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

This study aimed to characterize the clinical heterogeneity of Alzheimer's disease (AD) by implementing an integrated biological and clinical staging scheme for AD.

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.

Relative to the W₀ group, the W_- group showed a faster cognitive decline and higher progression risk (hazard ratio [HR]=2.40, 95% confidence interval [CI]=1.20-4.83), while the 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 α-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.

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.