Authors
Kanhao Zhao, Hua Xie, Gregory A Fonzo, Nancy B Carlisle, Tovia Jacobs, Ricardo S Osorio, Arpana Church, Feng Vankee Lin, Yu Zhang, Alzheimer’s Disease Neuroimaging Initiative
Published in
Science advances. Volume 12. Issue 45. Pages eaed9351. Nov 06, 2026. Epub Nov 04, 2026.
Abstract
Identifying the neurobiological basis of cognitive vulnerability is essential for preventing Alzheimer's disease (AD). We derived the Alzheimer's Resilience-Vulnerability Connectome (ARC) by contrasting SuperAgers (SA), an extreme phenotype of preserved late-life memory, with AD using resting-state fMRI. ARC distinguished SA from AD in a discovery cohort (N = 290; AUC = 0.85) and replicated independently (N = 143), involving prefrontal, temporal, and insular networks and associating with brain age. Applied to cognitively unimpaired adults (discovery: N = 818; replication: N = 497), ARC-based subtyping revealed SA-like and AD-like subgroups with comparable baseline cognition but divergent longitudinal trajectories. AD-like individuals exhibited faster cognitive decline, greater amyloid-β accumulation, and higher AD conversion risk. Exploratory GWAS nominated CLYBL and FRMD6 as candidate novel loci associated with the subtype difference. These findings suggest that ARC captures a continuous connectomic dimension of cognitive aging spanning SA, cognitively typical aging, and AD, highlighting the potential of functional connectomic variation for early risk stratification in AD.
PMID:
42981415
Bibliographic data and abstract were imported from PubMed on 05 Nov 2026.
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