MAPT and Alzheimer disease: This temporal shift aligns well with the known cascade of AD biomarkers: pathological amyloid and tau changes occur first (though not measured by our MRI-based model), then structural neurodegeneration in the cortex emerges, and finally widespread tissue loss and accumulated vascular injury appear as the disease progresses (Hadjichrysanthou et al., 2020; Jack et al., 2010).