Thanks, Misha! Would love your thoughts. We're interested in how this layers on with APOE!

Thanks to my funders: NIH, NIA, BrightFocus, CART Fund

Big congratulations to our team! @rileyirmen.bsky.social for leading this works. Collabs: @johnsonlab.bsky.social Adam Bauer, Dan Lee, Pat Sullivan, Velu, and all coauthors!

Together, these findings reveal that tau disrupts sleep not by starving the brain of energy, but by misusing or misdirecting it. By linking tau pathology to glycolytic flux , hyperexcitability and sleep loss, this work suggests new targets to restore sleep in Alzheimer’s disease & tauopathies.

We used quantitative EEG analysis to assess changes in sleep macro and micro-architecture. We found tau pathology disrupts NREM and REM sleep, specific to the light period, but compromising beta activity which normally reflects cortical synchrony and GABA activity.

EEG recordings confirmed this state of hyperexcitability and lack of coordination among brain networks, while wide field optical imaging showed exaggerated responses of excitatory neurons to sensory stimulation, despite less glutamatergic neurons, confirming hyperexcitability in the system.

By tracing how glucose is used in the brain, we discovered that tau redirects glucose toward making glutamate and not ATP. This increased excitatory activity, reduced inhibition. This creates E/I imbalance that favors overexcitation, even though brain's mitochondria remains intact.

In this study, we show that tau pathology rewires how the brain uses energy, causes hyperexcitability, network desynchrony, and sleep loss. In mice, we found that tau surprisingly preserves normal body-wide metabolism and daily fluctuations in metabolic rhythms typically lost with aging.

Alzheimer’s disease is best known for a buildup of amyloid plaques and tau tangles in the brain, but long before memory problems appear, the sleep patterns begin to change. How these early changes emerge- especially how tau affects brain metabolism and sleep- has been unclear.

I appreciated this. Dogma always suggests E3 is neutral, E4 is a risk allele, and E2 is protective. I like that this suggests that E3 carries its own risk. Unless I’m misinterpreting….

I feel this 😂