Application of the ATN classification scheme in a population without dementia: Findings from the EPAD cohort

Alzheimers Dement. 2021 Jul;17(7):1189-1204. doi: 10.1002/alz.12292. Epub 2021 Apr 3.


Background: We classified non-demented European Prevention of Alzheimer's Dementia (EPAD) participants through the amyloid/tau/neurodegeneration (ATN) scheme and assessed their neuropsychological and imaging profiles.

Materials and methods: From 1500 EPAD participants, 312 were excluded. Cerebrospinal fluid cut-offs of 1000 pg/mL for amyloid beta (Aß)1-42 and 27 pg/mL for p-tau181 were validated using Gaussian mixture models. Given strong correlation of p-tau and t-tau (R2 = 0.98, P < 0.001), neurodegeneration was defined by age-adjusted hippocampal volume. Multinomial regressions were used to test whether neuropsychological tests and regional brain volumes could distinguish ATN stages.

Results: Age was 65 ± 7 years, with 58% females and 38% apolipoprotein E (APOE) ε4 carriers; 57.1% were A-T-N-, 32.5% were in the Alzheimer's disease (AD) continuum, and 10.4% suspected non-Alzheimer's pathology. Age and cerebrovascular burden progressed with biomarker positivity (P < 0.001). Cognitive dysfunction appeared with T+. Paradoxically higher regional gray matter volumes were observed in A+T-N- compared to A-T-N- (P < 0.001).

Discussion: In non-demented individuals along the AD continuum, p-tau drives cognitive dysfunction. Memory and language domains are affected in the earliest stages.

Keywords: Alzheimer's disease (AD); European Prevention of Alzheimer's Dementia (EPAD); amyloid beta; amyloid/tau/neurodegeneration (ATN) staging; cognition; magnetic resonance imaging (MRI); neurodegeneration; neuroimaging; tau.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amyloid / cerebrospinal fluid*
  • Biomarkers / cerebrospinal fluid*
  • Europe
  • Female
  • Healthy Volunteers / statistics & numerical data*
  • Hippocampus / pathology*
  • Humans
  • Image Processing, Computer-Assisted
  • Magnetic Resonance Imaging
  • Male
  • Neuropsychological Tests / statistics & numerical data
  • tau Proteins / cerebrospinal fluid*


  • Amyloid
  • Biomarkers
  • tau Proteins