
included P-tau assays in the work-up of AD. Varied results across P-tau181
assays also highlights the importance of anti-tau antibodies for biomarker
performance. Classification of evidence: This study provides
class II evidence that phosphorylated tau at threonine 217 provides higher
diagnostic accuracy for diagnosis of AD dementia than P-tau at threonine
181 or 231.