AbstractAmyloid-beta (Aβ) deposition and altered brain structure are the most relevant neuroimaging biomarkers for Alzheimer’s disease (AD). However, their spatial inconsistency was always confusing and misleading. Furthermore, the relationship between this spatial inconsistency and AD progression is unclear. The current study introduced a regional radiomics similarity network (R2SN) to map structural MRI and Aβ positron emission tomography (PET) images to study their cross-modal interregional coupling. A total of 790 participants (248 normal controls, 390 mild cognitive impaired patients, and 152 AD patients) with their structural MRI and PET images were studied. The results showed that global and regional R2SN coupling significantly decreased according to the severity of cognitive decline, from mild cognitive impairment to AD dementia. The global coupling patterns are discriminative between different APOE ε4, Aβ, and Tau subgroups. R2SN coupling was probed for relationships with neuropsychiatric measures and peripheral biomarkers. Kaplan–Meier analysis showed that lowerglobal coupling scorescould reveal worse clinical progression of dementia. The R2SN coupling scores derived from the coupling between Aβ and atrophy over individual brain regions could reflect the specific pathway of AD progression, which would be a reliable biomarker for AD.