A multimodal examination of functional network health and its relationship with tau deposition

Abstract Alzheimer’s disease (AD) affects millions of people worldwide, and its prevalence is expected to increase dramatically in the coming years. Although some people are resilient to AD pathology with normal cognition despite tau and amyloid deposits, understanding the factors that drive such resilience will be critical for identifying

treatments for those at the highest risk of impairment. In the research proposed here, we will use cognitive neuroscience methods to develop a systems-level understanding of the mechanisms that underlie early-stage AD. We will examine tau deposition and functional network health in a sample of participants with normal

cognition to understand the etiology of AD and individual differences in cognitive resilience. Recent results have shown that tau is present in different parts of the brain in different people. Thus, we hypothesize that tau deposits in a particular brain network disrupt functional network health, and patients who appear cognitively normal

despite pathology have tau deposits in locations that have a minimal impact on functional networks. To test this hypothesis, we will use tau positron emission tomography (PET) to quantify the spatial distribution of tau pathology. We will also determine the role of brain network connectivity and atrophy in the health of a cohort

of diverse participants enriched for individuals at risk for AD. In Aim 1, we will use data from the publicly available Alzheimer's Disease Neuroimaging Initiative dataset to test our hypotheses by determining how tau deposits affect the health of pre-defined brain networks. We will measure functional network health based on network

segregation, neural dynamics, and cortical atrophy. In Aim 2, we will determine how segregation, dynamics, atrophy, and tau deposits affect network flexibility. We will recruit 150 cognitively normal participants aged 55 or older from diverse populations enriched in participants with blood markers indicating tau and, thus, at high risk

for developing AD. They will undergo tau PET and resting-state functional magnetic resonance imaging (fMRI) as part of a University of Alabama at Birmingham Alzheimer's Disease Center study and will undergo fMRI during an auditory/visual attention task. In Aim 3, we will determine how these variables interact to affect cognitive and

sensory performance and whether they predict longitudinal cognitive decline. Successful completion of this work will result in a better understanding of how tau deposits affect the normal patterns of brain activity and patterns of brain atrophy. These studies will provide new information on the mechanisms through which tau results in a

system-wide decline and the conditions that lead to resilience. This knowledge may suggest treatments for patients with AD and patient-specific training or behavior modification strategies that, applied early in the course of AD, could mitigate its long-term effects.