Neuroimaging Epicenters as Vulnerable Nodes in Plasma p-tau217/Aβ42-Positive Alzheimer's Disease

Plasma p-tau217/Aβ42 accurately captures the systemic molecular risk of Alzheimer's disease (AD) but lacks the spatial resolution necessary to predict individualized clinical trajectories. Here, we combined plasma biomarker stratification with normative connectome mapping to identify macroscale neurodegenerative epicenters and developed a personalized prognostic tool, the Network Vulnerability Index (NVI). Across the Alzheimer's Disease Neuroimaging Initiative and independent China ADNI cohorts, plasma p-tau217/Aβ42-positive individuals exhibited highly reproducible epicenters tightly anchored to the default mode network and limbic axis. Multiscale analyses revealed that this spatial vulnerability aligned with transcriptomic signatures of synaptic and mitochondrial dysfunction, monoaminergic receptor density gradients, and memory-related cognitive domains. Longitudinally, baseline epicenter centrality strictly dictated future localized atrophy rates. To translate these group-level topological constraints into a personalized prognostic metric, we utilized least absolute shrinkage and selection operator regression to formulate the NVI. Cross-sectionally, the NVI robustly tracked progressive tau-positron emission tomography accumulation (meta-temporal r = 0.547) and hippocampal atrophy (r = -0.455). Crucially, the NVI demonstrated robust, stage-dependent prognostic utility. When evaluated across the continuous disease spectrum, incorporating the NVI into a fully adjusted baseline model comprising plasma p-tau217/Aβ42 and APOE-ε4, and clinical scores significantly improved the prediction of conversion from mild cognitive impairment to dementia (hazard ratio = 1.47, P = 0.004), providing essential incremental prognostic value. Collectively, our spatially contextualized framework demonstrates that mapping systemic molecular risk onto structural network vulnerability supports a highly scalable "plasma pre-screen plus standard MRI" triage pathway for precision staging in Alzheimer's disease.