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Comprehensive Anatomical Staging Predicts Clinical Progression in Mild Cognitive Impairment: A Data-Driven Approach

R. Tandon,Yajun Mei,James J. Lah,Cassie S. Mitchell

Published 2025 in International Journal of Molecular Sciences

ABSTRACT

Alzheimer’s disease (AD) presents significant challenges in clinical practice due to its heterogeneous manifestation and variable progression rates. This work develops a comprehensive anatomical staging framework to predict progression from mild cognitive impairment (MCI) to AD. Using the ADNI database, the scalable Subtype and Stage Inference (s-SuStaIn) model was applied to 118 neuroanatomical features from cognitively normal (n = 504) and AD (n = 346) participants. The framework was validated on 808 MCI participants through associations with clinical progression, CSF and FDG-PET biomarkers, and neuropsychiatric measures, while adjusting for common confounders (age, gender, education, and APOE ε4 alleles). The framework demonstrated superior prognostic accuracy compared to traditional risk assessment (C-index = 0.73 vs. 0.62). Four distinct disease subtypes showed differential progression rates, biomarker profiles (FDG-PET and CSF Aβ42), and cognitive trajectories: Subtype 1, subcortical-first pattern; Subtype 2, executive–cortical pattern; Subtype 3, disconnection pattern; and Subtype 4, frontal–executive pattern. Stage-dependent changes revealed systematic deterioration across diverse cognitive domains, particularly in learning acquisition, visuospatial processing, and functional abilities. This data-driven approach captures clinically meaningful disease heterogeneity and improves prognostication in MCI, potentially enabling more personalized therapeutic strategies and clinical trial design.

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