Discordant Alzheimer's neurodegenerative biomarkers and their clinical outcomes

Abstract Objective In the 2018 ATN framework, Alzheimer's neurodegenerative biomarkers comprised cerebrospinal fluid (CSF) total tau, 18F‐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.