Abstract
OBJECTIVE: In the 2018 ATN framework, Alzheimer's neurodegenerative biomarkers comprised cerebrospinal fluid (CSF) total tau, (18) F-fluorodeoxyglucose-positron emission tomography, and brain atrophy. We aimed to assess the clinical outcomes of having discordant Alzheimer's neurodegenerative biomarkers. METHODS: A total of 721 non-demented individuals from the Alzheimer's Disease Neuroimaging Initiative database were included and then further categorized into concordant-negative, discordant, and concordant-positive groups. Demographic distributions of the groups were compared. Longitudinal changes in clinical outcomes and risk of conversion were assessed using linear mixed-effects models and multivariate Cox proportional hazard models, respectively. RESULTS: Discordant group was intermediate to concordant-negative and concordant-positive groups in terms of APOE ε4 positivity, CSF amyloid-beta, and phosphorylated tau. Compared with concordant-negative group, discordant group deteriorated faster in cognitive scores (Mini-Mental State Examination, the Clinical Dementia Rating Scale-Sum of Boxes, and the Functional Activities Questionnaire) and demonstrated greater rates of atrophy in brain structures (hippocampus, entorhinal cortex, and whole brain), and concordant-positive group performed worse over time than discordant group. Moreover, the risk of cognitive decline increased from concordant-negative to discordant to concordant-positive. The results from longitudinal analyses were validated in A+T+, cognitively normal, and mild cognitive impairment individuals, and were also validated by applying different cutoffs and neurodegenerative biomarkers. INTERPRETATION: Discordant neurodegenerative status denotes a stage of cognitive function which is intermediate between concordant-negative and concordant-positive. Identification of discordant cases would provide insights into intervention and new therapy approaches, particularly in A+T+ individuals. Moreover, this work may be a complement to the ATN scheme.