UC Berkeley

Alzheimer’s disease is characterized by two hallmark neuropathologies: A plaques and hyperphosphorylated tau protein. A tends to arise in a diffuse manner throughout cortex, whereas tau pathology accumulates in a stereotyped pattern first in medial temporal lobe and then in selectively vulnerable neocortical regions as the disease progresses. The processes facilitating the propagation of tau pathology are still unknown, but converging cellular and neuroimaging evidence suggests that tau spreads transneuronally along pathways of functional connectivity throughout the brain. In this work, we utilize multimodal human neuroimaging data in older adults without Alzheimer’s disease to investigate the factors involved in the spread of tau at the earliest stages of pathology accumulation. First, we measure resting state functional connectivity between hippocampus and medial parietal cortex to show that greater connectivity strength along this pathway is associated with downstream tau pathology burden cross-sectionally, with consequences for memory function. Next, we identify networks of functional connectivity specific to either episodic memory or executive function, and show that these networks are altered by the presence of tau pathology before widespread neurodegeneration is evident. Finally, we show that baseline connectivity strength and AD pathology interact to predict longitudinal rate of tau pathology accumulation and rate of cognitive decline in a multicohort sample of cognitively unimpaired older adults. Together, this work reveals that functional connectivity can be used to better understand the extent and distribution of the earliest tau accumulation, and outlines what effects this accumulation has on changes in functional brain networks and the cognitive domains they support.