Clinical Implications of an Integrated Clinical and Biological Staging Scheme for Alzheimer's Disease

Abstract

Background and Purpose This study aimed to characterize the clinical heterogeneity of Alzheimer's disease (AD) by implementing an integrated biological and clinical staging scheme Methods Clinical staging was performed in 193 participants from the Alzheimer's Disease Neuroimaging Initiative based on cognitive scores, while biological staging was performed based on global tau deposition in tau positron-emission tomography (PET). The discrepancy between clinical and biological stages was quantified as standardized residuals (W-scores), and classified into the following groups: concordant clinical and biological stages (W0), worse clinical stage (W-), and better clinical stage (W+). Longitudinal changes in cognition, clinical progression, copathology burden, and brain metabolism on [18F]-fluorodeoxyglucose PET scans were compared between these groups. Results Relative to the W0 group, the W- group showed a faster cognitive decline and higher W+ group had a lower progression risk (HR=0.43, 95% CI=0.19-0.96). The copathology burden at autopsy (n=7) was correlated with the W-score (partial r=-0.87, p=0.023); however, this finding should be interpreted with caution due to the small sample. The ratio of cerebrospinal fluid alpha-synuclein positivity differed significantly between the groups, reaching 56.3% in the W- group. Brain metabolism in the occipital, orbitofrontal, dorsolateral frontal, inferior and medial temporal cortex, and precuneus was lower in the W- group than in the W0 group, whereas it was higher in the W+ group in the prefrontal, parietal, and temporal cortex. Conclusions The integration of clinical and biological staging has significant potential in clinical practice by providing information about copathologies, underlying neurodegeneration, and the progression of AD.