Intrinsic connectivity of the human brain provides scaffold for tau aggregation in clinical variants of Alzheimer's disease

Abstract

AbstractBackgroundPreclinical models suggest that tau pathology spreads intracellularly, thought to explain the topographical distribution of tau observed in Alzheimer’s disease (AD). However, these findings have yet to be extended to humans.MethodWe assessed 131 cognitively unimpaired elderly and 63 AD individuals who underwent amyloid‐PET with [18F]AZD4694, tau‐PET with [18F]MK6240, structural MRI, fMRI and diffusion‐weighted MRI. Of the subjects with AD, 11 had behavioural/ dysexecutive AD, 18 had PCA and 11 had Logopenic variant PPA, while 23 subjects had an amnestic presentation (all were Ab+/Tau+). A voxelwise multivariate regression model was employed to determine the peak difference in [18F]MK6240 SUVR between each AD variant and CU elderly, with each clinical diagnosis entered as a different categorical variable and correcting for age, gender and MMSE score. Within each AD variant, the peak voxels derived from the regression model were used to compute the correlation between [18F]MK6240 SUVR in the seed voxel and [18F]MK6240 SUVR in every voxel, thus generating an [18F]MK6240 covariance network for each AD group. The same seeds were also employed in functional connectivity and diffusion tractography analyses in the CU elderly group. To determine whether the topographical distribution of tau pathology is related to connectivity properties of the human brain, we applied regression models to assess the relationship between functional/structural connectivity values from the CU population and [18F]MK6240 in each variant of AD.ResultTau organization differed between AD groups, reflecting clinical phenotypes and organizing within distinct brain networks. Furthermore, structural (Figure 1) and functional (Figure 2) connectivity patterns of the human brain predicted in vivo [18F]MK6240 SUVR across the cerebral cortex in each variant of AD.ConclusionThese results support a framework in which the intrinsic connectivity of the human brain provides a scaffold for tau pathology to spread to anatomically distant regions.