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Ingala, Silvia; De Boer, Casper; Masselink, Larissa A.; Vergari, Ilaria; Lorenzini, Luigi; Blennow, Kaj; Chetelat, Gael; Di Perri, Carol; Ewers, Michael; Flier, Wiesje M. van der; Fox, Nick C.; Gispert, Juan Domingo; Haller, Sven; Molinuevo, Jose Luis; Muniz-Terrera, Graciela; Mutsaerts, Henri J. M. M.; Ritchie, Craig W.; Ritchie, Karen; Schmidt, Mark; Schwarz, Adam J.; Vermunt, Lisa; Waldman, Adam D.; Wardlaw, Joanna; Wink, Alle Meije; Wolz, Robin; Wottschel, Viktor; Scheltens, Philip; Visser, Pieter Jelle and Barkhof, Frederik (2021): Application of the ATN classification scheme in a population without dementia: Findings from the EPAD cohort. In: Alzheimers & Dementia, Vol. 17, No. 7: pp. 1189-1204

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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) epsilon 4 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.

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