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

Silvia Ingala, Casper De Boer, Larissa A. Masselink, Ilaria Vergari, Luigi Lorenzini, Kaj Blennow, Gael Chetelat, Carol Di Perri, Michael Ewers, Wiesje M. van der Flier, Nick C. Fox, Juan Domingo Gispert, Sven Haller, Jose Luis Molinuevo, Graciela Muniz-Terrera, Henri J. M. M. Mutsaerts, Craig W. Ritchie, Karen Ritchie, Mark Schmidt, Adam J. SchwarzLisa Vermunt, Adam D. Waldman, Joanna Wardlaw, Alle Meije Wink, Robin Wolz, Viktor Wottschel, Philip Scheltens, Pieter Jelle Visser, Frederik Barkhof

Research output: Contribution to journalArticleAcademicpeer-review


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 (R 2 = 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.

Original languageEnglish
Pages (from-to)1189-1204
Number of pages16
JournalAlzheimer's and Dementia
Issue number7
Early online date2021
Publication statusPublished - Jul 2021

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