Tau pathology reprograms glucose metabolism to support cortical hyperexcitability, excitatory/inhibitory imbalance, and sleep loss.

Alzheimer's disease (AD) is not only defined by amyloid-β and tau pathology but by early metabolic disruptions and hyperexcitability. How tau independently reshapes the coupling of metabolism-excitability to impact processes like sleep remains unclear. Here, hyperphosphorylated tau preserves whole-body metabolic function while driving cortical hyperexcitability and sleep loss in mouse models of tauopathy. Tau pathology prevented age-related decline in glucose tolerance and maintained diurnal hippocampal interstitial fluid (ISF) glucose and lactate rhythms, which were lost in aging wildtype mice. Stable isotope-resolved metabolomics revealed that tau pathology preferentially shunts glucose toward glutamate synthesis at the expense of GABA, suggesting an excitatory/inhibitory (E/I) imbalance not explained by synaptic mitochondrial deficits but by glycolytic flux. Hallmarks of hyperexcitability and impaired inhibitory tone were confirmed by continuous EEG/EMG recordings where decreased beta power, reduced cortical coherence, a flatter aperiodic slope, and abnormal gamma oscillations were associated with NREM and REM sleep loss. Widefield optical imaging confirmed exaggerated glutamatergic calcium activity during whisker stimulation. Together, these findings show that tau pathology drives glucose-dependent hyperexcitability while impairing network synchrony and sleep/wake architecture. This work identifies E/I imbalance as a mechanistic link between tau, metabolism, and sleep loss, highlighting a therapeutic target for tauopathies like AD.