Study: Tau Pathology Influences MBI Through Alterations in the Brain’s Salience Network

New research published in the Alzheimer’s Association’s journal, Alzheimer’s & Dementia, showcases new theories about what is happening in the brains of individuals who are experiencing signs of dementia-related behavior changes, even in the earliest stages. The study suggests that tau disrupts the integrity of the brain’s salience network, which is a “highway” of connections between specific regions of the brain that is significant in the ability to understand and decide how to react to what is happening around someone. This highway, according to the authors, helps individuals process their thoughts and emotions.^1,2

For this study, the investigators tested a novel model that assessed the direct relationships between Alzheimer disease (AD) biomarker status and mild behavioral impairment (MBI) symptoms, as well as mediated effects through segregation of the salience and default-mode networks. Two types of advanced medical imaging were used—functional MRI (fMRI) and positron emission tomography (PET) scans—to study the brains of 128 participants who were diagnosed with amnestic mild cognitive impairment or mild dementia, AD type. The fMRI traced the 3 different networks that connect far-flung areas of the brain, and the PET scans showed whether the participants’ brains contained excess tau protein as well as amyloid beta (Aβ).^1,2

According to the findings, a mediated effect of tau positivity on MBI through functional segregation of the salience network from other high-level, association networks. In particular, the investigators observed that those who were positive for both Aβ and tau demonstrated an overall lower segregation of the salience network compared with those who were AD biomarker negative.²

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“What we see is that the presence tau pathology relates to behavioral symptoms not in a direct relationship, but rather through dysfunction of a specific network in the brain—the salience network. The more affected this network is, the more severe the behavioral symptoms,” said lead author Alexandru D. Iordan, PhD, neuroscientist, department of psychiatry, University of Michigan Medical School, in a news release. “This is the first study that links the biomarker status of an individual with the dysfunction of this network, and behavioral symptoms, in people on the AD spectrum.”¹

Further, the investigators also observed that tau is a critical factor and may be the main driver of MBI-related symptoms. The authors note that these findings also build on prior research by identifying salience network dysfunction as a potential mechanism through which tau pathology influences MBI symptoms. Additionally, the findings offer a potential solution to prior inconsistencies demonstrated in research.²

According to the authors, the 1-time imaging of the 128 participants cannot show cause and effect, however, the association between tau, behavior change, and the salience network disruption are still worth investigating. Further research is also needed to determine whether the connection is present in other populations, to evaluate the change over time to assess what is happening within the pathways of connected brain cells that create the salience network, and to explore how it relates to the tau buildup and behavioral changes over the course of years. In addition, the investigators hope to test whether behavioral changes can be slowed in patients with early-stage dementia by targeting the salience network with mild magnetic fields or electrical currents that are applied from outside the skull and guided via precise imaging.^1,2

“Our findings provide us with a functional target for potential intervention,” said Iordan. “We will soon be able to see if brain stimulation changes these relationships thanks to a larger study…that evaluates the effects of different doses of weak electrical currents applied to the brain,” said Iordan in the news release. “This larger study is nearing completion, and we are very excited to see what the results show…”¹

REFERENCES

1. Michigan Medicine—University of Michigan. Brain network study reveals clues about dementia’s behavior changes. News release. October 7, 2024. Accessed October 11, 2024. https://www.eurekalert.org/news-releases/1060382

2. Iordan AD, Ploutz-Snyder R, Ghosh B, et al. Salience network segregation mediates the effect of tau pathology on mild behavioral impairment. Alzheimer's Dement. 2024;1-11. doi:10.1002/alz.14229