CLOSED-LOOP SUPPRESSION OF EARLY NETWORK HYPEREXCITIBILITY FOR DEMENTIAS ASSOCIATED WITH TAUOPATHY

Aberrant accumulation of tau protein is implicated in many neurodegenerative diseases underscored by dementia, including Alzheimer’s Disease and primary tauopathies like Frontotemporal Dementia and Progressive Supranuclear Palsy, for which there are currently no disease-modifying therapies. These disorders share etiological overlaps with epilepsies and early network aberrations, such as subclinical epileptiform activity and overt seizures, have been detected years before cognitive decline in preclinical AD patients and genetically at-risk individuals. Network changes are associated with circuits inherently vulnerable to tau pathology and there is robust evidence to suggest the activity-dependent, cell-to-cell propagation of pathological tau is a primary driver of disease progression. Current therapeutic approaches fail to address tauopathies as disorders of early network dysfunction and a largely unexplored avenue for treatment is early modulation of networks that are transiently hyperexcitable. We use a genetic strategy to selectively suppress pathologically hyperactive circuits at the pre-symptomatic stage in a mouse model of tauopathy. Presymptomatic administration is sufficient in mitigating the onset of cognitive decline and downstream markers of pathology. We propose early network hyperactivity to be an actionable biomarker for the prophylaxis of tau-associated dementias and to enable the stratification of individuals with the highest risk for their inclusion in disease-modifying trials.