TY - JOUR T1 - Hippocampal connectivity with retrosplenial cortex is linked to neocortical tau accumulation and memory function JF - The Journal of Neuroscience JO - J. Neurosci. DO - 10.1523/JNEUROSCI.0990-21.2021 SP - JN-RM-0990-21 AU - Jacob Ziontz AU - Jenna N. Adams AU - Theresa M. Harrison AU - Suzanne L. Baker AU - William J. Jagust Y1 - 2021/09/16 UR - http://www.jneurosci.org/content/early/2021/09/15/JNEUROSCI.0990-21.2021.abstract N2 - The mechanisms underlying accumulation of Alzheimer’s disease (AD)-related tau pathology outside of the medial temporal lobe (MTL) in older adults are unknown but crucial to understanding cognitive decline. A growing body of evidence from human and animal studies strongly implicates neural connectivity in the propagation of tau in humans, but the pathways of neocortical tau spread and its consequences for cognitive function are not well understood. Using resting state fMRI and tau PET imaging from a sample of 97 male and female cognitively normal older adults, we examined MTL structures involved in medial parietal tau accumulation and associations with memory function. Functional connectivity between hippocampus and retrosplenial cortex, a key region of the medial parietal lobe, was associated with tau in medial parietal lobe. By contrast, connectivity between entorhinal and retrosplenial cortices did not correlate with medial parietal lobe tau. Further, greater hippocampal-retrosplenial connectivity was associated with a stronger correlation between MTL and medial parietal lobe tau. Finally, an interaction between connectivity strength and medial parietal tau was associated with episodic memory performance, particularly in the visuospatial domain. This pattern of tau accumulation thus appears to reflect pathways of neural connectivity, and propagation of tau from entorhinal cortex to medial parietal lobe via the hippocampus may represent a critical process in the evolution of cognitive dysfunction in aging and AD.SIGNIFICANCE STATEMENTThe accumulation of tau pathology in the neocortex is a fundamental process underlying Alzheimer’s disease. Here, we use functional connectivity in cognitively normal older adults to track the accumulation of tau in the medial parietal lobe, a key region for memory processing that is affected early in the progression of AD. We show that the strength of connectivity between the hippocampus and retrosplenial cortex is related to medial parietal tau burden, and that these tau and connectivity measures interact to associate with episodic memory performance. These findings establish the hippocampus as the origin of medial parietal tau and implicate tau pathology in this region as a crucial marker of the beginnings of Alzheimer’s disease. ER -