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


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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.
Original languageEnglish
Article number2
JournalAlzheimer's Research and Therapy
Issue number1
Publication statusPublished - 1 Dec 2021


  • Alzheimer’s disease
  • CSF tau
  • Gaussian mixture modelling
  • Prognosis

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