Time course of phosphorylated tau181 in blood across the Alzheimer’s disease spectrum

Abstract

Tau phosphorylated at threonine 181 (p-tau181) measured in blood plasma has recently been proposed as an accessible, scalable, and highly specific biomarker for Alzheimer's disease. Longitudinal studies, however, investigating the temporal dynamics of this novel biomarker are lacking. It is therefore unclear when in the disease process plasma p-tau181 increases above physiological levels and how it relates to the spatiotemporal progression of Alzheimer's disease-characteristic pathologies. We aimed to establish the natural time course of plasma p-tau181 across the sporadic Alzheimer's disease spectrum in comparison to those of established imaging- and fluid-derived biomarkers of Alzheimer's disease. We examined longitudinal data from a large prospective cohort of elderly individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n=1067) covering a wide clinical spectrum from normal cognition to dementia, and with measures of plasma p-tau181 and an [18F]florbetapir amyloid-β (Aβ) positron emission tomography (PET) scan at baseline. A subset of participants (n=864) also had measures of Aβ1-42 and p-tau181 levels in cerebrospinal fluid (CSF), and another subset (n=298) had undergone an [18F]flortaucipir tau PET scan six years later. We performed brain-wide analyses to investigate the associations of plasma p-tau181 baseline levels and longitudinal change with progression of regional Aβ pathology and tau burden six years later, and estimated the time course of changes in plasma p-tau181 and other Alzheimer's disease biomarkers employing a previously developed method for the construction of long-term biomarker temporal trajectories using shorter-term longitudinal data. Spline regressions demonstrated that earliest plasma p-tau181 changes occurred even before Aβ-markers reached abnormal levels, with greater rates of change correlating with increased Aβ pathology. Voxel-wise PET analyses yielded relatively weak, yet significant, associations of plasma p-tau181 with Aβ pathology in early-accumulating brain regions in cognitively healthy individuals, while the strongest associations with Aβ were observed in late-accumulating regions in patients with mild cognitive impairment. Cross-sectional and particularly longitudinal measures of plasma p-tau181 were associated with widespread cortical tau aggregation six years later, covering temporo-parietal regions typical for neurofibrillary tangle distribution in Alzheimer's disease. Finally, we estimated that plasma p-tau181 reaches abnormal levels approximately 6.5 and 5.7 years after CSF- and PET-measures of Aβ, respectively, following similar dynamics as CSF p-tau181. Our findings suggest that plasma p-tau181 increases are associated with the presence of widespread cortical Aβ pathology and with prospective Alzheimer's disease-typical tau aggregation, providing clear implications for the use of this novel blood biomarker as a diagnostic and screening tool for Alzheimer's disease.

The diagnostic and prognostic capabilities of plasma biomarkers in Alzheimer's disease

“…Yet, it must be recognized that further information on plasma P‐tau181 is required to fulfill these applications: optimal preanalytical conditions, optimal sample matrices type ( eg , EDTA plasma or serum), the influence of hemolysis, fasting versus non‐fasting sample collection, centrifugation conditions, and how freeze‐thaw cycles affect precision. Furthermore, although there are emerging data on longitudinal measures of P‐tau181, 19,41,44 including this study, how P‐tau181 concentrations fluctuate in serial sampling over a shorter period is not yet known.…”

Ultrasensitive assays for detection of plasma tau and phosphorylated tau 181 in Alzheimer’s disease: a systematic review and meta-analysis

“…We have to mention that some studies on ptau181 were recently published during the final revision of the manuscript, and were not included. These latest studies have investigated the dynamic changes of plasma ptau181 across the AD spectrum [100] and the relationship between polygenic risk scores for AD and plasma ptau181 [101]. They have also compared performance of ptau181 with other biomarkers in AD and MCI prediction [102] or amyloid PET status prediction [103].…”

Contrasting Metabolic Insufficiency in Aging and Dementia

“…These include analysis of peptides and metabolites, for example [120,121]. Tau may also be detected in serum [10,12,122]. The relative efficacy of several of these biomarkers has also been assessed for early detection of AD [61,103,115,122,123].…”