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. 2025 Nov;21(6):502-513.
doi: 10.3988/jcn.2025.0218.

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

Young-Gun Lee  1 , Sung Woo Kang  2 , Sangwon Lee  3 , Seun Jeon  4 , Byoung Seok Ye  5 , Mijin Yun  3 ; Alzheimer's Disease Neuroimaging Initiative
Affiliations

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

Young-Gun Lee et al. J Clin Neurol. 2025 Nov.

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 for AD.

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 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.

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.

Keywords: Alzheimer's disease; copathologies; heterogeneity; metabolism; tau.

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Conflict of interest statement

Dr. Mijin Yun declares that she is the Chief Executive Officer of Newcure M, Inc. The other authors declare that they had no conflicts of interest.

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