Abstract
Alzheimer’s disease (AD) is characterised by a long preclinical phase. Although phosphorylated tau (p‐tau) species such as p‐tau217 and p‐tau231 provide accurate detection of early pathological changes, other biomarkers capable of staging disease progression during preclinical AD are still needed. Combining exploratory and targeted mass spectrometry methods in neuropathologically confirmed brain tissue, we observed that p‐tau235 is a prominent feature of AD pathology. In addition, p‐tau235 seemed to be preceded by p‐tau231, in what appeared to be a sequential phosphorylation event. To exploit its biomarker potential in cerebrospinal fluid (CSF), we developed and validated a new p‐tau235 Simoa assay. Using three clinical cohorts, we demonstrated that (i) CSF p‐235 increases early in AD continuum, and (ii) changes in CSF p‐tau235 and p‐tau231 levels during preclinical AD are consistent with the sequential phosphorylation evidence in AD brain. In conclusion, CSF p‐tau235 appears to be not only a highly specific biomarker of AD but also a promising staging biomarker for the preclinical phase. Thus, it could prove useful tracking disease progression and help enriching clinical trial recruitment.
Highlights
The 2018 world Alzheimer’s disease (AD) report estimated that 50 million people worldwide suffered from dementia and that the number of cases would triple by 2050, which is paralleled by an increase in the medical costs estimated as 2 trillion US$ by 2030
We report a novel biomarker discovery, p-tau235, starting from its quantitative assessment in AD brain tissue, followed by immunoassay development and quantification in cerebrospinal fluid (CSF)
By the combined use of exploratory and targeted IP-mass spectrometry (MS) approaches, we were able to identify and quantify a double-phosphorylated tau species containing p-tau235 in human brain tissue, which we demonstrated to be highly increased in AD
Summary
The 2018 world Alzheimer’s disease (AD) report estimated that 50 million people worldwide suffered from dementia and that the number of cases would triple by 2050, which is paralleled by an increase in the medical costs estimated as 2 trillion US$ by 2030. Juan Lantero-Rodriguez et al into intraneuronal neurofibrillary tangles (NFTs) and dystrophic neurites surrounding the plaques, which together represent the hallmarks of the disease (Braak & Braak, 1991; Thal et al, 2002). To this day, post-mortem examination confirming the presence of both NFTs and Ab plaques is required for definitive diagnosis of AD (Blennow et al, 2006; Jack et al, 2013). Decreased levels of CSF Ab1–42 reflect Ab burden in the brain as a result of its accumulation into plaques, whereas ptau181 and t-tau have been suggested to reflect increased tau phosphorylation and general tau secretion from Ab-affected neurons (both appear predictive of AD-type tangle pathology and neurodegeneration, respectively) (Molinuevo et al, 2018)
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