PTau heterogeneity as a measure for disease severity in incipient Alzheimer's disease

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AbstractBackgroundThe presence of p‐tau in biofluids has previously been proposed to be a response to neurofibrillary tangle pathology, one of the hallmarks of Alzheimer’s disease (AD). However, the increase of p‐tau in cerebrospinal fluid (CSF) precedes detectable neurofibrillary tangle pathology, as indexed by tau Positron Emission Tomography (PET), by up to a decade, suggesting that soluble tau could be an indication of early tau pathology. With this study, we investigated the heterogeneity of p‐tau species in CSF to assess the disease status of participants of the Translational Biomarkers of Aging and Dementia (TRIAD) cohort.MethodsSupport vector machines were used to determine cutoff values of p‐tau181, p‐tau217, p‐tau231 and p‐tau235 in CSF, identifying a group of participants that were amyloid positive (58 from a total of 165 participants). Amyloid positivity was determined by using an [18F]AZD4694 SUVR threshold value of 1.55 in the neocortex. Using these cutoff values, signatures were calculated on an individual level to identify the number of phosphorylated sites. Based on the number of phosphorylated sites, [18F]MK6240 SUVR maps and [18F]AZD4694 SUVR maps were calculated.ResultsWhen combining different CSF p‐tau species, the largest contribution in identifying amyloid positivity came from p‐tau217, followed by p‐tau231, p‐tau181 and p‐tau235. Achieving the cutoff for multiple p‐tau species was associated with more tau pathology particularly in the later Braak stages (fig 1) and increased amyloid‐β plaque accumulation (fig 2).ConclusionOur findings suggest that heterogeneity in p‐tau species carries predictive power in the identification of disease severity in incipient Alzheimer’s Disease.