Neurodegenerative tauopathies are characterized by distinct tau fibril structures that correlate with specific neuropathological phenotypes. ET, a progressive neurological disease, is associated with an elevated risk of dementia in cohort studies. Published postmortem studies demonstrate a higher tau burden in ET than matched controls. Understanding the structure of tau assemblies in ET may aid in developing diagnostic and therapeutic strategies, particularly in patients with cognitive decline.

To investigate the conformation of tau assemblies in essential tremor (ET) patients with tau pathology using a tau biosensor alanine (Ala) scanning approach, and to determine their structural similarity to tau assemblies in other tauopathies.

Eighteen ET patient brains with tau pathology were studied using tau biosensor assays, which measure tau seeding activity after incubation with brain homogenate. The structural classification of tau seeds was conducted using an Ala scanning approach, which systematically introduced serial Ala point substitutions in the tau monomer and then evaluated the incorporation of each mutant into seeded aggregates from ET patients. The results for ET cases were compared to other tauopathies, including Alzheimer’s disease (AD), primary age-related tauopathy (PART), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), and progressive supranuclear palsy (PSP).

Tau seeding above 5% was detected in 9 out of 18 patients (50.0%), and only one case had concurrent high amyloid-β (Aβ) plaque pathology. The amino acid requirements for tau monomer incorporation into aggregates from ET brains in our biosensor cells were identical to those found in AD and PART, but distinct from tau seeds in CBD, CTE, and PSP.

The tau assemblies in a subset of ET cases with significant tau pathology share structural features with those in AD and PART, suggesting a commonality in tau pathology across these conditions. This finding may lead to more accurate diagnoses and tailored therapies for ET patients experiencing cognitive impairment.