Journal Article

Rates of clinical progression according to biological Alzheimer's disease stages

Gauthier, Serge, Vitali, Paolo, Hosseini, Seyyed Ali, Fernandez‐Arias, Jaime, Braskie, Meredith N., Trudel, Lydia, Meeker, Karin L., Aumont, Étienne, Macedo, Arthur C., Hall, Brandon, Toga, Arthur W., Servaes, Stijn, Pascoal, Tharick A., Zheng, Yansheng, Hsiao, Chris Hung‐Hsin, Wang, Yi‐Ting, Rahmouni, Nesrine, Bezgin, Gleb, Rosa‐Neto, Pedro, Therriault, Joseph, Hopewell, Robert, Chan, Tevy, Soucy, Jean‐Paul, O'Bryant, Sid E.

2025

Overview

INTRODUCTION Predicting the rate of cognitive decline and the likelihood of progression to dementia remains a critical unmet need in clinical settings. METHODS We assessed progression to mild cognitive impairment (MCI) and all‐cause dementia in 492 individuals from the TRIAD, ADNI, and HABS‐HD cohorts followed for an average of 2.49 years. Amyloid‐positive participants were staged according to the Alzheimer's Association biological staging framework (A+T2‐/A+T2MTL+/A+T2MOD+/A+T2HIGH+). RESULTS Cognitively unimpaired (CU) individuals in the A+T2MTL+, A+T2MOD+, and A+T2HIGH+ biological Alzheimer's disease (AD) stages were at significantly higher risk of clinical progression compared to non‐AD CU individuals. In individuals with MCI, advanced tau stage was associated with an 83% likelihood of developing dementia over 4 years. Biological AD staging demonstrated superior accuracy in predicting clinical progression compared to amyloid‐PET (positron emission tomography) status, tau‐PET status, and demographic information. All tau‐PET‐positive individuals showed a significantly faster rate of cognitive decline than non‐AD controls, with the A+T2HIGH+ stage showing the steepest rate of decline (p < 0.001). DISCUSSION Our results highlight the prognostic value of biological AD staging. Highlights Cognitively unimpaired (CU) individuals in all tau‐PET (positron emission tomography)–positive biological Alzheimer's disease (AD) stages were at significantly higher risk of clinical progression compared to individuals without AD. In individuals with mild cognitive impairment (MCI), only the A+T2HIGH+ stage reached a point where 50% of individuals had progressed to all‐cause dementia, after 2.36 years. Biological AD staging demonstrated superior accuracy in predicting clinical progression to dementia compared to other PET biomarkers and demographic information. All tau‐PET‐positive individuals showed a significantly faster rate of cognitive decline than individuals without AD, with the A+T2HIGH+ stage showing the steepest rate of decline.

• Subject: Aged / Aged, 80 and over / Alzheimer Disease - diagnostic imaging / Alzheimer Disease - pathology / Alzheimer's disease / Brain - diagnostic imaging / Brain - metabolism / Cognitive Dysfunction - diagnostic imaging / Cohort Studies / Disease Progression / Female / Humans / Longitudinal Studies / Male / Positron-Emission Tomography / prognostic value / risk of progression / tau Proteins - metabolism / tau‐PET imaging