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

Abstract

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.

Figure 1. Box and whisker plots for observed baseline plasma p-tau181 concentration across the 3 groups.

The measured unadjusted plasma p-tau181 concentrations at baseline are shown. Mutation carriers have been divided into those who are symptomatic and those who are presymptomatic. A box shows the median, and 25^th and 75^th percentiles; the whiskers extend to the largest value less than or equal to the upper quartile + 1.5 times the interquartile range, and the smallest value greater than or equal to the lower quartile - 1.5 times the interquartile range; values outside this range are shown individually.

Figure 2. Age- and sex-adjusted receiver operating characteristic (ROC) curves

2a Symptomatic mutation carriers versus non-carriers. 2b Presymptomatic mutation carriers within 7 years of expected symptom onset versus non-carriers. Area under the curve (AUC) values are the probability that a randomly selected ’case’ (here, a symptomatic mutation carrier or a presymptomatic carrier within 7 years of expected onset, respectively) is ranked as being at greater risk of being a ’case’ than a randomly selected control of the same age and sex.

Figure 3. Trajectory of plasma biomarkers against estimated and actual years to/from onset.

Mutation carriers represented in red; non-carriers in black. Modelled changes in geometric mean plasma p-tau181 (a) and plasma NfL (b), for a hypothetical female aged 38·1 years (the average age of non-carriers), against estimated years to/from onset. Modelled changes in geometric mean plasma p-tau181 (c) and plasma NfL (d) against actual years to/from symptom onset for a hypothetical female carrier aged 38·1. There were 24 symptomatic subjects where actual age at onset was known, 19 of whom were already symptomatic at time of first plasma sampling and five subjects who became symptomatic after their baseline sample; for three of these plasma sampling took place before and after symptom onset. Dotted lines indicate 95% confidence intervals (a-d). Observed plasma p-tau181(e) and plasma NfL(e) concentrations against estimated years to/from symptom onset. To preserve blinding to genetic status of all observed values for timepoints more than 19 years before expected symptom onset and more than 10 years after expected symptom onset are shown in grey; some timepoints have been removed for at risk individuals who could be identified by their number of visits.