MRI measures of cortical microstructural damage associate with tau accumulation in presymptomatic Alzheimer’s disease

Abstract Objectives Amyloid lowering therapies for Alzheimer’s disease are most effective in those without significant neocortical tau spread. Currently, the only method for anatomically staging tau is through PET scanning, which is largely unavailable in clinical settings. We assessed whether advanced MRI biomarkers of cortical microstructure may provide a more accessible option for assessing early neocortical tau accumulation. Methods 217 asymptomatic individuals underwent amyloid-β PET, tau PET and multi-shell diffusion 3T MRI. Neurite orientation dispersion and density imaging (NODDI) metrics including orientation dispersion index (ODI; a proxy measure of dendritic complexity), and free water fraction (FWF) were calculated. Analysis focused on a meta-temporal cortical composite region, the first site of neocortical tau beyond the medial temporal lobe (MTL). Results Meta-temporal tau burden was associated with meta-temporal ODI (Pearson’s r=-0.24, p=0.001), with a weaker association also seen with meta-temporal FWF (r=-0.14, p=0.07). Within the amyloid-β positive group, ODI discriminated between those with and without meta-temporal tau positivity (area under the curve=0.86). Discussion NODDI-derived ODI is associated with tau PET signal, even in preclinical disease and may discriminate individuals with-and without tau beyond the MTL. NODDI represents a potential alternative imaging tool for staging tau spread, aiding future treatment stratification and delivery.