Cerebrospinal fluid p-tau231 as an early indicator of emerging pathology in Alzheimer’s disease

Abstract

Biomarkers for early phosphorylation of tau constitute an unmet need for disease modifying intervention in early stages of Alzheimer’s disease (AD). Recent advances in targeted mass spectrometry and immunoassays have revealed phosphorylation sites, in the cerebrospinal fluid (CSF), with potentially greater utility as preclinical and diagnostic biomarkers as compared to the well validated biomarker – phosphorylated tau at threonine 181 (p-tau181). Phosphorylated tau (p-tau) epitopes in cerebrospinal fluid (CSF) are highly accurate biomarkers for Alzheimer’s disease (AD) neuropathology and are already increased before cognitive symptoms have manifested. However, it is unknown if these preclinical increases transpire earlier, prior to amyloid-beta (Aβ) positivity threshold, and if an ordinal sequence of p-tau epitopes occurs at this incipient phase. In this study, we measured cerebrospinal (CSF) p-tau181, p-tau217 and p-tau231 in 171 participants across the AD continuum compared to AD neuropathology as indexed by Ab ([18F]AZD4694) and tau ([18F]MK6240) position emission tomography. CSF P-tau217 and p-tau231 predicted Aβ and tau at the preclinical and dementia stages to a similar degree but p-tau231 attained abnormal levels first. P-tau231 was more sensitive to the earliest changes in Aβ in the medial orbitofrontal, precuneus and posterior cingulate cortices before global Aβ PET positivity had been achieved. Our findings demonstrate that CSF p-tau231 increases early in development of AD pathology and is a principal candidate for detecting incipient Aβ pathology for therapeutic trial application.

Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology

“…The horizontal grey bars shows the mean and 95% confidence intervals (CI) of plasma p-tau231 and p-tau181 as well as CSF p-tau217 in elderly individuals (CU, MCI, AD) segregated Aβ PET quartiles. Plasma p-tau231 showed abnormally increased levels from Aβ PET quartile 2 to 4; plasma p-tau181 in quartile 4, and CSF in quartiles [3][4] However, it demonstrated, much like the CSF comparisons that have preceded this study, that plasma p-tau231 was not significantly superior nor inferior to plasma p-tau181 in the aforementioned analysis. One exception to this being plasma p-tau231 being able to distinguish CU Aβ-positive participants from Aβ-negative MCI cases with higher accuracy and significantly superior to plasma p-tau181 (supplementary table 7, online resource).…”

“…This demonstrates that soluble tau, in CSF and plasma, is likely indicative of early tau pathology which is closely correlated with Aβ deposition. We have recently described the increase of different phosphoforms of tau in CSF in preclinical and prodromal disease [3,28,58]. In two independent studies [3,58], we found that CSF p-tau phosphorylated at threonine 231 (p-tau231) is a biomarker of very early tau pathology.…”

“…We have recently described the increase of different phosphoforms of tau in CSF in preclinical and prodromal disease [3,28,58]. In two independent studies [3,58], we found that CSF p-tau phosphorylated at threonine 231 (p-tau231) is a biomarker of very early tau pathology. CSF p-tau231 begins to increase concurrently with Aβ pathology in preclinical disease [58] and in Aβ-negative CU individuals shows focal associations with emerging Aβ pathology in the medial orbitofrontal, precuneus and posterior cingulate cortices [3].…”

“…In two independent studies [3,58], we found that CSF p-tau phosphorylated at threonine 231 (p-tau231) is a biomarker of very early tau pathology. CSF p-tau231 begins to increase concurrently with Aβ pathology in preclinical disease [58] and in Aβ-negative CU individuals shows focal associations with emerging Aβ pathology in the medial orbitofrontal, precuneus and posterior cingulate cortices [3]. To this end, given the successful translation of the CSF p-tau181 and CSF p-tau217 assays to blood tests, we hypothesized that the detection of p-tau231 in plasma would be possible, and further, would reflect the advantageous characteristics of CSF p-tau231 being a biomarker for very early AD pathology, which begins to increase before Aβ PET positivity is achieved.…”

The validation status of blood biomarkers of amyloid and phospho-tau assessed with the 5-phase development framework for AD biomarkers

“…Later studies have since confirmed that CSF p-tau181 can be used to differentiate AD from other dementias, such as frontotemporal dementia (FTD) and dementia with Lewy bodies [91][92][93]. Recently, five studies have shown that CSF p-tau217 perform somewhat better than CSF p-tau181 when differentiating AD from non-AD diseases [92][93][94][95][96]. These findings have now been largely replicated using blood p-tau.…”