Biomarker-integrated prognostic stagings for Alzheimer's Disease.

Abstract

Accurately predicting disease progression remains a major challenge in Alzheimer's disease (AD). Here we show that a biomarker-integrated prognostic staging system can stratify progression risk across the disease course by jointly incorporating cognitive status, established risk factors, plasma biomarkers, and neuroimaging measures. In the K-ROAD cohort (N = 1,263), the dominant prognostic contributors varied by clinical context-GFAP in cognitively unimpaired individuals, hippocampal volume in mild cognitive impairment, and age in dementia-while plasma phosphorylated tau-217 provided consistent secondary prognostic information across stages. Outcome-specific staging captured clinically meaningful gradients of progression risk and informed construction of a unified six-stage framework (Stage 0-IVB) with distinct inflection points of accelerated decline. External validation in the ADNI cohort (N = 290) demonstrated consistent patterns of worsening prognosis, particularly in early and intermediate stages. This system provides a clinically interpretable approach to risk stratification and may serve as an exploratory framework for biomarker-integrated prognostic stratification in AD.