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Background  As Alzheimer’s disease (AD) pathology presents decades before dementia manifests, unbiased biomarker cut-points may more closely reflect presence of pathology than clinically defined cut-points. Currently, unbiased cerebrospinal fluid (CSF) tau cut-points are lacking.    Methods  We investigated CSF t-tau and p-tau cut-points across the clinical spectrum using Gaussian mixture modelling, in two independent cohorts (Amsterdam Dementia Cohort and ADNI) .Results  Individuals with normal cognition (NC) (total  n  = 1111), mild cognitive impairment (MCI) (total  n  = 1213) and Alzheimer’s disease dementia (AD) (total  n  = 1524) were included. In both cohorts, four CSF t- and p-tau distributions and three corresponding cut-points were identified. Increasingly high tau subgroups were characterized by steeper MMSE decline and higher progression risk to AD (cohort/platform-dependent HR, t-tau 1.9–21.3; p-tau 2.2–9.5).    Limitations  The number of subjects in some subgroups and subanalyses was small, especially in the highest tau subgroup and in tau PET analyses.    Conclusions  In two independent cohorts, t-tau and p-tau levels showed four subgroups. Increasingly high tau subgroups were associated with faster clinical decline, suggesting our approach may aid in more precise prognoses.

Four subgroups based on tau levels in Alzheimer’s disease observed in two independent cohorts