Stage-specific regional distribution of amyloid and tau deposition across the Alzheimer’s disease continuum revealed by tau-to-amyloid ratio imaging

BACKGROUND: Amyloid-β and tau deposition follow distinct spatial and temporal trajectories across the Alzheimer's disease (AD) continuum. Amyloid accumulation occurs early in the disease course, whereas tau pathology is more closely associated with neurodegeneration and clinical progression. Characterizing stage-specific regional divergence between amyloid and tau deposition may refine biomarker-based disease staging and improve prognostic assessment. METHODS: F-MK-6240, and 3D MRI within a three-month interval. Participants were classified into cognitively normal amyloid-negative controls (CNA, n = 101) and the AD continuum (n = 102), comprising preclinical AD (PCA, n = 47), mild cognitive impairment due to AD (MCA, n = 24), and AD dementia (ADD, n = 31). Standardized uptake value ratios (SUVRs) were calculated using the Centiloid and CenTauR frameworks, and voxel-wise tau-to-amyloid ratio (TAR) images were generated. Voxel-wise and region-of-interest analyses were performed to compare regional patterns of amyloid deposition, tau accumulation, and TAR across disease stages. RESULTS: Amyloid deposition was already widespread at the PCA stage, involving the frontal, posterior cingulate/precuneus, and temporal cortices. In contrast, tau deposition in PCA was largely confined to the medial temporal lobe. With progression to MCA and ADD, tau burden increased substantially and extended to the lateral temporal, parietal, and frontal cortices. TAR analysis demonstrated high values in the medial temporal cortex at the PCA stage, followed by decreasing TAR in frontal regions during MCA and a tau-dominant neocortical pattern in ADD. CONCLUSIONS: Amyloid and tau exhibit distinct and stage-dependent regional dissociation across the AD continuum. TAR imaging effectively captures this divergence, reflecting early medial temporal tau predominance and subsequent neocortical tau expansion. These findings support the utility of integrated amyloid-tau PET metrics for refined disease staging and longitudinal therapeutic monitoring.