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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC Berkeley Electronic Theses and Dissertations (2024)

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.

    Cover page: Functional networks in aging and Alzheimer’s disease: Contributions and consequences
    • Article
    • Peer Reviewed
    UC Berkeley Previously Published Works (2021)
    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 functional magnetic resonance imaging (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 (HC) and retrosplenial cortex (RsC), a key region of the medial parietal lobe, was associated with tau in medial parietal lobe. By contrast, connectivity between entorhinal cortex (EC) and RsC did not correlate with medial parietal lobe tau. Further, greater hippocampal-retrosplenial (HC-RsC) 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 EC to medial parietal lobe via the HC may represent a critical process in the evolution of cognitive dysfunction in aging and AD.SIGNIFICANCE STATEMENT The accumulation of tau pathology in the neocortex is a fundamental process underlying Alzheimer's disease (AD). 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 (HC) and retrosplenial cortex (RsC) 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 HC as the origin of medial parietal tau and implicate tau pathology in this region as a crucial marker of the beginnings of AD.
      Cover page: Hippocampal Connectivity with Retrosplenial Cortex is Linked to Neocortical Tau Accumulation and Memory Function.
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