Plasma phospho-tau181 in presymptomatic and symptomatic familial Alzheimer’s disease: a longitudinal cohort study


Blood biomarkers have great potential to advance clinical care and accelerate trials in Alzheimer’s disease (AD). Plasma phospho-tau181 (p-tau181) is a promising blood biomarker however, it is unknown if levels increase in presymptomatic AD. Therefore, we investigated the timing of p-tau181 changes using 153 blood samples from 70 individuals in a longitudinal study of familial AD (FAD). Plasma p-tau181 was measured, using an in-house single molecule array assay. We compared p-tau181 between symptomatic carriers, presymptomatic carriers, and non-carriers, adjusting for age and sex. We examined the relationship between p-tau181 and neurofilament light and estimated years to/from symptom onset (EYO), as well as years to/from actual onset in a symptomatic subgroup. In addition, we studied associations between p-tau181 and clinical severity, as well testing for differences between genetic subgroups. Twenty-four were presymptomatic carriers (mean baseline EYO −9.6 years) while 27 were non-carriers. Compared with non-carriers, plasma p-tau181 concentration was higher in both symptomatic (p < 0.001) and presymptomatic mutation carriers (p < 0.001). Plasma p-tau181 showed considerable intra-individual variability but individual values discriminated symptomatic (AUC 0.93 [95% CI 0.85–0.98]) and presymptomatic (EYO ≥ −7 years) (AUC 0.86 [95% CI 0.72–0.94]) carriers from non-carriers of the same age and sex. From a fitted model there was evidence (p = 0.050) that p-tau181 concentrations were higher in mutation carriers than non-carriers from 16 years prior to estimated symptom onset. Our finding that plasma p-tau181 concentration is increased in symptomatic and presymptomatic FAD suggests potential utility as an easily accessible biomarker of AD pathology.

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Fig. 1: Box and whisker plots for observed baseline plasma p-tau181 concentrations across the three groups.
Fig. 2: Age- and sex-adjusted receiver operating characteristic (ROC) curves.
Fig. 3: Trajectory of plasma biomarkers against estimated and actual years to/from onset.


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AOC is supported by an Alzheimer’s Society clinical research training fellowship. TKK was supported by the Swedish Alzheimer Foundation, the Swedish Dementia Foundation, Gamla Tjänarinnor, the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation, and the Anna Lisa and Brother Björnsson’s Foundation. NJA is funded by the Wallenburg Centre for Molecular and Translational. NSR is supported by a University of London Chadburn Academic Clinical Lectureship. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931) and the UK Dementia Research Institute at UCL. This work was supported by the NIHR UCLH/UCL Biomedical Research Centre, the Rosetrees Trust, the MRC Dementia Platform UK and the UK Dementia Research Institute at UCL which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK.

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AOC, NCF did the literature search. AOC, TKK, KB, HZ and NCF designed the study. AOC, PSJW, NSR, IP and AK contributed to recruitment. Data were collected by AOC, PSJW and NSR. Blood samples were processed and analysed by AJH, EA, EC, IS, NJA, JLR, TKK and HZ. TP and CF carried out the statistical analysis. SM and JP contributed to the genetic analysis. TP created the figures. All authors were involved in the interpretation of results and writing the report.

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Correspondence to Henrik Zetterberg or Nick C. Fox.

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Conflict of interest

KB has served as a consultant or at advisory boards for Abcam, Axon, Biogen, Lilly, MagQu, Novartis and Roche Diagnostics, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. The other authors declare that they have no conflict of interest.

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O’Connor, A., Karikari, T.K., Poole, T. et al. Plasma phospho-tau181 in presymptomatic and symptomatic familial Alzheimer’s disease: a longitudinal cohort study. Mol Psychiatry (2020).

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