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

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.

Automated summary

The study classified non-demented EPAD participants and assessed their neuropsychological and imaging profiles. Age and cerebrovascular burden progressed with biomarker positivity, with p-tau driving cognitive dysfunction and memory and language domains affected in the earliest stages.