Background: In Alzheimer’s disease, early amyloid‐β and tau deposition may have differential downstream effects on synaptic function and neuronal loss in a stage‐dependent manner. Amyloid‐related synaptic changes are thought to precede tau accumulation, which starts in the medial temporal lobe before propagating and leading to neurodegeneration. We explored whether microstructural MRI measures can detect these different sequential cortical changes.Method: Seventy‐nine healthy, asymptomatic individuals, recruited from the Insight 46 study of the British 1946 birth cohort underwent combined PET/MR with [18F]florbetapir Aβ‐PET at ∼73yrs, and [18F]MK‐6240 tau‐PET at ∼76yrs. Standard uptake value ratios were calculated using a whole cerebellar reference for florbetapir and an inferior cerebellar reference for MK‐6240. Multi‐shell diffusion MRI was acquired; neurite orientation dispersion and density imaging was used to quantify neurite density (NDI) and orientation dispersion (ODI, a proxy measure of dendritic morphology/complexity), with DTI measuring mean diffusivity (MD), a less specific measure of degenerative change. PET and microstructural MRI biomarkers were assessed in a neocortical composite ROI and across Braak stages.Result: Thirty‐six participants were amyloid positive, 18 of whom were tau positive (eight Braak stage 1‐2, four Braak 3‐4, six Braak 5‐6). Across all participants, in the neocortical composite, significant differences between amyloid positive and amyloid negative individuals were found in both tau PET (p = 0.0092) and ODI (p = 0.030) but not for other measures. Within the amyloid positive group, in the cortical composite, significant differences in MD (p = 0.0093) but not ODI were seen when comparing those who were tau positive and negative. In the amyloid positive group, there was an association between tau PET and MD in the MTL (Braak 1‐2) (r = 0.34, p = 0.040) and Braak 3‐4 (r = 0.37, p = 0.025), with an association between tau and ODI (r = 0.48, p = 0.0031) in Braak 3‐4 only. After adjusting for volume, only the association between tau PET and ODI in Braak 3‐4 remained (p = 0.038).Conclusion: Our results are consistent with amyloid deposition causing dendritic/changes (as assessed by ODI) with consequent synaptic dysfunction. Later tau propogation is then associated with frank neuronal breakdown (as measured by MD). dMRI cortical imaging biomarkers have the potential to provide proxy measures of underlying AD stage/pathology prior to symptom onset.