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We examined the cerebrospinal fluid (CSF) MTBR\u2010tau species in dominantly inherited Alzheimer's disease (DIAD) mutation carriers to assess the association with Alzheimer's disease (AD) biomarkers and clinical symptoms.<\/jats:p><\/jats:sec>Methods<\/jats:title>Cross\u2010sectional and longitudinal CSF from 229 DIAD mutation carriers and 130 mutation non\u2010carriers had sequential characterization of N\u2010terminal\/mid\u2010domain phosphorylated tau (p\u2010tau) followed by MTBR\u2010tau species and tau positron emission tomography (tau PET), other soluble tau and amyloid biomarkers, comprehensive clinical and cognitive assessments, and brain magnetic resonance imaging of atrophy.<\/jats:p><\/jats:sec>Results<\/jats:title>CSF MTBR\u2010tau species located within the putative \u201cborder\u201d region and one species corresponding to the \u201ccore\u201d region of aggregates in neurofibrillary tangles (NFTs) increased during the presymptomatic stage and decreased during the symptomatic stage. The \u201cborder\u201d MTBR\u2010tau species were associated with amyloid pathology and CSF p\u2010tau; whereas the \u201ccore\u201d MTBR\u2010tau species were associated stronger with tau PET and CSF measures of neurodegeneration. The ratio of the border to the core species provided a continuous measure of increasing amounts that tracked clinical progression and NFTs.<\/jats:p><\/jats:sec>Interpretation<\/jats:title>Changes in CSF soluble MTBR\u2010tau species preceded the onset of dementia, tau tangle increase, and atrophy in DIAD. The ratio of 4R\u2010specific MTBR\u2010tau (border) to the NFT (core) MTBR\u2010tau species corresponds to the pathology of NFTs in DIAD and change with disease progression. The dynamics between different MTBR\u2010tau species in the CSF may serve as a marker of tau\u2010related disease progression and target engagement of anti\u2010tau therapeutics. 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