Tau deposition patterns within the medial temporal lobe follow the connectivity of the entorhinal cortex – a combined post‐mortem and 7T fMRI study

Abstract

AbstractBackgroundIn aging, tau pathology develops in the medial temporal lobe (MTL), but spreads extensively to the cortex in the presence of amyloid‐beta, driving neurodegeneration and Alzheimer’s disease (AD) dementia development. This suggests that earliest age‐related MTL tau is a pre‐requisite for cortical tau spreading and the development of AD. Using tau‐PET in AD, we found previously that functional connectivity routes the cortical expansion of tau, supporting the concept of trans‐neuronal tau spreading. However, it is unclear whether MTL tau accumulation follows within‐MTL connections, in particular those of the entorhinal (EC) and transentorhinal cortex (A35), i.e. the earliest sites of tau accumulation. To address this, we combined post‐mortem histopathological MTL tau assessments with high‐resolution 7T functional MRI to determine MTL subregional connectivity.MethodWe included 3D post‐mortem quantitative histopathological tau assessments of 14 MTL subregions (Fig.1A) in 18 participants with overall low AD neuropathological change to capture earliest tau (Fig.1B), and 7T resting‐state fMRI from young and healthy controls (n = 29) to characterize MTL functional connectivity. Using post‐mortem data, we assessed the covariance of AT8‐stained tau among MTL subregions (Fig.1C) and assessed the correlation with functional connectivity among the same regions (Fig.1D). Further, we determined seed‐based connectivity to determine which MTL subregions connectivity pattern was the best predictor of MTL‐wide tau patterns.ResultPost‐mortem tau levels were highest in the amygdala, followed by A35 and the EC (Fig.2A). As hypothesized, we found an association between MTL connectivity and covariance in MTL tau (r = 0.42, p<0.001, Fig.2B), where closely connected regions showed correlated tau. When assessing seed‐based connectivity as a predictor of MTL tau patterns, EC connectivity was the best predictor for MTL tau deposition patterns (Fig.2C).ConclusionClosely connected MTL subregions show correlated histopathologically‐assessed tau load, suggesting connectivity to route earliest within MTL tau spreading. Despite highest tau in the amygdala, EC connectivity was the best predictor of MTL tau patterns, suggesting that the EC is a key source for within MTL tau spreading. This can be critical to assess EC connectivity as a potential treatment target to prevent cortical tau spreading and thus neurodegeneration and cognitive decline in AD.