Cortical microstructural associations with CSF amyloid and pTau

Diffusion MRI (dMRI) can be used to probe microstructural properties of brain tissue and holds great promise as a means to non-invasively map Alzheimer's disease (AD) pathology. Few studies have evaluated multi-shell dMRI models, such as neurite orientation dispersion and density imaging (NODDI) and mean apparent propagator (MAP)-MRI, in cortical gray matter where many of the earliest histopathological changes occur in AD. Here, we investigated the relationship between CSF pTau₁₈₁ and Aβ_1-42 burden and regional cortical NODDI and MAP-MRI indices in 46 cognitively unimpaired individuals, 18 with mild cognitive impairment, and two with dementia (mean age: 71.8±6.2 years) from the Alzheimer's Disease Neuroimaging Initiative. We compared findings to more conventional cortical thickness measures. Lower CSF Aβ_1-42 and higher pTau₁₈₁ were associated with cortical dMRI measures reflecting less hindered or restricted diffusion and greater diffusivity. Cortical dMRI measures were more widely associated with Aβ_1-42 than pTau₁₈₁ and better distinguished Aβ+ from Aβ- participants than pTau+/- participants. Conversely, cortical thickness was more tightly linked with pTau₁₈₁. dMRI associations mediated the relationship between CSF markers and delayed logical memory performance, commonly impaired in early AD. dMRI measures sensitive to early AD pathogenesis and microstructural damage may elucidate mechanisms underlying cognitive decline.