Tau buildup in progressive supranuclear palsy alters brain networks linked to thinking and behavior

Researchers at Japan's National Institutes for Quantum Science and Technology (QST) have found that tau buildup in progressive supranuclear palsy (PSP) may affect brain networks involved in thinking and behavior. The findings suggest that symptoms may arise not only from where tau builds up in the brain, but also from how those affected areas are connected to distant brain regions.

The study was published online on July 10, 2026, in Science Advances.

PSP is a rare neurodegenerative disease caused by the abnormal accumulation of tau, a protein associated with several forms of dementia. The disease often leads to falls, problems with eye movement, stiffness, and cognitive or behavioral symptoms such as reduced attention and difficulty controlling emotions.

A long-standing question in PSP is why patients develop cognitive symptoms even when tau is concentrated mainly in deep brain regions involved in movement. Many of the symptoms appear to involve the cerebral cortex, the outer layer of the brain that supports attention, decision-making, and flexible behavior, even when those cortical areas show little direct tau buildup.

To investigate this mismatch, the QST team combined tau positron emission tomography (tau PET) with brain network mapping. Using a tau PET tracer developed by QST, the researchers visualized tau deposits in 37 patients with PSP. They then combined each patient's tau-affected areas with brain connectivity data from 100 healthy individuals to identify distant regions that were functionally connected to the sites of pathology.

Although the precise locations of tau buildup differed from patient to patient, the affected regions were commonly connected to a shared set of cortical areas. These included the prefrontal cortex, anterior cingulate cortex, anterior insula, and parietal cortex-regions involved in executive functions such as attention, planning, inhibition, and behavioral control. The researchers call this shared circuit the "PSP-tau network."

The strength of the connection between each patient's tau deposits and this PSP-tau network was associated with the severity of frontal cognitive impairment. In contrast, the amount of tau in deep brain regions was associated with motor symptoms, such as eye movement problems, but not with the same cognitive symptoms. The findings suggest that movement and cognitive symptoms in PSP may arise through different mechanisms: local tau-related damage in motor-related regions and remote disruption of a broader cognitive network.

Our study began with a clinical question that could not be answered by looking only at where tau accumulates. We wanted to know whether local tau pathology could affect distant brain regions through neural circuits and whether that remote effect could explain the symptoms patients experience."

Dr. Toshiyuki Hirabayashi, Senior Principal Researcher at the Advanced Neuroimaging Center, QST

The results provide evidence that tau pathology in PSP can be linked to cognitive symptoms through a common remote brain network, even when the visible pattern of tau accumulation varies among patients. This circuit-based view may help explain why people with different patterns of brain pathology can develop similar symptoms.

The findings may also have implications beyond PSP. Tau buildup is a key feature of several neurodegenerative diseases, including Alzheimer's disease. If disease-related proteins can impair cognition by disrupting connected brain circuits, similar approaches could help identify symptom-related networks in other disorders and support more accurate prediction of disease-related changes.

"These results suggest that we should not view neurodegenerative disease only as damage at isolated spots in the brain," Dr. Hirabayashi said. "By identifying the circuits that connect pathology to symptoms, we hope to contribute to treatments that are better matched to each patient's condition."

In the longer term, this network-based view could help researchers better understand how tau-related diseases affect the brain and may support future efforts toward earlier diagnosis, more accurate symptom prediction, and more personalized treatment strategies.