Patient‐tailored Alzheimer’s disease staging based on integrated biomarker timelines

Abstract

Background: Considerable evidence confirms the accumulation of fibrillar Amyloidβ(Aβ) and aggregates of hyperphosphorylated tau as early Alzheimer's Disease (AD) biomarker changes. However, the relationships between amyloid and tau within AD pathogenesis are not fully understood. Estimating the integrated order of these two biomarkers abnormality and identifying associations between two biomarkers in vivo could facilitate accurate prediction of patient-tailored prognosis in early disease stage. Method:We recruited 74 healthy controls, 75 MCI patients, and 38 AD patients with T1-weighted magnetic resonance image (MRI) and two PET scans ([ 18 F]Flortaucipir for tau and [ 18 F]Florbetaben for Aβ) with about two-year follow-up data. All regional Aβ and regional tau were aligned simultaneously in the order of posterior probabilities of biomarkers becoming abnormal using the DEBM algorithm. All participants were then labeled with disease staging score based on the integrated biomarker timelines. We then explored the relationship between the disease score at baseline and the patient's diagnosis in follow and annual change of CDR-SB scores.Result: Firstly, the integrated biomarker ordering shows a partially overlapped sequence of the Thal stage (in terms of the Aβ biomarker) and the Braak stage (in terms of the tau biomarker). Tau accumulates first within a region called the entorhinal cortex, then spreads out of that region. In the neocortical region (except the entorhinal cortex), the aggregation of amyloid precedes that of tau. Secondly, MCI patients' stage at baseline matches well with the diagnosis labels at the same time point, and also significantly correlates to the change of CDR-SB scores. Furthermore, MCI patients with higher disease stage scores at baseline have significantly higher chance to convert to AD at follow-up. Conclusion:In this study, we proposed in vivo temporal alterations of both regional amyloid and regional tau simultaneously. All biomarkers exhibited analogous trends to previous research. Amyloid aggregation generally occurs at early stages of the disease and seems to affect not tau seeding but initial tau spreading. Patient staging based on the integrated order of regional biomarker abnormality can help prediction of AD prognosis and future cognition change in early disease stage.