Optimal Combinations of Biomarkers to Determine AT(N) in the Alzheimer’s Disease 

Abstract Background: National Institute on Aging—Alzheimer’s Association (NIA-AA) proposed the AT(N) system based on β-amyloid deposition, pathologic tau, and neurodegeneration, which considered the definition of Alzheimer’s disease (AD) as a biological construct. However, the associations between different AT(N) combinations and clinical stage and progression have been poorly explored systematically. The aim of this study is to compare different AT(N) combinations using recognized biomarkers within the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.Methods: A total of 341 participants from ADNI cohort were classified into AT(N) groups, including 200 cognitively unimpaired (CU) participants and 141 cognitively impaired (CI) participants (101 mild cognitive impairment [MCI] and 40 Alzheimer’s disease [AD]). CSF Aβ42 and amyloid-PET ([18F]flutemetamol) were used as biomarkers for A; CSF phosphorylated tau (p-tau) and tau-PET ([18F]flortaucipir) were used as biomarkers for T; CSF total tau (t-tau), FDG-PET, hippocampal volume, temporal cortical thickness and plasma neurofilament light (NfL) were used as biomarkers for (N). Binarization of biomarkers was acquired from Youden index and public cutoffs. The relationship between different AT(N) biomarkers combinations and cognitive changes (longitudinal Mini-Mental State Examination scores and Clinical Dementia Rating Sum of Boxes) was examined using linear mixed modeling and coefficient of variation.Results: Among CU participants, A−T−(N)− variants were most common. More T+ cases were shown using p-tau than tau PET, and more N+ cases were shown using fluid biomarkers than neuroimaging. Among CI participants, A+T+(N)+ was more common. Tau PET combined with cortical thickness best predicted longitudinal cognitive decline in CI and MRI measurements in CU participants. Conclusion: These findings suggest that optimal combinations of biomarkers to determine AT(N) are differed by clinical stage. Different biomarkers within a specific component for defining AT(N) cannot be used identically. Furthermore, different strategies for discontinuous biomarkers will be an important area for the future studies.