Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer's disease

Abstract

Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer's disease (AD), reflecting abnormal tau metabolism in the brain. Here we investigate the performance of CSF p-tau217 as a biomarker of AD in comparison to p-tau181. In the Swedish BioFINDER cohort (n = 194), p-tau217 shows stronger correlations with the tau positron emission tomography (PET) tracer [¹⁸F]flortaucipir, and more accurately identifies individuals with abnormally increased [¹⁸F]flortaucipir retention. Furthermore, longitudinal increases in p-tau217 are higher compared to p-tau181 and better correlate with [¹⁸F]flortaucipir uptake. P-tau217 correlates better than p-tau181 with CSF and PET measures of neocortical amyloid-β burden and more accurately distinguishes AD dementia from non-AD neurodegenerative disorders. Higher correlations between p-tau217 and [¹⁸F]flortaucipir are corroborated in an independent EXPEDITION3 trial cohort (n = 32). The main results are validated using a different p-tau217 immunoassay. These findings suggest that p-tau217 might be more useful than p-tau181 in the diagnostic work up of AD.

Fig. 1. CSF p-tau in diagnostic groups.

a CSF p-tau217, b CSF p-tau181, c CSF p-tau217/t-tau, and d CSF p-tau181/t-tau in CU Aβ⁺ (n = 25), CU Aβ⁺ (n = 40), MCI Aβ⁺ (n = 29), AD Aβ⁺ (n = 43) and non-AD neurodegenerative disorders (n = 57). Non-AD neurodegenerative disorders group included 10 PD, 17 PDD, 6 PSP, 7 DLB, 7 CBS, 4 SD, and 6 bvFTD patients. P values (unadjusted for multiple comparisons) are from univariate general linear models adjusted for age and sex; boxes show interquartile range, the horizontal lines are medians and the whiskers were plotted using Tukey method. Abbreviations: AD Alzheimer’s disease, bvFTD behavioral-variant frontotemporal dementia, CBS corticobasal syndrome, CSF cerebrospinal fluid, CU cognitively unimpaired controls, DLB dementia with Lewy bodies, MCI Mild Cognitive Impairment, PD Parkinson’s disease, PDD Parkinson’s disease with dementia, PSP progressive supranuclear palsy, SD semantic dementia.

Fig. 2. Associations between[¹⁸F]flortaucipir and p-tau.

a, b BioFINDER cohort, voxel-wise regression analysis of p-tau217 (a) and p-tau181 (b) vs [¹⁸F]flortaucipir corrected for age. c–e BioFINDER cohort, associations between [¹⁸F]flortaucipir retention in a priori defined brain regions linked to tau pathology in AD and CSF p-tau217 and p-tau181. f Validation cohort, associations between [¹⁸F]flortaucipir MUBADA SUVR and CSF p-tau217 and p-tau181. In c–f, data are shown as Spearman correlation coefficients (rho), lines are linear regression lines with 95% CI (shaded area). Differences between the correlation coefficients were tested using estimated Spearman coefficients and method described in Rosner et al.. Abbreviations: ROI region of interest, SUVR standardized uptake value ratio.

Fig. 3. Longitudinal changes in CSF p-tau across the Braak ROI groups.

Study participants were staged into different Braak ROI groups using [¹⁸F]flortaucipir PET. [¹⁸F]flortaucipir data was dichotomized based on the SUVR cutoff of 1.3. Annual changes in CSF p-tau217 (a), p-tau181 (b), t-tau (c), p-tau217/t-tau (d), and p-tau181/t-tau (e) in the Braak 0-I–II (normal [¹⁸F]flortaucipir retention or abnormal [¹⁸F]flortaucipir retention limited to ROI I–II, n = 69), III–IV (abnormal [¹⁸F]flortaucipir retention in ROIs III–IV, n = 16) and V–VI (abnormal [¹⁸F]flortaucipir retention in ROI V–VI, n = 12) groups. P values (unadjusted for multiple comparisons) are from Mann–Whitney test; boxes show interquartile range, the horizontal lines are medians and the whiskers were plotted using Tukey method.