Amyloid‐β–Related Cortical Susceptibility Alterations in Individuals Under Assessment for Alzheimer's Disease: A χ‐Separation Study

BACKGROUND: Assessment of amyloid-β (Aβ) burden and associated iron deposition and neurodegeneration is important for Alzheimer's disease (AD) management. Although quantitative susceptibility mapping (QSM) detects iron and myelin changes, conventional metrics suffer from signal cancelation between paramagnetic and diamagnetic components. Consequently, spatial interactions between these independent susceptibility sources and Aβ burden remain unestablished. PURPOSE: To investigate spatial associations between regional Aβ burden and independent paramagnetic and diamagnetic susceptibility sources using χ-separation. STUDY TYPE: Prospective. POPULATION: F-florbetapir). FIELD STRENGTH/SEQUENCE: 3 T/QSM (3-dimensional multi-echo gradient-echo sequence). ASSESSMENT: χ-separation decomposed QSM data into paramagnetic (χ-para) and diamagnetic (χ-dia) components. Centiloid-scale maps standardized PET quantification for voxel-wise analysis. The spatial relationship between Aβ load and susceptibility metrics was analyzed using voxel-wise correlations within AD-signature cortical regions. STATISTICAL TESTS: Voxel-wise spatial associations between Centiloid values and QSM metrics were evaluated using Pearson's coefficients. Spatial association was considered statistically significant if the 99% confidence interval (CI) did not cross zero. RESULTS: Conventional QSM showed near-zero cortical susceptibility and obscured pathological details owing to physiological cancelation. χ-separation unmasked susceptibility sources. Local Aβ deposition was consistently associated with reduced absolute χ-dia across cortical regions (mean r range: -0.267 to -0.098; all 99% CIs did not cross zero), consistent with alterations in net diamagnetic susceptibility sources, potentially involving myelin-related components. χ-para showed weaker and regionally heterogeneous associations with Aβ burden, with a positive association most evident in the precuneus (mean r = 0.072, 99% CI: 0.052-0.092). DATA CONCLUSION: χ-separation reveals region-specific cortical alteration associated with regional Aβ pathology. By separating these susceptibility sources, this method may provide complementary information to conventional QSM, offering a refined, noninvasive approach for characterizing amyloid-associated tissue changes in AD. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 2.