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Background: Detection of biomarkers in the CSF has proven to be useful to follow and understand the metabolism of molecular actors of Alzheimer's disease (AD), as well as, for diagnosis purposes. Immunodetection is mostly used to detect and quantify these biomarkers but this approach has sometime a poor specify and a limited detection range of the different isoforms of the molecules. Hence, we are often missing the full spectrum of the presence and significance of the biomarkers in the cerebrospinal fluid (CSF). This is particularly true for the tau protein which is present in different isoforms and subjected to many modifications including truncation, hyper-phosphorylation or aggregation. Importantly, the understanding of tau metabolism and implication in AD pathology is a major challenge as this molecule is now a major therapeutic target and diagnosis biomarker. Methods: We developed a strategy termed Sequence Quantitative Analysis (SEQUANA) that combined the in-depth protein sequence analysis by sensitive multiplexing peptide capability of high resolution targeted mass spectrometry (MS) with protein absolute quantification. The method was applied to the full length MS quantification of the femto molar concentrations of the tau protein in CSF. It allowed without immunoprecipitation the highly reproducible, sensitive, quantitative follow-up of 22 peptides covering the all tau protein sequence. This approach was applied to the CSF of a cohort of memory clinics patients affected by various neurological disorders including FTLD, LBD or AD. Results: We could quantify in these clinical situations the relative presence of the different tau peptides corresponding the N-terminus, the central core, the C-terminus of the protein, some of them being exon (2, 3, 10) - isoform (0N,1N,2N,3R,4R) specific or the subject of phosphorylation. This allowed us to link the presence of truncated/modified tau isoforms to the different clinical diagnoses. The quantification of some specific peptides allowed us to differentiate AD from differential diagnosis even in the context of elevated tau. Conclusions: The MS detection of specific peptides encompassing the all tau protein sequence is a new analytical tool. When applied to the CSF of patients it demonstrated its interest to understand the pathophysiology of this protein and for diagnosis purposes.

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