Plasma p-tau181 accurately predicts Alzheimer's disease pathology at least 8 years prior to post-mortem and improves the clinical characterisation of cognitive decline

Abstract

The neuropathological confirmation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFT) remains the gold standard for a definitive diagnosis of Alzheimer's disease (AD). Nowadays, the in vivo diagnosis of AD is greatly aided by both cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers. Although highly accurate, their broad implementation is restricted by high cost, limited accessibility and invasiveness. We recently developed a high-performance, ultrasensitive immunoassay for the quantification of tau phosphorylated at threonine-181 (p-tau181) in plasma, which identifies AD pathophysiology with high accuracy. However, it remains unclear whether plasma p-tau181, measured years before the death, can predict the eventual neuropathological confirmation of AD, and successfully discriminates AD from non-AD dementia pathologies. We studied a unique cohort of 115 individuals with longitudinal blood collections with clinical evaluation at 8, 4 and 2 years prior to neuropathological assessment at death. The results demonstrate that plasma p-tau181 associates better with AD neuropathology and Braak staging than a clinical diagnosis 8 years before post-mortem. Moreover, while all patients had a diagnosis of AD dementia during life, plasma p-tau181 proved to discriminate AD from non-AD pathologies with high accuracy (AUC = 97.4%, 95% CI = 94.1-100%) even 8 years before death. Additionally, the longitudinal trajectory of plasma p-tau181 was assessed in all patients. We found that the main increases in plasma p-tau181 occurred between 8 and 4 years prior to death in patients with AD neuropathology and later plateauing. In contrast, non-AD pathologies and controls exhibited minor, albeit significant, increases in p-tau181 up until death. Overall, our study demonstrates that plasma p-tau181 is highly predictive and specific of AD neuropathology years before post-mortem examination. These data add further support for the use of plasma p-tau181 to aid clinical management in primary care and recruitment for clinical trials.

Keywords: Alzheimer’s disease; Blood biomarkers; Braak; Neuropathology; p-tau181.

Fig. 1

Study design. a The study design and timeline of sample collection, subsequent brain donation and plasma p-tau181 measurements. The current study included a total of 115 individuals from the Maudsley and King’s Healthcare Partners Dementia Case Register (DCR) and Alzheimer's Research UK (ARUK) cohorts, which underwent multiple clinical examinations between 2001 and 2012. To be included in the present study, individuals must have completed > 1 blood and clinical assessment via the DCR cohort and separately, a neuropathological assessment from the Medical Research Council (MRC) London Neurodegenerative Diseases Brain. Stored plasma samples were analysed for p-tau181 at clinical neurochemistry laboratory, Sweden. Plasma timepoints were specifically selected from each individual based on the time (in years) from the recorded date of post-mortem (b); timepoint 1 = 7.88 mean years (SD = 1.15, range = 6.33–9.43), timepoint 2 = 4.15 mean years (SD = 0.91, range = 2.90–6.05) and timepoint 3 = 2.08 mean years (SD = 0.70, range = 0.86–3.21)

Fig. 2

Plasma p-tau181 associates with post-mortem confirmed AD pathology. Plasma concentrations of p-tau181 categorised by clinical diagnosis (a) and neuropathological diagnosis given at post-mortem (b). The concentrations of plasma p-tau181 are shown at three different time points; 8 years, 4 years prior and 2 years prior to post-mortem. In a, the clinical diagnosis assigned at each timepoint are given on the x-axis and individual data points are colour coded according the neuropathological diagnosis given at post-mortem to visualise the disparity in clinical classification given at each visitation and underlying pathology uncovered at post-mortem; controls (blue), AD (red), non-AD (green). At timepoint 1, 111 individuals were included (control, n = 27; MCI, n = 6; AD, n = 78). At timepoint 2, 100 individuals were included (control, n = 24; MCI, n = 5; AD, n = 71). At timepoint 3, 87 individuals were included (control, n = 20; MCI, n = 5; AD, n = 62). In b, the neuropathological diagnosis given at post-mortem is on the x-axis with the same colour coding as (b)

Fig. 3

Plasma p-tau181 associates Braak staging. Plasma concentrations of p-tau181 categorised by Braak staging assigned at post-mortem (Braak I–II, Transentorhinal; Braak III–IV, Limbic; Braak V–VI, Isocortical). The concentrations of plasma p-tau181 are shown at three different time points; 8 years, 4 years prior and 2 years prior to post-mortem

Fig. 4

Plasma p-tau181 predicts AD pathology from non-AD pathology 8 years before post-mortem irrespective of clinical diagnosis. a A detailed breakdown of neuropathological classification of individuals at post-mortem on the x-axis and their corresponding plasma p-tau181 at timepoint 1 (8 years before post-mortem). ROC curves demonstrate the ability of plasma p-tau181 to separate AD (b) and mixed AD (c) from other neuropathological confirmed pathologies 8 years prior to post-mortem

Fig. 5

Longitudinal trajectories of p-tau181 are dependent on post-mortem pathology. A repeated measures one-way ANOVA demonstrated the longitudinal changes of plasma p-tau181 in AD, mixed AD, non-AD and controls confirmed at post-mortem