Hippocampal connectivity with retrosplenial cortex drives neocortical tau accumulation and memory function

Abstract 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. Neural connectivity has recently been implicated in the propagation of tau in humans, consistent with data from animal studies. Using resting state functional connectivity and tau PET imaging, we examined MTL structures involved in medial parietal tau deposition in cognitively normal older adults. Functional connectivity between retrosplenial cortex and hippocampus, but not entorhinal cortex, correlated with tau in medial parietal lobe. Further, hippocampal-retrosplenial connectivity strength modulated the correlation between MTL and medial parietal lobe tau, as well as between medial parietal tau and episodic memory. Medial parietal tau spread thus reflects patterns of neural connectivity that represent a critical step in the evolution of cognitive dysfunction in aging and AD.