Beyond statistical thresholds: Mapping sequential ATN cascade transitions via brain structural topography in Alzheimer’s disease
Year: 2026
Type: article
Abstract: Alzheimer's disease is widely conceptualized as a biological continuum initiated by amyloid-β (Aβ) accumulation, followed by tau aggregation and neurodegeneration. Although the ATN framework is commonly used to define disease stages, its static biomarker categories may not fully capture the dynamic pathological transitions that determine the optimal window for anti-Aβ therapies. Here, we introduce a Biological Continuum framework that distinguishes dynamic pathological cascades from static biomarker categories. Using neuroimaging-derived brain network topology, we identify four reproducible subgroups that exhibit distinct biological processes, biomarker signatures, and longitudinal cognitive trajectories. Integrated proteomic analyses suggest that these subgroups reflect sequential molecular transitions corresponding to early vulnerability, initiation, amplification, and terminal stages. Post hoc analysis indicates that slower cognitive decline after amyloid-targeting treatment was observed mainly in the initiation stage group. These findings provide a biologically grounded stratification system that captures disease dynamics overlooked by threshold-based models and offers mechanistic insight into the timing of anti-Aβ therapies.
Source: Science Advances
Institutions: Beijing University of Posts and Telecommunications, Qilu Hospital of Shandong University, Capital Medical University, Xuan Wu Hospital of the Capital Medical University, Brigham and Women's Hospital, Harvard University, Chinese PLA General Hospital, Tianjin Huanhu Hospital, Zhejiang Provincial People's Hospital, Hangzhou Medical College, Beijing Institute for Brain Disorders, Tianjin Medical University General Hospital, Tianjin Medical University, University of Chinese Academy of Sciences
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,500
Funders: U.S. Department of Defense, Alzheimer's Association, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Brigham and Women's Hospital, Biogen, University of Southern California, F. Hoffmann-La Roche, Meso Scale Diagnostics, Alzheimer's Disease Neuroimaging Initiative, BioClinica, Northern California Institute for Research and Education, GHR Foundation, National Natural Science Foundation of China, Beijing University of Posts and Telecommunications, Eisai, Servier, H. Lundbeck A/S, IXICO, National Institutes of Health, Genentech, Avid Radiopharmaceuticals, Canadian Institutes of Health Research, National Institute on Aging
Awards: G104586243, G1298807586, G1593117279, G1880935189, G2152643862, G2189010064, G2340207221, G2835601961, G29951154, G3131374986, G3146424788, G3553156159, G3710456697, G3752451908, G3870774570, G3908963977, G3966393351, G43180419, G4501223628, G5207404921, G5209990037, G5654639750, Alzheimer's Disease Neuroimaging Initiative, G5740349702, G6210868510, G6371410416, G6412110892, G6899163935, G6948409098, G7221832363, G7298697282, G7799614282, G781725486, G8414502683, G8852128998, G8895907669, G8897063270, G9000039018, G9000122335, G9000379370, G900504732
OpenAlex ID: W7159933073