Diagnostic performance and prediction of clinical progression of plasma phospho-tau181 in the Alzheimer’s Disease Neuroimaging Initiative

Abstract

Whilst cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers for amyloid-β (Aβ) and tau pathologies are accurate for the diagnosis of Alzheimer's disease (AD), their broad implementation in clinical and trial settings are restricted by high cost and limited accessibility. Plasma phosphorylated-tau181 (p-tau181) is a promising blood-based biomarker that is specific for AD, correlates with cerebral Aβ and tau pathology, and predicts future cognitive decline. In this study, we report the performance of p-tau181 in >1,000 individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU), mild cognitive impairment (MCI) and AD dementia patients characterized by Aβ PET. We confirmed that plasma p-tau181 is increased at the preclinical stage of Alzheimer and further increases in MCI and AD dementia. Individuals clinically classified as AD dementia but having negative Aβ PET scans did not show increased plasma p-tau181. Despite being a multicenter study, plasma p-tau181 demonstrated high diagnostic accuracy to identify AD dementia (AUC=85.3%; 95% CI, 81.4%-89.2%), as well as to distinguish between Aβ-and Aβ+ individuals along the Alzheimer's continuum (AUC=76.9%; 95% CI, 74.0%-79.8%). Higher baseline concentrations of plasma p-tau181 accurately predicted future dementia and performed comparably to the baseline prediction of CSF p-tau181. Longitudinal measurements of plasma p-tau181 revealed low intra-individual variability, which could be of potential benefit in disease-modifying trials seeking a measurable response to a therapeutic target. This study adds significant weight to the growing body of evidence in the use of plasma p-tau181 as a non-invasive diagnostic and prognostic tool for AD, regardless of clinical stage, which would be of great benefit in clinical practice and a large cost-saving in clinical trial recruitment.a Continuous variables are given as mean (SD) b Aβ status defined by Aβ PET. * p<0.05 compared with the Aβ+ AD group # p<0.05 compared with the Aβ-CU group Continuous variables were compared with one-way ANOVA followed by Tukey's post-hoc test. Categorical variables were compared with Chi test

Plasma biomarkers of Alzheimer’s disease predict cognitive decline and could improve clinical trials in the cognitively unimpaired elderly

“…The strengths of this study include the standardized collection and measurement of relevant biomarkers in both plasma and CSF—which allowed for direct comparison between biomarkers and across the two modalities—and the availability of multi-year follow-up data in a large number of participants. Our study improves in particular on previous studies linking novel plasma tau levels on their own with cognitive decline and neurodegeneration in similar populations 43,44 . Understanding the overlapping contributions of novel tau biomarkers is therefore a major contribution of our results.…”

“…7 This has led to an increasing focus on cognitively unimpaired (CU) older individuals at risk for progression to AD dementia on the basis of biomarker evidence of brain AD pathology. 8 Studies on combinations of blood-based Aβ42/Aβ40, P-tau and NfL have reported findings on their diagnostic accuracy for the separation of AD dementia from CU individuals and patients with non-AD disorders, 11,13,17-21 but data is lacking on their performance in predicting cognitive decline and clinical progression in CU individuals. We therefore tested the usefulness of plasma Aβ42/Aβ40, P-tau217, and NfL (separately and combined) for predicting cognitive decline and clinical outcomes in CU individuals who were followed longitudinally.…”

The validation status of blood biomarkers of amyloid and phospho-tau assessed with the 5-phase development framework for AD biomarkers

“…In the study by Janelidze et al, [80] it was found that individuals who had abnormal baseline levels of p-tau181 had a substantially increased risk of developing AD dementia in the future (HR = 10.9, 95% CI = 5.0-24.0). In a similar manner, using the ADNI data resource [113], higher plasma p-tau181 in MCI patients (HR = 22.75, 95% CI = 9.90-52.3) and Aβ + CU individuals (HR = 3.25, 95% CI = 1.12-9.40) had a greater risk of developing AD dementia over a 48-month period. The hazard ratios (HR) observed for plasma where similar for CSF results from the same patients (MCI, HR = 37.1, 95% CI = 15.0-91.8; HR Aβ + CU = 5.4, 95% CI = 1.8-16.3) [79].…”

“…The secondary aim 4 of phase 3 is to determine a biomarker testing interval for phase 4 if repeated testing is of interest. Longitudinal measurements of plasma p-tau have revealed low intra-individual variability, which could be of potential benefit in disease-modifying trials seeking a measurable response to a therapeutic target [25,98,106,113]. However, the stability of p-tau has not been common in all studies, namely in the longitudinal evaluation of familial AD [114], which may reflect different preanalytical protocols or a difference in how p-tau is expressed in familial AD.…”

Plasma biomarker profiles and the correlation with cognitive function across the clinical spectrum of Alzheimer’s disease

“…The cognitive performance is a pivotal indicator in AD management and efficacy evaluation. Previous studies found plasma Aβ 1-42 [10], NfL [11, 12], and p-tau181 [3, 4, 13] were significantly different in participants with mild cognitive impairment (MCI) and AD compared with participants with normal cognition (NC). However, few studies depicted plasma biomarkers’ profiles based on the cognitive performance and compared their discrepancy during the entire course of AD.…”